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Sample records for postsynaptic cerebellar ltp

  1. Multiple forms of LTP in hippocampal CA3 neurons use a common postsynaptic mechanism.

    PubMed

    Yeckel, M F; Kapur, A; Johnston, D

    1999-07-01

    We investigated long-term potentiation (LTP) at mossy fiber synapses on CA3 pyramidal neurons in the hippocampus. Using Ca2+ imaging techniques, we show here that when postsynaptic Ca2+ was sufficiently buffered so that [Ca2+]i did not rise during synaptic stimulation, the induction of mossy fiber LTP was prevented. In addition, induction of mossy fiber LTP was suppressed by postsynaptic injection of a peptide inhibitor of cAMP-dependent protein kinase. Finally, when ionotropic glutamate receptors were blocked, LTP depended on the postsynaptic release of Ca2+ from internal stores triggered by activation of metabotropic glutamate receptors. These results support the conclusion that mossy fiber LTP and LTP at other hippocampal synapses share a common induction mechanism involving an initial rise in postsynaptic [Ca2+].

  2. Theta Burst Firing Recruits BDNF Release and Signaling in Postsynaptic CA1 Neurons in Spike-Timing-Dependent LTP.

    PubMed

    Edelmann, Elke; Cepeda-Prado, Efrain; Franck, Martin; Lichtenecker, Petra; Brigadski, Tanja; Leßmann, Volkmar

    2015-05-20

    Timing-dependent LTP (t-LTP) is a physiologically relevant type of synaptic plasticity that results from repeated sequential firing of action potentials (APs) in pre- and postsynaptic neurons. t-LTP can be observed in vivo and is proposed to be a cellular correlate of memory formation. While brain-derived neurotrophic factor (BDNF) is essential to high-frequency stimulation-induced LTP in many brain areas, the role of BDNF in t-LTP is largely unknown. Here, we demonstrate a striking change in the expression mechanism of t-LTP in CA1 of the hippocampus following two distinct modes of synaptic activation. Single postsynaptic APs paired with presynaptic stimulation activated a BDNF-independent canonical t-LTP. In contrast, a theta burst of postsynaptic APs preceded by presynaptic stimulation elicited BDNF-dependent postsynaptic t-LTP that relied on postsynaptic BDNF secretion. This suggests that BDNF release during burst-like patterns of activity typically observed in vivo may play a crucial role during memory formation.

  3. Critical involvement of postsynaptic protein kinase activation in LTP at hippocampal mossy fiber synapses on CA3 interneurons

    PubMed Central

    Galván, Emilio J.; Cosgrove, Kathleen E.; Mauna, Jocelyn C.; Card, J. Patrick; Thiels, Edda; Meriney, Stephen D.; Barrionuevo, Germán

    2010-01-01

    Hippocampal mossy fiber (MF) synapses on area CA3 lacunosum-moleculare (L-M) interneurons are capable of undergoing a Hebbian form of NMDAR-independent LTP induced by the same type of high-frequency stimulation (HFS) that induces LTP at MF synapses on pyramidal cells. LTP of MF input to L-M interneurons occurs only at synapses containing mostly calcium impermeable (CI)-AMPARs. Here, we demonstrate that HFS-induced LTP at these MF-interneuron synapses requires postsynaptic activation of protein kinase A (PKA) and protein kinase C (PKC). Brief extracellular stimulation of PKA with forskolin (FSK) alone or in combination with 1-Methyl-3-isobutylxanthine (IBMX) induced a long-lasting synaptic enhancement at MF synapses predominantly containing CI-AMPARs. However, the FSK/IBMX-induced potentiation in cells loaded with the specific PKA inhibitor peptide PKI6–22 failed to be maintained. Consistent with these data, delivery of HFS to MFs synapsing onto L-M interneurons loaded with PKI6–22 induced posttetanic potentation (PTP) but not LTP. Hippocampal sections stained for the catalytic subunit of PKA revealed abundant immunoreactivity in interneurons located in strata radiatum and L-M of area CA3. We also found that extracellular activation of PKC with phorbol 12,13-diacetate induced a pharmacological potentiation of the isolated CI-AMPAR component of the MF EPSP. However, HFS delivered to MF synapses on cells loaded with the PKC inhibitor chelerythrine exhibited PTP followed by a significant depression. Together, our data indicate that MF LTP in L-M interneurons at synapses containing primarily CI-AMPARs requires some of the same signaling cascades as does LTP of glutamatergic input to CA3 or CA1 pyramidal cells. PMID:20181582

  4. Electron Tomographic Structure and Protein Composition of Isolated Rat Cerebellar, Hippocampal and Cortical Postsynaptic Densities

    PubMed Central

    Farley, MM; Swulius, MT; Waxham, MN

    2015-01-01

    Electron tomography and immunogold labeling were used to analyze similarities and differences in the morphology and protein composition of postsynaptic densities (PSDs) isolated from adult rat cerebella, hippocampi, and cortices. There were similarities in physical dimensions and gross morphology between cortical, hippocampal and most cerebellar PSDs, although the morphology among cerebellar PSDs could be categorized into three distinct groups. The majority of cerebellar PSDs were composed of dense regions of protein, similar to cortical and hippocampal PSDs, while others were either composed of granular or latticelike protein regions. Significant differences were found in protein composition and organization across PSDs from the different brain regions. The signaling protein, βCaMKII, was found to be a major component of each PSD type and was more abundant than αCaMKII in both hippocampal and cerebellar PSDs. The scaffold molecule PSD-95, a major component of cortical PSDs, was found absent in a fraction of cerebellar PSDs and when present was clustered in its distribution. In contrast, immunogold labeling for the proteasome was significantly more abundant in cerebellar and hippocampal PSDs than cortical PSDs. Together, these results indicate that PSDs exhibit remarkable diversity in their composition and morphology, presumably as a reflection of the unique functional demands placed on different synapses. PMID:26215919

  5. 2', 3'-cyclic nucleotide 3'-phosphodiesterase is expressed in dissociated rat cerebellar cells and included in the postsynaptic density fraction.

    PubMed

    Cho, Sun-Jung; Jung, Jae Seob; Jin, IngNyol; Moon, Il Soo

    2003-08-31

    We have shown by protein sequencing that the phosphotyrosine-containing 48 kDa protein band of the rat cerebellar postsynaptic density fraction (CBL-PSD) is 2', 3'-cyclic nucleotide 3'-phosphodiesterase 2 (CNP2). Immunoblot analysis indicated that both CNP1 and CNP2 isoforms are present in the CBL-PSD fraction, whereas there is little CNP2 in the forebrain (FB)-PSD fraction. Both isoforms in the CBL-PSD fraction were tyrosine-phosphorylated to a basal extent. They were efficiently dissociated from the complexes in the PSD fraction by salt, but not by non-ionic detergents such as n-octyl glucoside (OG) and Triton X-100. Immunocytochemistry of dissociated cerebellar cultures revealed patchy CNP staining in oligodendrocytes (OLs), Purkinje cells (PCs), and unidentified PSD95-positive cells, but no staining in granule cells (GCs). Our results indicate that both CNP1 and CNP2 are expressed in cerian populations of cerebellar cells in addition to OL, and that they are associated with complexes that are co-isolated with the PSD.

  6. Theta-Burst LTP

    PubMed Central

    Larson, John; Munkácsy, Erin

    2014-01-01

    This review covers the spatial and temporal rules governing induction of hippocampal long-term potentiation (LTP) by theta-burst stimulation. Induction of LTP in field CA1 by high frequency stimulation bursts that resemble the burst discharges (complex-spikes) of hippocampal pyramidal neurons involves a multiple-step mechanism. A single burst is insufficient for LTP induction because it evokes both excitatory and inhibitory currents that partially cancel and limit postsynaptic depolarization. Bursts repeated at the frequency (~5 Hz) of the endogenous theta rhythm induce maximal LTP, primarily because this frequency disables feed-forward inhibition and allows sufficient postsynaptic depolarization to activate voltage-sensitive NMDA receptors. The disinhibitory process, referred to as “priming”, involves presynaptic GABA autoreceptors that inhibit GABA release. Activation of NMDA receptors allows a calcium flux into dendritic spines that serves as the proximal trigger for LTP. We include new data showing that theta-burst stimulation is more efficient than other forms of stimulation for LTP induction. In addityion, we demonstrate that associative interactions between synapses activated during theta-bursts are limited to major dendritic domains since such interactions occur within apical or basal dendritic trees but not between them. We review evidence that recordings of electrophysiological responses during theta burst stimulation can help to determine if experimental manipulations that affect LTP do so by affecting events antecedent to the induction process, such as NMDA receptor activation, or downstream signaling cascades that result from postsynaptic calcium fluxes. Finally, we argue that theta-burst LTP represents a minimal model for stable, non-decremental LTP that is more sensitive to a variety of experimental manipulations than is LTP induced by other stimulation paradigms. PMID:25452022

  7. Cerebellar Norepinephrine Modulates Learning of Delay Classical Eyeblink Conditioning: Evidence for Post-Synaptic Signaling via PKA

    ERIC Educational Resources Information Center

    Fister, Mathew; Bickford, Paula C.; Cartford, M. Claire; Samec, Amy

    2004-01-01

    The neurotransmitter norepinephrine (NE) has been shown to modulate cerebellar-dependent learning and memory. Lesions of the nucleus locus coeruleus or systemic blockade of noradrenergic receptors has been shown to delay the acquisition of several cerebellar-dependent learning tasks. To date, no studies have shown a direct involvement of…

  8. Recycling Endosomes Supply AMPA Receptors for LTP

    NASA Astrophysics Data System (ADS)

    Park, Mikyoung; Penick, Esther C.; Edwards, Jeffrey G.; Kauer, Julie A.; Ehlers, Michael D.

    2004-09-01

    Long-term potentiation (LTP) of synaptic strength, the most established cellular model of information storage in the brain, is expressed by an increase in the number of postsynaptic AMPA receptors. However, the source of AMPA receptors mobilized during LTP is unknown. We report that AMPA receptors are transported from recycling endosomes to the plasma membrane for LTP. Stimuli that triggered LTP promoted not only AMPA receptor insertion but also generalized recycling of cargo and membrane from endocytic compartments. Thus, recycling endosomes supply AMPA receptors for LTP and provide a mechanistic link between synaptic potentiation and membrane remodeling during synapse modification.

  9. A postsynaptic transient K+ current modulated by arachidonic acid regulates synaptic integration and threshold for LTP induction in hippocampal pyramidal cells

    PubMed Central

    Ramakers, Geert M. J.; Storm, Johan F.

    2002-01-01

    Voltage-gated ion channels in the dendrites and somata of central neurons can modulate the impact of synaptic inputs. One of the ionic currents contributing to such modulation is the fast inactivating A-type potassium current (IA). We have investigated the role of IA in synaptic integration in rat CA1 pyramidal cells by using arachidonic acid (AA) and heteropodatoxin-3 (HpTX3), a selective blocker of the Kv4 channels underlying much of the somatodendritic IA. AA and HpTX3 each reduced IA by 60–70% (measured at the soma) and strongly enhanced the amplitude and summation of excitatory postsynaptic responses, thus facilitating action potential discharges. HpTX3 also reduced the threshold for induction of long-term potentiation. We conclude that the postsynaptic IA is activated during synaptic depolarizations and effectively regulates the somatodendritic integration of high-frequency trains of synaptic input. AA, which can be released by such input, enhances synaptic efficacy by suppressing IA, which could play an important role in frequency-dependent synaptic plasticity in the hippocampus. PMID:12114547

  10. Long-Term Potentiation at the Mossy Fiber-Granule Cell Relay Invokes Postsynaptic Second-Messenger Regulation of Kv4 Channels.

    PubMed

    Rizwan, Arsalan P; Zhan, Xiaoqin; Zamponi, Gerald W; Turner, Ray W

    2016-11-02

    Mossy fiber afferents to cerebellar granule cells form the primary synaptic relay into cerebellum, providing an ideal site to process signal inputs differentially. Mossy fiber input is known to exhibit a long-term potentiation (LTP) of synaptic efficacy through a combination of presynaptic and postsynaptic mechanisms. However, the specific postsynaptic mechanisms contributing to LTP of mossy fiber input is unknown. The current study tested the hypothesis that LTP induces a change in intrinsic membrane excitability of rat cerebellar granule cells through modification of Kv4 A-type potassium channels. We found that theta-burst stimulation of mossy fiber input in lobule 9 granule cells lowered the current threshold to spike and increases the gain of spike firing by 2- to 3-fold. The change in postsynaptic excitability was traced to hyperpolarizing shifts in both the half-inactivation and half-activation potentials of Kv4 that occurred upon coactivating NMDAR and group I metabotropic glutamatergic receptors. The effects of theta-burst stimulation on Kv4 channel control of the gain of spike firing depended on a signaling cascade leading to extracellular signal-related kinase activation. Under physiological conditions, LTP of synaptically evoked spike output was expressed preferentially for short bursts characteristic of sensory input, helping to shape signal processing at the mossy fiber-granule cell relay.

  11. Enhanced AMPA receptor function promotes cerebellar long-term depression rather than potentiation.

    PubMed

    van Beugen, Boeke J; Qiao, Xin; Simmons, Dana H; De Zeeuw, Chris I; Hansel, Christian

    2014-12-01

    Ampakines are allosteric modulators of AMPA receptors that facilitate hippocampal long-term potentiation (LTP) and learning, and have been considered for the treatment of cognition and memory deficits. Here, we show that the ampakine CX546 raises the amplitude and slows the decay time of excitatory postsynaptic currents (EPSCs) at cerebellar parallel fiber (PF) to Purkinje cell synapses, thus resembling CX546 effects described at hippocampal synapses. Using the fluorescent calcium indicator dye Oregon Green BAPTA-2 and an ultra-high-speed CCD camera, we also monitored calcium transients in Purkinje cell dendrites. In the presence of CX546 in the bath, PF-evoked calcium transients were enhanced and prolonged, suggesting that CX546 not only enhances synaptic transmission, but also boosts dendritic calcium signaling at cerebellar synapses. In contrast to previous observations in the hippocampus, however, CX546 applied during cerebellar recordings facilitates long-term depression (LTD) rather than LTP at PF synapses. These findings show that ampakines selectively modify the LTP-LTD balance depending on the brain area and type of synapse, and may provide tools for the targeted regulation of synaptic memories.

  12. Hebbian spike-timing dependent plasticity at the cerebellar input stage.

    PubMed

    Sgritta, M; Locatelli, F; Soda, T; Prestori, F; D'Angelo, E

    2017-02-10

    Spike-timing dependent plasticity (STDP) is a form of long-term synaptic plasticity exploiting the time relationship between postsynaptic action potentials (AP) and EPSPs. Surprisingly enough, very little was known about STDP in the cerebellum, although it is thought to play a critical role for learning appropriate timing of actions. We speculated that low-frequency oscillations observed in the granular layer may provide a reference for repetitive EPSP/AP phase coupling. Here we show that EPSP-spike pairing at 6Hz can optimally induce STDP at the mossy fiber - granule cell synapse in rats. Spike timing-dependent long-term potentiation and depression (st-LTP and st-LTD) were confined to a ±25 ms time-window. Since EPSPs led APs in st-LTP while APs led EPSPs in st-LTD, STDP was Hebbian in nature. STDP occurred at 6-10 Hz but vanished above 50 Hz or below 1 Hz (where only LTP or LTD occurred). STDP disappeared with randomized EPSP/AP pairing or high intracellular Ca(2+) buffering and its sign was inverted by GABA-A receptor activation. Both st-LTP and st-LTD required NMDA receptors, but st-LTP also required reinforcing signals mediated by mGluRs and intracellular calcium stores. Importantly, st-LTP and st-LTD were significantly larger than LTP and LTD obtained by modulating the frequency and duration of mossy fiber bursts, probably because STDP expression involved postsynaptic in addition to presynaptic mechanisms. These results thus show that a Hebbian form of STDP occurs at the cerebellum input stage providing the substrate for phase-dependent binding of mossy fiber spikes to repetitive theta-frequency cycles of granule cell activity.SIGNIFICANCE STATEMENTLong-term synaptic plasticity is a fundamental property of the brain causing persistent modifications of neuronal communication thought to provide the cellular basis of learning and memory. The cerebellum is critical for learning the appropriate timing of sensorimotor behaviors but whether and how appropriate

  13. L-Type Calcium Channels Are Required for One Form of Hippocampal Mossy Fiber LTP

    PubMed Central

    Kapur, Ajay; Yeckel, Mark F.; Gray, Richard; Johnston, Daniel

    2010-01-01

    The requirement of postsynaptic calcium influx via L-type channels for the induction of long-term potentiation (LTP) of mossy fiber input to CA3 pyramidal neurons was tested for two different patterns of stimulation. Two types of LTP-inducing stimuli were used based on the suggestion that one of them, brief high-frequency stimulation (B-HFS), induces LTP postsynaptically, whereas the other pattern, long high-frequency stimulation (L-HFS), induces mossy fiber LTP presynaptically. To test whether or not calcium influx into CA3 pyramidal neurons is necessary for LTP induced by either pattern of stimulation, nimodipine, a L-type calcium channel antagonist, was added during stimulation. In these experiments nimodipine blocked the induction of mossy fiber LTP when B-HFS was given [34 ± 5% (mean ± SE) increase in control versus 7 ± 4% in nimodipine, P < 0.003]; in contrast, nimodipine did not block the induction of LTP with L-HFS (107 ± 10% in control vs. 80 ± 9% in nimodipine, P > 0.05). Administration of nimodipine after the induction of LTP had no effect on the expression of LTP. In addition, B- and L-HFS delivered directly to commissural/ associational fibers in stratum radiatum failed to induce a N-methyl-d-aspartate-independent form of LTP, obviating the possibility that the presumed mossy fiber LTP resulted from potentiation of other synapses. Nimodipine had no effect on calcium transients recorded from mossy fiber presynaptic terminals evoked with the B-HFS paradigm but reduced postsynaptic calcium transients. Our results support the hypothesis that induction of mossy fiber LTP by B-HFS is mediated postsynaptically and requires entry of calcium through L-type channels into CA3 neurons. PMID:9535977

  14. Enhanced AMPA receptor function promotes cerebellar long-term depression rather than potentiation

    PubMed Central

    van Beugen, Boeke J.; Qiao, Xin; Simmons, Dana H.; De Zeeuw, Chris I.

    2014-01-01

    Ampakines are allosteric modulators of AMPA receptors that facilitate hippocampal long-term potentiation (LTP) and learning, and have been considered for the treatment of cognition and memory deficits. Here, we show that the ampakine CX546 raises the amplitude and slows the decay time of excitatory postsynaptic currents (EPSCs) at cerebellar parallel fiber (PF) to Purkinje cell synapses, thus resembling CX546 effects described at hippocampal synapses. Using the fluorescent calcium indicator dye Oregon Green BAPTA-2 and an ultra-high-speed CCD camera, we also monitored calcium transients in Purkinje cell dendrites. In the presence of CX546 in the bath, PF-evoked calcium transients were enhanced and prolonged, suggesting that CX546 not only enhances synaptic transmission, but also boosts dendritic calcium signaling at cerebellar synapses. In contrast to previous observations in the hippocampus, however, CX546 applied during cerebellar recordings facilitates long-term depression (LTD) rather than LTP at PF synapses. These findings show that ampakines selectively modify the LTP–LTD balance depending on the brain area and type of synapse, and may provide tools for the targeted regulation of synaptic memories. PMID:25403454

  15. Presynaptic LTP and LTD of excitatory and inhibitory synapses.

    PubMed

    Castillo, Pablo E

    2012-02-01

    Ubiquitous forms of long-term potentiation (LTP) and depression (LTD) are caused by enduring increases or decreases in neurotransmitter release. Such forms or presynaptic plasticity are equally observed at excitatory and inhibitory synapses and the list of locations expressing presynaptic LTP and LTD continues to grow. In addition to the mechanistically distinct forms of postsynaptic plasticity, presynaptic plasticity offers a powerful means to modify neural circuits. A wide range of induction mechanisms has been identified, some of which occur entirely in the presynaptic terminal, whereas others require retrograde signaling from the postsynaptic to presynaptic terminals. In spite of this diversity of induction mechanisms, some common induction rules can be identified across synapses. Although the precise molecular mechanism underlying long-term changes in transmitter release in most cases remains unclear, increasing evidence indicates that presynaptic LTP and LTD can occur in vivo and likely mediate some forms of learning.

  16. Expression mechanisms underlying long-term potentiation: a postsynaptic view, 10 years on.

    PubMed

    Granger, Adam J; Nicoll, Roger A

    2014-01-05

    This review focuses on the research that has occurred over the past decade which has solidified a postsynaptic expression mechanism for long-term potentiation (LTP). However, experiments that have suggested a presynaptic component are also summarized. It is argued that the pairing of glutamate uncaging onto single spines with postsynaptic depolarization provides the final and most elegant demonstration of a postsynaptic expression mechanism for NMDA receptor-dependent LTP. The fact that the magnitude of this LTP is similar to that evoked by pairing synaptic stimulation and depolarization leaves little room for a substantial presynaptic component. Finally, recent data also require a revision in our thinking about the way AMPA receptors (AMPARs) are recruited to the postsynaptic density during LTP. This recruitment is independent of subunit type, but does require an adequate reserve pool of extrasynaptic receptors.

  17. Non-Hebbian spike-timing-dependent plasticity in cerebellar circuits

    PubMed Central

    Piochon, Claire; Kruskal, Peter; MacLean, Jason; Hansel, Christian

    2013-01-01

    Spike-timing-dependent plasticity (STDP) provides a cellular implementation of the Hebb postulate, which states that synapses, whose activity repeatedly drives action potential firing in target cells, are potentiated. At glutamatergic synapses onto hippocampal and neocortical pyramidal cells, synaptic activation followed by spike firing in the target cell causes long-term potentiation (LTP)—as predicted by Hebb—whereas excitatory postsynaptic potentials (EPSPs) evoked after a spike elicit long-term depression (LTD)—a phenomenon that was not specifically addressed by Hebb. In both instances the action potential in the postsynaptic target neuron is an instructive signal that is capable of supporting synaptic plasticity. STDP generally relies on the propagation of Na+ action potentials that are initiated in the axon hillhock back into the dendrite, where they cause depolarization and boost local calcium influx. However, recent studies in CA1 hippocampal pyramidal neurons have suggested that local calcium spikes might provide a more efficient trigger for LTP induction than backpropagating action potentials. Dendritic calcium spikes also play a role in an entirely different type of STDP that can be observed in cerebellar Purkinje cells. These neurons lack backpropagating Na+ spikes. Instead, plasticity at parallel fiber (PF) to Purkinje cell synapses depends on the relative timing of PF-EPSPs and activation of the glutamatergic climbing fiber (CF) input that causes dendritic calcium spikes. Thus, the instructive signal in this system is externalized. Importantly when EPSPs are elicited before CF activity, PF-LTD is induced rather than LTP. Thus, STDP in the cerebellum follows a timing rule that is opposite to its hippocampal/neocortical counterparts. Regardless, a common motif in plasticity is that LTD/LTP induction depends on the relative timing of synaptic activity and regenerative dendritic spikes which are driven by the instructive signal. PMID:23335888

  18. Non-Hebbian spike-timing-dependent plasticity in cerebellar circuits.

    PubMed

    Piochon, Claire; Kruskal, Peter; Maclean, Jason; Hansel, Christian

    2012-01-01

    Spike-timing-dependent plasticity (STDP) provides a cellular implementation of the Hebb postulate, which states that synapses, whose activity repeatedly drives action potential firing in target cells, are potentiated. At glutamatergic synapses onto hippocampal and neocortical pyramidal cells, synaptic activation followed by spike firing in the target cell causes long-term potentiation (LTP)-as predicted by Hebb-whereas excitatory postsynaptic potentials (EPSPs) evoked after a spike elicit long-term depression (LTD)-a phenomenon that was not specifically addressed by Hebb. In both instances the action potential in the postsynaptic target neuron is an instructive signal that is capable of supporting synaptic plasticity. STDP generally relies on the propagation of Na(+) action potentials that are initiated in the axon hillhock back into the dendrite, where they cause depolarization and boost local calcium influx. However, recent studies in CA1 hippocampal pyramidal neurons have suggested that local calcium spikes might provide a more efficient trigger for LTP induction than backpropagating action potentials. Dendritic calcium spikes also play a role in an entirely different type of STDP that can be observed in cerebellar Purkinje cells. These neurons lack backpropagating Na(+) spikes. Instead, plasticity at parallel fiber (PF) to Purkinje cell synapses depends on the relative timing of PF-EPSPs and activation of the glutamatergic climbing fiber (CF) input that causes dendritic calcium spikes. Thus, the instructive signal in this system is externalized. Importantly when EPSPs are elicited before CF activity, PF-LTD is induced rather than LTP. Thus, STDP in the cerebellum follows a timing rule that is opposite to its hippocampal/neocortical counterparts. Regardless, a common motif in plasticity is that LTD/LTP induction depends on the relative timing of synaptic activity and regenerative dendritic spikes which are driven by the instructive signal.

  19. Alcohol Impairs Long-Term Depression at the Cerebellar Parallel Fiber–Purkinje Cell Synapse

    PubMed Central

    Belmeguenai, Amor; Botta, Paolo; Weber, John T.; Carta, Mario; De Ruiter, Martijn; De Zeeuw, Chris I.; Valenzuela, C. Fernando; Hansel, Christian

    2008-01-01

    Acute alcohol consumption causes deficits in motor coordination and gait, suggesting an involvement of cerebellar circuits, which play a role in the fine adjustment of movements and in motor learning. It has previously been shown that ethanol modulates inhibitory transmission in the cerebellum and affects synaptic transmission and plasticity at excitatory climbing fiber (CF) to Purkinje cell synapses. However, it has not been examined thus far how acute ethanol application affects long-term depression (LTD) and long-term potentiation (LTP) at excitatory parallel fiber (PF) to Purkinje cell synapses, which are assumed to mediate forms of cerebellar motor learning. To examine ethanol effects on PF synaptic transmission and plasticity, we performed whole cell patch-clamp recordings from Purkinje cells in rat cerebellar slices. We found that ethanol (50 mM) selectively blocked PF–LTD induction, whereas it did not change the amplitude of excitatory postsynaptic currents at PF synapses. In contrast, ethanol application reduced voltage-gated calcium currents and type 1 metabotropic glutamate receptor (mGluR1)–dependent responses in Purkinje cells, both of which are involved in PF–LTD induction. The selectivity of these effects is emphasized by the observation that ethanol did not impair PF–LTP and that PF–LTP could readily be induced in the presence of the group I mGluR antagonist AIDA or the mGluR1a antagonist LY367385. Taken together, these findings identify calcium currents and mGluR1-dependent signaling pathways as potential ethanol targets and suggest that an ethanol-induced blockade of PF–LTD could contribute to the motor coordination deficits resulting from alcohol consumption. PMID:18922952

  20. Copper Inhibits NMDA Receptor-Independent LTP and Modulates the Paired-Pulse Ratio after LTP in Mouse Hippocampal Slices

    PubMed Central

    Salazar-Weber, Nina L.; Smith, Jeffrey P.

    2011-01-01

    Copper misregulation has been implicated in the pathological processes underlying deterioration of learning and memory in Alzheimer's disease and other neurodegenerative disorders. Supporting this, inhibition of long-term potentiation (LTP) by copper (II) has been well established, but the exact mechanism is poorly characterized. It is thought that an interaction between copper and postsynaptic NMDA receptors is a major part of the mechanism; however, in this study, we found that copper (II) inhibited NMDA receptor-independent LTP in the CA3 region of hippocampal slices. In addition, in the CA3 and CA1 regions, copper modulated the paired-pulse ratio (PPR) in an LTP-dependent manner. Combined, this suggests the involvement of a presynaptic mechanism in the modulation of synaptic plasticity by copper. Inhibition of the copper-dependent changes in the PPR with cyclothiazide suggested that this may involve an interaction with the presynaptic AMPA receptors that regulate neurotransmitter release. PMID:22028985

  1. The effect of interburst intervals on measures of hippocampal LTP in the freely moving adult male rat.

    PubMed

    Fortin, D A; Bronzino, J D

    2001-08-01

    An important factor in the induction and maintenance of long-term potentiation (LTP) is the tetanization paradigm. This paper presents the changes associated with the induction and maintenance of hippocampal LTP in the freely moving adult male rat, subjected to three different tetanization paradigms. These results indicate that specific LTP measures including (1) synaptic activation, as measured by the slope of the dentate granule cell population excitatory postsynaptic potential, and (2) cellular response, as measured by the dentate population spike amplitude, evoked by single-pulse stimulation of the medial perforant pathway are dependent on the interburst interval of the bursting paradigm commonly used in LTP studies.

  2. The 5-HT7 receptor triggers cerebellar long-term synaptic depression via PKC-MAPK.

    PubMed

    Lippiello, Pellegrino; Hoxha, Eriola; Speranza, Luisa; Volpicelli, Floriana; Ferraro, Angela; Leopoldo, Marcello; Lacivita, Enza; Perrone-Capano, Carla; Tempia, Filippo; Miniaci, Maria Concetta

    2016-02-01

    The 5-HT7 receptor (5-HT7R) mediates important physiological effects of serotonin, such as memory and emotion, and is emerging as a therapeutic target for the treatment of cognitive disorders and depression. Although previous studies have revealed an expression of 5-HT7R in cerebellum, particularly at Purkinje cells, its functional role and signaling mechanisms have never been described. Using patch-clamp recordings in cerebellar slices of adult mice, we investigated the effects of a selective 5-HT7R agonist, LP-211, on the main plastic site of the cerebellar cortex, the parallel fiber-Purkinje cell synapse. Here we show that 5-HT7R activation induces long-term depression of parallel fiber-Purkinje cell synapse via a postsynaptic mechanism that involves the PKC-MAPK signaling pathway. Moreover, a 5-HT7R antagonist abolished the expression of PF-LTD, produced by pairing parallel fiber stimulation with Purkinje cell depolarization; whereas, application of a 5-HT7R agonist impaired LTP induced by 1 Hz parallel fiber stimulation. Our results indicate for the first time that 5-HT7R exerts a fine regulation of cerebellar bidirectional synaptic plasticity that might be involved in cognitive processes and neuropsychiatric disorders involving the cerebellum.

  3. Coexistence of Two Forms of LTP in ACC Provides a Synaptic Mechanism for the Interactions between Anxiety and Chronic Pain

    PubMed Central

    Koga, Kohei; Descalzi, Giannina; Chen, Tao; Ko, Hyoung-Gon; Lu, Jinshan; Li, Shermaine; Son, Junehee; Kim, TaeHyun; Kwak, Chuljung; Huganir, Richard L.; Zhao, Ming-gao; Kaang, Bong-Kiun; Collingridge, Graham L.; Zhuo, Min

    2015-01-01

    SUMMARY Chronic pain can lead to anxiety and anxiety can enhance the sensation of pain. Unfortunately, little is known about the synaptic mechanisms that mediate these re-enforcing interactions. Here we characterized two forms of long-term potentiation (LTP) in the anterior cingulate cortex (ACC); a presynaptic form (pre-LTP) that requires kainate receptors and a postsynaptic form (post-LTP) that requires N-methyl-D-aspartate receptors. Pre-LTP also involves adenylyl cyclase and protein kinase A and is expressed via a mechanism involving hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Interestingly, chronic pain and anxiety both result in selective occlusion of pre-LTP. Significantly, microinjection of the HCN blocker ZD7288 into the ACC in vivo produces both anxiolytic and analgesic effects. Our results provide a mechanism by which two forms of LTP in the ACC may converge to mediate the interaction between anxiety and chronic pain. PMID:25556835

  4. Dendritic NMDA spikes are necessary for timing-dependent associative LTP in CA3 pyramidal cells

    PubMed Central

    Brandalise, Federico; Carta, Stefano; Helmchen, Fritjof; Lisman, John; Gerber, Urs

    2016-01-01

    The computational repertoire of neurons is enhanced by regenerative electrical signals initiated in dendrites. These events, referred to as dendritic spikes, can act as cell-intrinsic amplifiers of synaptic input. Among these signals, dendritic NMDA spikes are of interest in light of their correlation with synaptic LTP induction. Because it is not possible to block NMDA spikes pharmacologically while maintaining NMDA receptors available to initiate synaptic plasticity, it remains unclear whether NMDA spikes alone can trigger LTP. Here we use dendritic recordings and calcium imaging to analyse the role of NMDA spikes in associative LTP in CA3 pyramidal cells. We show that NMDA spikes produce regenerative branch-specific calcium transients. Decreasing the probability of NMDA spikes reduces LTP, whereas increasing their probability enhances LTP. NMDA spikes and LTP occur without back-propagating action potentials. However, action potentials can facilitate LTP induction by promoting NMDA spikes. Thus, NMDA spikes are necessary and sufficient to produce the critical postsynaptic depolarization required for associative LTP in CA3 pyramidal cells. PMID:27848967

  5. LISA and the LTP

    NASA Astrophysics Data System (ADS)

    Jennrich, O.

    The primary objective of the LISA (Laser Interferometer Space Antenna mission is the detection and observation of gravitational waves from massive black holes (MBH) and galactic binaries in the frequency range 10 -4 Hz … 10 -1 Hz. This low-frequency range is inaccessible to ground-based interferometers due to the background of local gravitational noise and because ground-based interferometers are limited in length to a few kilometres. LISA is envisaged as an ESA/NASA collaborative project, selected an ESA cornerstone mission and included in NASA's strategic plan and with a nominal launch date in 2011. SMART-2 is primarily intended to demonstrate the key technologies for the ESA/NASA collaborative LISA cornerstone mission. The synergy with the technology being used for Darwin motivates the utilization of SMART-2 for both missions. To this end, SMART-2 will accommodate a LISA technology package (LTP), provided by European institutes and industry and possibly also a Disturbance Reduction System (DRS) that is very similar to the LTP and has the same goals but is provided by US institutes and industry.

  6. Cerebellar Synaptic Plasticity and the Credit Assignment Problem.

    PubMed

    Jörntell, Henrik

    2016-04-01

    The mechanism by which a learnt synaptic weight change can contribute to learning or adaptation of brain function is a type of credit assignment problem, which is a key issue for many parts of the brain. In the cerebellum, detailed knowledge not only of the local circuitry connectivity but also of the topography of different sources of afferent/external information makes this problem particularly tractable. In addition, multiple forms of synaptic plasticity and their general rules of induction have been identified. In this review, we will discuss the possible roles of synaptic and cellular plasticity at specific locations in contributing to behavioral changes. Focus will be on the parts of the cerebellum that are devoted to limb control, which constitute a large proportion of the cortex and where the knowledge of the external connectivity is particularly well known. From this perspective, a number of sites of synaptic plasticity appear to primarily have the function of balancing the overall level of activity in the cerebellar circuitry, whereas the locations at which synaptic plasticity leads to functional changes in terms of limb control are more limited. Specifically, the postsynaptic forms of long-term potentiation (LTP) and long-term depression (LTD) at the parallel fiber synapses made on interneurons and Purkinje cells, respectively, are the types of plasticity that mediate the widest associative capacity and the tightest link between the synaptic change and the external functions that are to be controlled.

  7. Long-term potentiation in hippocampal oriens interneurons: postsynaptic induction, presynaptic expression and evaluation of candidate retrograde factors.

    PubMed

    Nicholson, Elizabeth; Kullmann, Dimitri M

    2014-01-05

    Several types of hippocampal interneurons exhibit a form of long-term potentiation (LTP) that depends on Ca(2+)-permeable AMPA receptors and group I metabotropic glutamate receptors. Several sources of evidence point to a presynaptic locus of LTP maintenance. The retrograde factor that triggers the expression of LTP remains unidentified. Here, we show that trains of action potentials in putative oriens-lacunosum-moleculare interneurons of the mouse CA1 region can induce long-lasting potentiation of stimulus-evoked excitatory postsynaptic currents that mimics LTP elicited by high-frequency afferent stimulation. We further report that blockers of nitric oxide production or TRPV1 receptors failed to prevent LTP induction. The present results add to the evidence that retrograde signalling underlies N-methyl-d-aspartate (NMDA) receptor-independent LTP in oriens interneurons, mediated by an unidentified factor.

  8. Induction of Anti-Hebbian LTP in CA1 Stratum Oriens Interneurons: Interactions between Group I Metabotropic Glutamate Receptors and M1 Muscarinic Receptors

    PubMed Central

    Savary, Etienne; Kullmann, Dimitri M.; Miles, Richard

    2015-01-01

    An anti-Hebbian form of LTP is observed at excitatory synapses made with some hippocampal interneurons. LTP induction is facilitated when postsynaptic interneurons are hyperpolarized, presumably because Ca2+ entry through Ca2+-permeable glutamate receptors is enhanced. The contribution of modulatory transmitters to anti-Hebbian LTP induction remains to be established. Activation of group I metabotropic receptors (mGluRs) is required for anti-Hebbian LTP induction in interneurons with cell bodies in the CA1 stratum oriens. This region receives a strong cholinergic innervation from the septum, and muscarinic acetylcholine receptors (mAChRs) share some signaling pathways and cooperate with mGluRs in the control of neuronal excitability. We therefore examined possible interactions between group I mGluRs and mAChRs in anti-Hebbian LTP at synapses which excite oriens interneurons in rat brain slices. We found that blockade of either group I mGluRs or M1 mAChRs prevented the induction of anti-Hebbian LTP by pairing presynaptic activity with postsynaptic hyperpolarization. Blocking either receptor also suppressed long-term effects of activation of the other G-protein coupled receptor on interneuron membrane potential. However, no crossed blockade was detected for mGluR or mAchR effects on interneuron after-burst potentials or on the frequency of miniature EPSPs. Paired recordings between pyramidal neurons and oriens interneurons were obtained to determine whether LTP could be induced without concurrent stimulation of cholinergic axons. Exogenous activation of mAChRs led to LTP, with changes in EPSP amplitude distributions consistent with a presynaptic locus of expression. LTP, however, required noninvasive presynaptic and postsynaptic recordings. SIGNIFICANCE STATEMENT In the hippocampus, a form of NMDA receptor-independent long-term potentiation (LTP) occurs at excitatory synapses made on some inhibitory neurons. This is preferentially induced when postsynaptic

  9. Action Potentials are required for nitric oxide dependent LTP in CA1 neurons of adult GluR1 knockout and Wild-type mice

    PubMed Central

    Phillips, Keith G.; Hardingham, Neil R.; Fox, Kevin

    2009-01-01

    Neocortical LTP consists of both pre- and postsynaptic components that rely on nitric oxide (NO) and GluR1 respectively. In this study, we found that hippocampal LTP, induced by theta-burst stimulation in mature (> 8 week old) GluR1 knockout mice was almost entirely NO-dependent and involved both the α splice variant of NO synthase-1 (αNOS-1) and the NO synthase-3 (NOS-3) isoforms of NO synthase. Theta-burst induced LTP was also partly NO-dependent in wild-type mice, and made up approximately 50% of the potentiation 2 hours post-tetanus. Theta-burst stimulation reliably produced postsynaptic spikes including a high probability of complex spikes. Inhibition of postsynaptic somatic spikes with intracellular QX314 or local TTX application prevented LTP in the GluR1 knockout mice and also blocked the NO-component of LTP in wild-types. We conclude that theta-burst stimulation is particularly well suited to producing the somatic postsynaptic spikes required for NO-dependent LTP. PMID:19109486

  10. Synapse-specific compartmentalization of signaling cascades for LTP induction in CA3 interneurons.

    PubMed

    Galván, E J; Pérez-Rosello, T; Gómez-Lira, G; Lara, E; Gutiérrez, R; Barrionuevo, G

    2015-04-02

    Inhibitory interneurons with somata in strata radiatum and lacunosum-molecular (SR/L-M) of hippocampal area CA3 receive excitatory input from pyramidal cells via the recurrent collaterals (RCs), and the dentate gyrus granule cells via the mossy fibers (MFs). Here we demonstrate that Hebbian long-term potentiation (LTP) at RC synapses on SR/L-M interneurons requires the concomitant activation of calcium-impermeable AMPARs (CI-AMPARs) and N-methyl-d-aspartate receptors (NMDARs). RC LTP was prevented by voltage clamping the postsynaptic cell during high-frequency stimulation (HFS; 3 trains of 100 pulses delivered at 100 Hz every 10s), with intracellular injections of the Ca(2+) chelator BAPTA (20mM), and with the NMDAR antagonist D-AP5. In separate experiments, RC and MF inputs converging onto the same interneuron were sequentially activated. We found that RC LTP induction was blocked by inhibitors of the calcium/calmodulin-dependent protein kinase II (CaMKII; KN-62, 10 μM or KN-93, 10 μM) but MF LTP was CaMKII independent. Conversely, the application of the protein kinase A (PKA) activators forskolin/IBMX (50 μM/25 μM) potentiated MF EPSPs but not RC EPSPs. Together these data indicate that the aspiny dendrites of SR/L-M interneurons compartmentalize synapse-specific Ca(2+) signaling required for LTP induction at RC and MF synapses. We also show that the two signal transduction cascades converge to activate a common effector, protein kinase C (PKC). Specifically, LTP at RC and MF synapses on the same SR/LM interneuron was blocked by postsynaptic injections of chelerythrine (10 μM). These data indicate that both forms of LTP share a common mechanism involving PKC-dependent signaling modulation.

  11. Hyperdopaminergic Tone Erodes Prefrontal LTP via a D2 Receptor-operated Protein Phosphatase Gate

    PubMed Central

    Xu, Tai-Xiang; Sotnikova, Tatyana D.; Liang, Chengyu; Zhang, Jingping; Jung, Jae U.; Spealman, Roger D.; Gainetdinov, Raul R.; Yao, Wei-Dong

    2009-01-01

    Dopamine (DA) plays crucial roles in the cognitive functioning of the prefrontal cortex (PFC), which, to a large degree, depends on lasting neural traces formed in prefrontal networks. The establishment of these permanent traces requires changes in cortical synaptic efficacy. DA, via the D1-class receptors, is thought to gate or facilitate synaptic plasticity in the PFC, with little role recognized for the D2-class receptors. Here we show that, when significantly elevated, DA erodes, rather than facilitates, the induction of long-term potentiation (LTP) in the PFC by acting at the far less abundant cortical D2-class receptors through a dominant coupling to the protein phosphatase 1 (PP1) activity in postsynaptic neurons. In mice with persistently elevated extracellular DA, resulting from inactivation of the DA transporter (DAT) gene, LTP in layer V PFC pyramidal neurons can not be established, regardless of induction protocols. Acute increase of dopaminergic transmission by DAT blockers or overstimulation of D2 receptors in normal mice have similar LTP shut-off effects. LTP in mutant mice can be rescued by a single in vivo administration of D2-class antagonists. Suppression of postsynaptic PP1 mimics and occludes the D2-mediated rescue of LTP in mutant mice, and prevents the acute erosion of LTP by D2 agonists in normal mice. Our studies reveal a mechanistically unique heterosynaptic PP1 gate that is constitutively driven by background DA to influence LTP induction. By blocking prefrontal synaptic plasticity, excessive DA may prevent storage of lasting memory traces in PFC networks and impair executive functions. PMID:19906957

  12. Synapse-specific compartmentalization of signaling cascades for LTP induction in CA3 interneurons

    PubMed Central

    Galván, Emilio J; Pérez-Rosello, Tamara; Gómez-Lira, Gisela; Lara, Erika; Gutiérrez, Rafael; Barrionuevo, Germán

    2015-01-01

    Inhibitory interneurons with somata in strata radiatum and lacunosun-moleculare (SR/L-M) of hippocampal area CA3 receive excitatory input from pyramidal cells via the recurrent collaterals (RC), and the dentate gyrus granule cells via the mossy fibers (MFs). Here we demonstrate that Hebbian long-term potentiation (LTP) at RC synapses on SR/L-M interneurons requires the concomitant activation of calcium-impermeable AMPARs (CI- AMPARs) and NMDARs. RC LTP was prevented by voltage clamping the postsynaptic cell during high-frequency stimulation (HFS; 3 trains of 100 pulses delivered at 100 Hz every 10 s), with intracellular injections of the Ca2+ chelator BAPTA (20 mM), and with the N-methyl-D-aspartate receptor (NMDAR) antagonist D-AP5. In separate experiments, RC and MF inputs converging onto the same interneuron were sequentially activated. We found that RC LTP induction was blocked by inhibitors of the calcium/calmodulin-dependent protein kinase II (CaMKII; KN-62, 10 μM or KN-93, 10 μM) but MF LTP was CaMKII independent. Conversely, the application of the protein kinase A (PKA) activators forskolin/IBMX(50 μM/25 μM) potentiated MF EPSPs but not RC EPSPs. Together these data indicate that the aspiny dendrites of SR/L-M interneurons compartmentalize synaptic-specific Ca2+ signaling required for LTP induction at RC and MF synapses. We also show that the two signal transduction cascades converge to activate a common effector, protein kinase C (PKC). Specifically, LTP at RC and MF synapses on the same SR/LM interneuron was blocked by postsynaptic injections of chelerythrine (10 μM). These data indicate that both forms of LTP share a common mechanism involving PKC-dependent signaling modulation. PMID:25637803

  13. [Cerebellar hypoplasias].

    PubMed

    Safronova, Marta Maia; Barbot, Clara; Resende Pereira, Jorge

    2010-01-01

    Cerebellar hypoplasias are cerebellar malformations with small but completely formed cerebellum. They can be divided in focal and in diffuse or generalized. It is sometimes difficult to make distinction between cerebellar atrophy (progressive condition) and hipoplasia (not progressive condition). Focal hypoplasias are restricted to one cerebellar hemisphere or to the vermis. Diffuse hypoplasias refer to both cerebellar hemispheres and vermis. If there is associated IVth ventricle enlargement, hypoplasias occur in the context of Dandy-Walker complex, a continuum of posterior fossa cystic anomalies. A revision of cerebellar hypoplasias and associated pathology is done, illustrated with 22 cases tha include focal and diffuse cerebellar hypoplasias, Dandy-Walker malformations and its variant, persistent Blake's pouch cyst, megacisterna magna, PEHO síndrome (progressive encephalopathy with oedema, hipsarrhythmia and optic atrophy), Joubert syndrome, congenital disorder of glycosylation type Ia, pontocerebellar hipoplasias Barth type I and II, diffuse subcortical heterotopia. The imaging finding of structural cerebellar anomalies frequently leads to diagnostic incertainty as the anomalies are mostly unspecific, implying an extenuating analytical and genetic workup. Their knowledge and classification may be useful to decide the patient adjusted laboratorial workup.

  14. Postsynaptic density-95 mimics and occludes hippocampal long-term potentiation and enhances long-term depression.

    PubMed

    Stein, Valentin; House, David R C; Bredt, David S; Nicoll, Roger A

    2003-07-02

    Previous studies have shown that overexpression of the protein PSD-95 (postsynaptic density-95) selectively enhances AMPA receptor-mediated synaptic responses in hippocampal pyramidal cells. To determine whether this effect is related to synaptic plasticity at these synapses, we examined whether PSD-95 expression mimics long-term potentiation (LTP), and also whether it influences LTP and long-term depression (LTD) in hippocampal slice cultures. Using simultaneous recording from transfected or infected cells and control pyramidal cells, we found that PSD-95, similar to LTP, increases the amplitude and frequency of miniature EPSCs. It also converts silent synapses to functional synapses, as does LTP. In addition, LTP is completely occluded in cells expressing PSD-95, whereas LTD is greatly enhanced. These results suggest that common mechanisms are involved in controlling synaptic AMPA receptors by PSD-95 and synaptic plasticity.

  15. Presynaptic mechanisms involved in the expression of STP and LTP at CA1 synapses in the hippocampus.

    PubMed

    Lauri, Sari E; Palmer, Mary; Segerstrale, Mikael; Vesikansa, Aino; Taira, Tomi; Collingridge, Graham L

    2007-01-01

    The study of long-term potentiation (LTP) has for many years been the centre of a raging debate as to whether the process is expressed by presynaptic or postsynaptic mechanisms. Here we present evidence that two forms of synaptic plasticity at CA3-CA1 synapses in the hippocampus are expressed by presynaptic changes. One form is short-term potentiation (STP) and the other a neonatal form of early-LTP (E-LTP). We review recent experimental data that suggests that this latter form of LTP involves an increase in the probability of neurotransmitter release (Pr). We describe how this is caused by the rapid down-regulation of a high affinity kainate receptor, which otherwise responds to ambient levels of l-glutamate by depressing Pr.

  16. Inhibition promotes long-term potentiation at cerebellar excitatory synapses

    PubMed Central

    Binda, F.; Dorgans, K.; Reibel, S.; Sakimura, K.; Kano, M.; Poulain, B.; Isope, P.

    2016-01-01

    The ability of the cerebellar cortex to learn from experience ensures the accuracy of movements and reflex adaptation, processes which require long-term plasticity at granule cell (GC) to Purkinje neuron (PN) excitatory synapses. PNs also receive GABAergic inhibitory inputs via GCs activation of interneurons; despite the involvement of inhibition in motor learning, its role in long-term plasticity is poorly characterized. Here we reveal a functional coupling between ionotropic GABAA receptors and low threshold CaV3 calcium channels in PNs that sustains calcium influx and promotes long-term potentiation (LTP) at GC to PN synapses. High frequency stimulation induces LTP at GC to PN synapses and CaV3-mediated calcium influx provided that inhibition is intact; LTP is mGluR1, intracellular calcium store and CaV3 dependent. LTP is impaired in CaV3.1 knockout mice but it is nevertheless recovered by strengthening inhibitory transmission onto PNs; promoting a stronger hyperpolarization via GABAA receptor activation leads to an enhanced availability of an alternative Purkinje-expressed CaV3 isoform compensating for the lack of CaV3.1 and restoring LTP. Accordingly, a stronger hyperpolarization also restores CaV3-mediated calcium influx in PNs from CaV3.1 knockout mice. We conclude that by favoring CaV3 channels availability inhibition promotes LTP at cerebellar excitatory synapses. PMID:27641070

  17. Postsynaptic Signaling and Plasticity Mechanisms

    NASA Astrophysics Data System (ADS)

    Sheng, Morgan; Jong Kim, Myung

    2002-10-01

    In excitatory synapses of the brain, specific receptors in the postsynaptic membrane lie ready to respond to the release of the neurotransmitter glutamate from the presynaptic terminal. Upon stimulation, these glutamate receptors activate multiple biochemical pathways that transduce signals into the postsynaptic neuron. Different kinds of synaptic activity elicit different patterns of postsynaptic signals that lead to short- or long-lasting strengthening or weakening of synaptic transmission. The complex molecular mechanisms that underlie postsynaptic signaling and plasticity are beginning to emerge.

  18. A neural model of cerebellar learning for arm movement control: cortico-spino-cerebellar dynamics.

    PubMed

    Contreras-Vidal, J L; Grossberg, S; Bullock, D

    1997-01-01

    A neural network model of opponent cerebellar learning for arm movement control is proposed. The model illustrates how a central pattern generator in cortex and basal ganglia, a neuromuscular force controller in spinal cord, and an adaptive cerebellum cooperate to reduce motor variability during multijoint arm movements using mono- and bi-articular muscles. Cerebellar learning modifies velocity commands to produce phasic antagonist bursts at interpositus nucleus cells whose feed-forward action overcomes inherent limitations of spinal feedback control of tracking. Excitation of alpha motoneuron pools, combined with inhibition of their Renshaw cells by the cerebellum, facilitate movement initiation and optimal execution. Transcerebellar pathways are opened by learning through long-term depression (LTD) of parallel fiber-Purkinje cell synapses in response to conjunctive stimulation of parallel fibers and climbing fiber discharges that signal muscle stretch errors. The cerebellar circuitry also learns to control opponent muscles pairs, allowing cocontraction and reciprocal inhibition of muscles. Learning is stable, exhibits load compensation properties, and generalizes better across movement speeds if motoneuron pools obey the size principle. The intermittency of climbing fiber discharges maintains stable learning. Long-term potentiation (LTP) in response to uncorrelated parallel fiber signals enables previously weakened synapses to recover. Loss of climbing fibers, in the presence of LTP, can erode normal opponent signal processing. Simulated lesions of the cerebellar network reproduce symptoms of cerebellar disease, including sluggish movement onsets, poor execution of multijoint plans, and abnormally prolonged endpoint oscillations.

  19. Principal component analysis of minimal excitatory postsynaptic potentials.

    PubMed

    Astrelin, A V; Sokolov, M V; Behnisch, T; Reymann, K G; Voronin, L L

    1998-02-20

    'Minimal' excitatory postsynaptic potentials (EPSPs) are often recorded from central neurones, specifically for quantal analysis. However the EPSPs may emerge from activation of several fibres or transmission sites so that formal quantal analysis may give false results. Here we extended application of the principal component analysis (PCA) to minimal EPSPs. We tested a PCA algorithm and a new graphical 'alignment' procedure against both simulated data and hippocampal EPSPs. Minimal EPSPs were recorded before and up to 3.5 h following induction of long-term potentiation (LTP) in CA1 neurones. In 29 out of 45 EPSPs, two (N=22) or three (N=7) components were detected which differed in latencies, rise time (Trise) or both. The detected differences ranged from 0.6 to 7.8 ms for the latency and from 1.6-9 ms for Trise. Different components behaved differently following LTP induction. Cases were found when one component was potentiated immediately after tetanus whereas the other with a delay of 15-60 min. The immediately potentiated component could decline in 1-2 h so that the two components contributed differently into early (< 1 h) LTP1 and later (1-4 h) LTP2 phases. The noise deconvolution techniques was applied to both conventional EPSP amplitudes and scores of separate components. Cases are illustrated when quantal size (upsilon) estimated from the EPSP amplitudes increased whereas upsilon estimated from the component scores was stable during LTP1. Analysis of component scores could show apparent double-fold increases in upsilon which are interpreted as reflections of synchronized quantal releases. In general, the results demonstrate PCA applicability to separate EPSPs into different components and its usefulness for precise analysis of synaptic transmission.

  20. Neonatal stress alters LTP in freely moving male and female adult rats.

    PubMed

    Kehoe, P; Bronzino, J D

    1999-01-01

    We previously reported that neonatal isolation stress significantly changes measures of hippocampal long-term potentiation (LTP) in male and female juvenile rats, i.e., at 30 days of age. The changes in dentate granule population measures, i.e., excitatory postsynaptic potential (EPSP) and population spike amplitude (PSA), evoked by tetanization of the medial perforant pathway, indicated that juvenile rats exposed to neonatal isolation exhibit different enhancement profiles with respect to both the magnitude and duration of LTP in a sex-specific manner. Isolated males showed a significantly greater enhancement of LTP, while female "isolates" showed significantly longer LTP duration when compared to all other groups. The present study was designed to determine whether the effects of the neonatal isolation stress paradigm endures into adulthood. Rats isolated from their mothers for 1 h per day during postnatal days 2-9 were surgically prepared at 70-90 days of age, with stimulating and recording electrodes placed in the medial perforant pathway and the hippocampal dentate gyrus, respectively. Prior to tetanization, no significant effect of sex or treatment was obtained for baseline measures of EPSP slope or PSA. In order to rule out baseline differences in hippocampal cell excitability in female adult rats, we measured the response of dentate granule cells for one estrus cycle and found no pretetanization enhancement in the evoked response in either controls or previously stressed rats. Following tetanization, there was a significant treatment and sex effect. During the induction of LTP, PSA values were significantly enhanced in both isolated males and females and had significantly longer LTP duration when compared to the unhandled control group. Additionally, we observed that females took longer to reach baseline levels than males. Taken together, these results indicate that repeated infant isolation stress enhances LTP induction and duration in both males and

  1. Blueberry-enriched diet ameliorates age-related declines in NMDA receptor-dependent LTP

    PubMed Central

    Bickford, Paula C.; Browning, Michael D.

    2008-01-01

    NMDA receptor-dependent long-term potentiation (LTP) in the hippocampus is widely accepted as a cellular substrate for memory formation. Age-related declines in the expression of both NMDAR-dependent LTP and NMDAR subunit proteins in the CA1 region of the hippocampus have been well characterized and likely underlie age-related memory impairment. In the current study, we examined NMDAR-dependent LTP in young Fischer 344 rats (4 months old) and aged rats (24 months old) given either a control diet or a diet supplemented with blueberry extract for 6–8 weeks. NMDAR-dependent LTP was evoked by high-frequency stimulation (HFS) in the presence of nifedipine, to eliminate voltage-gated calcium channel LTP. Field excitatory postsynaptic potentials (fEPSPs) were increased by 57% 1 h after HFS in young animals, but this potentiation was reduced to 31% in aged animals. Supplementation of the diet with blueberry extract elevated LTP (63%) in aged animals to levels seen in young. The normalization of LTP may be due to the blueberry diet preventing a decline in synaptic strength, as measured by the slope of the fEPSP for a given fiber potential. The blueberry diet did not prevent age-related declines in NMDAR protein expression. However, phosphorylation of a key tyrosine residue on the NR2B subunit, important for increasing NMDAR function, was enhanced by the diet, suggesting that an increase in NMDAR function might overcome the loss in protein. This report provides evidence that dietary alterations later in life may prevent or postpone the cognitive declines associated with aging. PMID:19424850

  2. Integrated plasticity at inhibitory and excitatory synapses in the cerebellar circuit.

    PubMed

    Mapelli, Lisa; Pagani, Martina; Garrido, Jesus A; D'Angelo, Egidio

    2015-01-01

    The way long-term potentiation (LTP) and depression (LTD) are integrated within the different synapses of brain neuronal circuits is poorly understood. In order to progress beyond the identification of specific molecular mechanisms, a system in which multiple forms of plasticity can be correlated with large-scale neural processing is required. In this paper we take as an example the cerebellar network, in which extensive investigations have revealed LTP and LTD at several excitatory and inhibitory synapses. Cerebellar LTP and LTD occur in all three main cerebellar subcircuits (granular layer, molecular layer, deep cerebellar nuclei) and correspondingly regulate the function of their three main neurons: granule cells (GrCs), Purkinje cells (PCs) and deep cerebellar nuclear (DCN) cells. All these neurons, in addition to be excited, are reached by feed-forward and feed-back inhibitory connections, in which LTP and LTD may either operate synergistically or homeostatically in order to control information flow through the circuit. Although the investigation of individual synaptic plasticities in vitro is essential to prove their existence and mechanisms, it is insufficient to generate a coherent view of their impact on network functioning in vivo. Recent computational models and cell-specific genetic mutations in mice are shedding light on how plasticity at multiple excitatory and inhibitory synapses might regulate neuronal activities in the cerebellar circuit and contribute to learning and memory and behavioral control.

  3. Simulation of Postsynaptic Glutamate Receptors Reveals Critical Features of Glutamatergic Transmission

    PubMed Central

    Greget, Renaud; Pernot, Fabien; Bouteiller, Jean-Marie C.; Ghaderi, Viviane; Allam, Sushmita; Keller, Anne Florence; Ambert, Nicolas; Legendre, Arnaud; Sarmis, Merdan; Haeberle, Olivier; Faupel, Michel; Bischoff, Serge; Berger, Theodore W.; Baudry, Michel

    2011-01-01

    Activation of several subtypes of glutamate receptors contributes to changes in postsynaptic calcium concentration at hippocampal synapses, resulting in various types of changes in synaptic strength. Thus, while activation of NMDA receptors has been shown to be critical for long-term potentiation (LTP) and long term depression (LTD) of synaptic transmission, activation of metabotropic glutamate receptors (mGluRs) has been linked to either LTP or LTD. While it is generally admitted that dynamic changes in postsynaptic calcium concentration represent the critical elements to determine the direction and amplitude of the changes in synaptic strength, it has been difficult to quantitatively estimate the relative contribution of the different types of glutamate receptors to these changes under different experimental conditions. Here we present a detailed model of a postsynaptic glutamatergic synapse that incorporates ionotropic and mGluR type I receptors, and we use this model to determine the role of the different receptors to the dynamics of postsynaptic calcium with different patterns of presynaptic activation. Our modeling framework includes glutamate vesicular release and diffusion in the cleft and a glutamate transporter that modulates extracellular glutamate concentration. Our results indicate that the contribution of mGluRs to changes in postsynaptic calcium concentration is minimal under basal stimulation conditions and becomes apparent only at high frequency of stimulation. Furthermore, the location of mGluRs in the postsynaptic membrane is also a critical factor, as activation of distant receptors contributes significantly less to calcium dynamics than more centrally located ones. These results confirm the important role of glutamate transporters and of the localization of mGluRs in postsynaptic sites in their signaling properties, and further strengthen the notion that mGluR activation significantly contributes to postsynaptic calcium dynamics only following

  4. Nanoscale Molecular Reorganization of the Inhibitory Postsynaptic Density Is a Determinant of GABAergic Synaptic Potentiation.

    PubMed

    Pennacchietti, Francesca; Vascon, Sebastiano; Nieus, Thierry; Rosillo, Christian; Das, Sabyasachi; Tyagarajan, Shiva K; Diaspro, Alberto; Del Bue, Alessio; Petrini, Enrica Maria; Barberis, Andrea; Cella Zanacchi, Francesca

    2017-02-15

    Gephyrin is a key scaffold protein mediating the anchoring of GABAA receptors at inhibitory synapses. Here, we exploited superresolution techniques combined with proximity-based clustering analysis and model simulations to investigate the single-molecule gephyrin reorganization during plasticity of inhibitory synapses in mouse hippocampal cultured neurons. This approach revealed that, during the expression of inhibitory LTP, the increase of gephyrin density at postsynaptic sites is associated with the promoted formation of gephyrin nanodomains. We demonstrate that the gephyrin rearrangement in nanodomains stabilizes the amplitude of postsynaptic currents, indicating that, in addition to the number of synaptic GABAA receptors, the nanoscale distribution of GABAA receptors in the postsynaptic area is a crucial determinant for the expression of inhibitory synaptic plasticity. In addition, the methodology implemented here clears the way to the application of the graph-based theory to single-molecule data for the description and quantification of the spatial organization of the synapse at the single-molecule level.SIGNIFICANCE STATEMENT The mechanisms of inhibitory synaptic plasticity are poorly understood, mainly because the size of the synapse is below the diffraction limit, thus reducing the effectiveness of conventional optical and imaging techniques. Here, we exploited superresolution approaches combined with clustering analysis to study at unprecedented resolution the distribution of the inhibitory scaffold protein gephyrin in response to protocols inducing LTP of inhibitory synaptic responses (iLTP). We found that, during the expression of iLTP, the increase of synaptic gephyrin is associated with the fragmentation of gephyrin in subsynaptic nanodomains. We demonstrate that such synaptic gephyrin nanodomains stabilize the amplitude of inhibitory postsynaptic responses, thus identifying the nanoscale gephyrin rearrangement as a key determinant for inhibitory

  5. Cerebellar Ataxia.

    PubMed

    Perlman

    2000-05-01

    There is nothing more discouraging than for a patient to be given a specific diagnosis, then to be told that there is nothing that can be done. Physicians are equally disheartened to see exponential progress being made in the understanding of the pathophysiology of a complex disorder but few direct benefits resulting for their patients. Over the past 5 years, molecular genetic research has completely revolutionized the way in which the progressive cerebellar ataxias are classified and diagnosed, but it has yet to produce effective gene-based, neuroprotective, or neurorestorative therapies. The treatment of cerebellar ataxia remains primarily a neurorehabilitation challenge, employing physical, occupational, speech, and swallowing therapy; adaptive equipment; driver safety training; and nutritional counseling. Modest additional gains are seen with the use of medications that can improve imbalance, incoordination, or dysarthria (amantadine, buspirone, acetazolamide); cerebellar tremor (clonazepam, propranolol); and cerebellar or central vestibular nystagmus (gabapentin, baclofen, clonazepam). Many of the progressive cerebellar syndromes have associated features involving other neurologic systems (eg, spasticity, dystonia or rigidity, resting or rubral tremor, chorea, motor unit weakness or fatigue, autonomic dysfunction, peripheral or posterior column sensory loss, neuropathic pain or cramping, double vision, vision and hearing loss, dementia, and bowel, bladder, and sexual dysfunction), which can impede the treatment of the ataxic symptoms or can worsen with the use of certain drugs. Treatment of the associated features themselves may in turn worsen the ataxia either directly (as side effects of medication) or indirectly (eg, relaxation of lower limb spasticity that was acting as a stabilizer for an ataxic gait). Secondary complications of progressive ataxia can include deconditioning or immobility, weight loss or gain, skin breakdown, recurrent pulmonary and

  6. ASIC-dependent LTP at multiple glutamatergic synapses in amygdala network is required for fear memory

    PubMed Central

    Chiang, Po-Han; Chien, Ta-Chun; Chen, Chih-Cheng; Yanagawa, Yuchio; Lien, Cheng-Chang

    2015-01-01

    Genetic variants in the human ortholog of acid-sensing ion channel-1a subunit (ASIC1a) gene are associated with panic disorder and amygdala dysfunction. Both fear learning and activity-induced long-term potentiation (LTP) of cortico-basolateral amygdala (BLA) synapses are impaired in ASIC1a-null mice, suggesting a critical role of ASICs in fear memory formation. In this study, we found that ASICs were differentially expressed within the amygdala neuronal population, and the extent of LTP at various glutamatergic synapses correlated with the level of ASIC expression in postsynaptic neurons. Importantly, selective deletion of ASIC1a in GABAergic cells, including amygdala output neurons, eliminated LTP in these cells and reduced fear learning to the same extent as that found when ASIC1a was selectively abolished in BLA glutamatergic neurons. Thus, fear learning requires ASIC-dependent LTP at multiple amygdala synapses, including both cortico-BLA input synapses and intra-amygdala synapses on output neurons. PMID:25988357

  7. Detrimental effects of postnatal exposure to propofol on memory and hippocampal LTP in mice.

    PubMed

    Wang, Yuan-Lin; Chen, Xin; Wang, Zhi-Ping

    2015-10-05

    Acute effects of propofol on memory and hippocampal long-term potentiation (LTP) in adult animals were reported. However, long-term effect of early postnatal application of propofol on memory was not totally disclosed. In this study, experiments were designed to verify the mechanisms underlying the long-term detrimental effects of propofol on memory and hippocampal synaptic plasticity. A consecutive propofol protocol from postnatal day 7 was applied to model anesthesia, long term memory and hippocampal synaptic plasticity were detected 2 months later. Our results showed that repeated propofol exposure in early phase affect the memory in the adult phase. Through recording the field excitatory postsynaptic potentials (fEPSPs) at Schaffer colletaral-CA1 synapses, both of basal synaptic transmission and hippocampal LTP were decreased after propofol application. While LTD induced by low frequency stimulation and 3,5-dihydroxyphenylglycine (3,5-DHPG) were not affected. Through analyzing the ultrastructure of dendrite in CA1 region, we found that propofol application decreased the spine density, which was consistent with the decrease of PSD-95 expression. In addition, p-AKT level was reduced after first propofol application. Intracerebroventricular injection of Akt inhibitor could mimic the propofol effects on basal synaptic transmission, hippocampal LTP and memory. Taken together, these results suggested that propofol possibly decreased AKT signaling pathway to restrict the spine development, finally leading to hippocampal LTP impairment and memory deficit.

  8. A neoHebbian framework for episodic memory; role of dopamine-dependent late LTP

    PubMed Central

    Grace, Anthony A.; Duzel, Emrah

    2011-01-01

    According to the Hebb rule, the change in the strength of a synapse depends only on the local interaction of presynaptic and postsynaptic events. Studies at many types of synapses indicate that the early phase of long-term potentiation (LTP) has Hebbian properties. However, it is now clear that the Hebb rule does not account for late LTP; this requires an additional signal that is non-local. For novel information and motivational events such as rewards, this signal at hippocampal CA1 synapses is mediated by the neuromodulator, dopamine. In this Review, we discuss recent experimental findings that support the view that this “neoHebbian” framework can account for memory behavior in a variety of learning situations. PMID:21851992

  9. Imaging and analysis of evoked excitatory-postsynaptic-calcium-transients by individual presynaptic-boutons of cultured Aplysia sensorimotor synapse.

    PubMed

    Malkinson, Guy; Spira, Micha E

    2010-04-01

    The use of the sensory-motor (SN-MN) synapse of the Aplysia gill withdrawal reflex has contributed immensely to the understanding of synaptic transmission, learning and memory acquisition processes. Whereas the majority of the studies focused on analysis of the presynaptic mechanisms, recent studies indicated that as in mammalian synapses, long term potentiation (LTP) formed by Aplysia SN-MN synapse depends on elevation of the postsynaptic free intracellular calcium concentration ([Ca2+](i)). Consistently, injection of the fast calcium chelator BAPTA to the MN prevents the formation of serotonin-induced LTP. Nevertheless, currently there are no published reports that directly examine and document whether evoked synaptic transmission is associated with transient increase in the postsynaptic [Ca2+](i). In the present study we imaged, for the first time, alterations in the postsynaptic [Ca2+](i) in response to presynaptic stimulation and analyzed the underlying mechanisms. Using live imaging of the postsynaptic [Ca2+](i) while monitoring the EPSP, we found that evoked transmitter release generates excitatory postsynaptic calcium concentration transients (EPSCaTs) by two mechanisms: (a) activation of DNQX-sensitive postsynaptic receptors-gated calcium influx and (b) calcium influx through nitrendipine-sensitive voltage-gated calcium channels (VGCCs). Concomitant confocal imaging of presynaptic boutons and EPSCaTs revealed that approximately 86% of the presynaptic boutons are associated with functional synapses.

  10. The cerebellar serotoninergic system and its possible involvement in cerebellar ataxia.

    PubMed

    Trouillas, P

    1993-05-01

    A review concerning the characteristics of the cerebellar serotoninergic system is presented. In rat, cat and oppossum, the perikarya of origin are located in the brain stem raphe nuclei and in other brainstem structures. The projections to the cerebellar layers and deep nuclei include synaptic connections, but also non synaptic terminals, especially in a diffuse cortical plexus. Serotoninergic receptors have been described: 5-HT1B in the molecular layer and 5-HT2 in the inferior olive. Serotonin exerts neurophysiological effects on several target cells, directly or indirectly, presynaptically or postsynaptically. A modulatory effect on Purkinje cells is well documented. In thiamine deprived animals, a specific serotoninergic cerebellar syndrome includes a selective degeneration of the serotoninergic cerebellar system, an increase of the 5-HIAA cerebellar values and an exaggerated serotoninergic turnover. In human heredoataxias (Friedreich's ataxia and cerebellar cortical atrophy), serotoninergic disturbances have been observed in the CSF, including low 5-HIAA values and an increased serotoninergic turnover. Therapeutic results have been obtained with L-5-HTP, a precursor of serotonin, in several conditions presenting cerebellar ataxia. L-5-HTP resistance of olivopontocerebellar atrophies may be explained by the destruction of serotonin-sensitive target cells, especially Purkinje cells.

  11. Photolysis of postsynaptic caged Ca2+ can potentiate and depress mossy fiber synaptic responses in rat hippocampal CA3 pyramidal neurons.

    PubMed

    Wang, Jun; Yeckel, Mark F; Johnston, Daniel; Zucker, Robert S

    2004-04-01

    The induction of mossy fiber-CA3 long-term potentiation (LTP) and depression (LTD) has been variously described as being dependent on either pre- or postsynaptic factors. Some of the postsynaptic factors for LTP induction include ephrin-B receptor tyrosine kinases and a rise in postsynaptic Ca2+ ([Ca2+]i). Ca2+ is also believed to be involved in the induction of the various forms of LTD at this synapse. We used photolysis of caged Ca2+ compounds to test whether a postsynaptic rise in [Ca2+]i is sufficient to induce changes in synaptic transmission at mossy fiber synapses onto rat hippocampal CA3 pyramidal neurons. We were able to elevate postsynaptic [Ca2+]i to approximately 1 microm for a few seconds in pyramidal cell somata and dendrites. We estimate that CA3 pyramidal neurons have approximately fivefold greater endogenous Ca2+ buffer capacity than CA1 neurons, limiting the rise in [Ca2+]i achievable by photolysis. This [Ca2+]i rise induced either a potentiation or a depression at mossy fiber synapses in different preparations. Neither the potentiation nor the depression was accompanied by consistent changes in paired-pulse facilitation, suggesting that these forms of plasticity may be distinct from synaptically induced LTP and LTD at this synapse. Our results are consistent with a postsynaptic locus for the induction of at least some forms of synaptic plasticity at mossy fiber synapses.

  12. Reinforcement of Rat Hippocampal LTP by Holeboard Training

    ERIC Educational Resources Information Center

    Frey, Julietta U.; Korz, Volker; Uzakov, Shukhrat

    2005-01-01

    Hippocampal long-term potentiation (LTP) can be dissociated in early-LTP lasting 4-5 h and late-LTP with a duration of more than 8 h, the latter of which requires protein synthesis and heterosynaptic activity during its induction. Previous studies in vivo have shown that early-LTP in the dentate gyrus can protein synthesis-dependently be…

  13. The effect of acute swim stress and training in the water maze on hippocampal synaptic activity as well as plasticity in the dentate gyrus of freely moving rats: revisiting swim-induced LTP reinforcement.

    PubMed

    Tabassum, Heena; Frey, Julietta U

    2013-12-01

    Hippocampal long-term potentiation (LTP) is a cellular model of learning and memory. An early form of LTP (E-LTP) can be reinforced into its late form (L-LTP) by various behavioral interactions within a specific time window ("behavioral LTP-reinforcement"). Depending on the type and procedure used, various studies have shown that stress differentially affects synaptic plasticity. Under low stress, such as novelty detection or mild foot shocks, E-LTP can be transformed into L-LTP in the rat dentate gyrus (DG). A reinforcing effect of a 2-min swim, however, has only been shown in (Korz and Frey (2003) J Neurosci 23:7281-7287; Korz and Frey (2005) J Neurosci 25:7393-7400; Ahmed et al. (2006) J Neurosci 26:3951-3958; Sajikumar et al., (2007) J Physiol 584.2:389-400) so far. We have reinvestigated these studies using the same as well as an improved recording technique which allowed the recording of field excitatory postsynaptic potentials (fEPSP) and the population spike amplitude (PSA) at their places of generation in freely moving rats. We show that acute swim stress led to a long-term depression (LTD) in baseline values of PSA and partially fEPSP. In contrast to earlier studies a LTP-reinforcement by swimming could never be reproduced. Our results indicate that 2-min swim stress influenced synaptic potentials as well as E-LTP negatively.

  14. Enhanced AMPA Receptor Function Promotes Cerebellar Long-Term Depression Rather than Potentiation

    ERIC Educational Resources Information Center

    van Beugen, Boeke J.; Qiao, Xin; Simmons, Dana H.; De Zeeuw, Chris I.; Hansel, Christian

    2014-01-01

    Ampakines are allosteric modulators of AMPA receptors that facilitate hippocampal long-term potentiation (LTP) and learning, and have been considered for the treatment of cognition and memory deficits. Here, we show that the ampakine CX546 raises the amplitude and slows the decay time of excitatory postsynaptic currents (EPSCs) at cerebellar…

  15. Studies in optimal configuration of the LTP

    NASA Astrophysics Data System (ADS)

    McKinney, Wayne R.; Anders, Mark; Barber, Samuel K.; Domning, Edward E.; Lou, Yunian; Morrison, Gregory Y.; Salmassi, Farhad; Smith, Brian V.; Yashchuk, Valeriy V.

    2010-08-01

    Brightness preservation requirements for ever brighter synchrotron radiation and free electron laser beamlines require surface slope tolerances of x-ray optics on the order of 0.2 μrad, or better. Hence, the accuracy of dedicated surface slope metrology must be 0.1 μrad, or even less. Achieving this level of measurement accuracy with the flagship instrument at synchrotron radiation metrology laboratories, the Long Trace Profiler (LTP), requires all significant sources of systematic, random, and instrumental drift errors to be identified, and reduced or eliminated. In this respect, the performance of certain components of the Advanced Light Source LTP-II design [Kirschman, et al., Proc. SPIE, 7077, 70770A-12 (2008)] is analyzed, considering the principal justification for inclusion of each component, possible systematic error due to the quality of its optical material, and drift effects due to generated heat, etc. We investigate the effects of replacement of the existing diode laser with a fiber-coupled laser light source, and demonstrate that reducing the number of components by using a single beam on the surface under test (SUT), rather than an original double beam maintains, or even improves the accuracy of measurement with our LTP. Based on the performance of the upgraded LTP, we trace the further steps for improving of the LTP optical system.

  16. Studies in Optimal Configuration of the LTP

    SciTech Connect

    McKinney, Wayne R.; Anders, Mark; Barber, Samuel K.; Domning, Edward E.; Lou, Yunian; Morrison, Gregory Y.; Salmassi, Farhad; Smith, Brian V.; Yashchuk, Valeriy V.

    2010-08-10

    Brightness preservation requirements for ever brighter synchrotron radiation and free electron laser beamlines require surface slope tolerances of x-ray optics on the order of 0.2 mu rad, or better. Hence, the accuracy of dedicated surface slope metrology must be 0.1 mu rad, or even less. Achieving this level of measurement accuracy with the flagship instrument at synchrotron radiation metrology laboratories, the Long Trace Profiler (LTP), requires all significant sources of systematic, random, and instrumental drift errors to be identified, and reduced or eliminated. In this respect, the performance of certain components of the Advanced Light Source LTP-II design [Kirschman, et al., Proc. SPIE, 7077, 70770A-12 (2008)] is analyzed, considering the principal justification for inclusion of each component, possible systematic error due to the quality of its optical material, and drift effects due to generated heat, etc. We investigate the effects of replacement of the existing diode laser with a fiber-coupled laser light source, and demonstrate that reducing the number of components by using a single beam on the surface under test (SUT), rather than an original double beam maintains, or even improves the accuracy of measurement with our LTP. Based on the performance of the upgraded LTP, we trace the further steps for improving of the LTP optical system.

  17. Parameter estimation techniques for LTP system identification

    NASA Astrophysics Data System (ADS)

    Nofrarias Serra, Miquel

    LISA Pathfinder (LPF) is the precursor mission of LISA (Laser Interferometer Space Antenna) and the first step towards gravitational waves detection in space. The main instrument onboard the mission is the LTP (LISA Technology Package) whose scientific goal is to test LISA's drag-free control loop by reaching a differential acceleration noise level between two masses in √ geodesic motion of 3 × 10-14 ms-2 / Hz in the milliHertz band. The mission is not only challenging in terms of technology readiness but also in terms of data analysis. As with any gravitational wave detector, attaining the instrument performance goals will require an extensive noise hunting campaign to measure all contributions with high accuracy. But, opposite to on-ground experiments, LTP characterisation will be only possible by setting parameters via telecommands and getting a selected amount of information through the available telemetry downlink. These two conditions, high accuracy and high reliability, are the main restrictions that the LTP data analysis must overcome. A dedicated object oriented Matlab Toolbox (LTPDA) has been set up by the LTP analysis team for this purpose. Among the different toolbox methods, an essential part for the mission are the parameter estimation tools that will be used for system identification during operations: Linear Least Squares, Non-linear Least Squares and Monte Carlo Markov Chain methods have been implemented as LTPDA methods. The data analysis team has been testing those methods with a series of mock data exercises with the following objectives: to cross-check parameter estimation methods and compare the achievable accuracy for each of them, and to develop the best strategies to describe the physics underlying a complex controlled experiment as the LTP. In this contribution we describe how these methods were tested with simulated LTP-like data to recover the parameters of the model and we report on the latest results of these mock data exercises.

  18. LTP Induction Modifies Functional Relationship among Hippocampal Neurons

    ERIC Educational Resources Information Center

    Yun, Sung H.; Lee, Deok S.; Lee, Hyunjung; Baeg, Eun H.; Kim, Yun B.; Jung, Min W.

    2007-01-01

    To obtain evidence linking long-term potentiation (LTP) and memory, we examined whether LTP induction modifies functional relationship among neurons in the rat hippocampus. In contrast to neurons in low-frequency stimulated or AP5-treated slices, LTP induction altered "functional connectivity," as defined by the degree of synchronous firing, among…

  19. The Cdk5 inhibitor Roscovitine increases LTP induction in corticostriatal synapses

    PubMed Central

    Miranda-Barrientos, Jorge; Nieto-Mendoza, Elizabeth; Hernández-Echeagaray, Elizabeth

    2014-01-01

    In corticostriatal synapses, LTD (long-term depression) and LTP (long-term potentiation) are modulated by the activation of DA (dopamine) receptors, with LTD being the most common type of long-term plasticity induced using the standard stimulation protocols. In particular, activation of the D1 signaling pathway increases cAMP/PKA (protein kinase A) phosphorylation activity and promotes an increase in the amplitude of glutamatergic corticostriatal synapses. However, if the Cdk5 (cyclin-dependent kinase 5) phosphorylates the DARPP-32 (dopamine and cAMP-regulated phosphoprotein of 32 kDa) at Thr75, DARPP-32 becomes a strong inhibitor of PKA activity. Roscovitine is a potent Cdk5 inhibitor; it has been previously shown that acute application of Roscovitine increases striatal transmission via Cdk5/DARPP-32. Since DARPP-32 controls long-term plasticity in the striatum, we wondered whether switching off CdK5 activity with Roscovitine contributes to the induction of LTP in corticostriatal synapses. For this purpose, excitatory population spikes and whole cell EPSC (excitatory postsynaptic currents) were recorded in striatal slices from C57/BL6 mice. Experiments were carried out in the presence of Roscovitine (20 μM) in the recording bath. Roscovitine increased the amplitude of excitatory population spikes and the percentage of population spikes that exhibited LTP after HFS (high-frequency stimulation; 100Hz). Results obtained showed that the mechanisms responsible for LTP induction after Cdk5 inhibition involved the PKA pathway, DA and NMDA (N-methyl-D-aspartate) receptor activation, L-type calcium channels activation and the presynaptic modulation of neurotransmitter release. PMID:24555476

  20. Serotonergic modulation of LTP at excitatory and inhibitory synapses in the developing rat visual cortex.

    PubMed

    Moreau, A W; Amar, M; Callebert, J; Fossier, P

    2013-05-15

    The stability and efficacy of neuronal circuits are achieved through a detailed balance between pyramidal cell and interneuron activities. Interestingly, the neocortical excitatory-inhibitory (E-I) balance is actively maintained at the soma of Layer 5 pyramidal neurons which receive 20% of excitation and 80% of inhibition after dendritic integration, and this is not affected by changes in synaptic strength. To infer the role of serotonergic neuromodulation on the activity-dependent maintenance of the E-I balance, we performed continuous voltage clamp measurements of stimulation-locked conductance dynamics in Layer 5 pyramidal neurons before and after long-term potentiation (LTP) induction, together with chronic or acute manipulation of serotonin function. When a theta-burst stimulation was applied in Layer 2/3 of 5-HT depleted cortical slices (after in vivo treatment with the tryptophan hydroxylase inhibitor p-chlorophenylalanine (pCPA)), or after in vitro perfusion of the potent 5-HT1A receptor antagonist WAY-100,635, we observed a persistent shift of the ratio between excitation and inhibition toward more inhibition. This was due to a strong LTP of inhibition co-aligned with a weak LTP of excitation, whereas the same protocol caused a similar potentiation of excitatory and inhibitory inputs when applied in control slices. In contrast, neither excitatory nor inhibitory postsynaptic currents were potentiated when LTP protocols were delivered in the presence of either the selective serotonin reuptake inhibitor citalopram or the 5-HT1A receptor agonist 8-OH-DPAT. This is the first demonstration that serotonergic neuromodulation is crucial for the maintenance of the neocortical E-I balance during high-frequency regimes.

  1. Calcium-permeable AMPA receptors provide a common mechanism for LTP in glutamatergic synapses of distinct hippocampal interneuron types.

    PubMed

    Szabo, Andras; Somogyi, Jozsef; Cauli, Bruno; Lambolez, Bertrand; Somogyi, Peter; Lamsa, Karri P

    2012-05-09

    Glutamatergic synapses on some hippocampal GABAergic interneurons exhibit activity-induced long-term potentiation (LTP). Interneuron types within the CA1 area expressing mutually exclusive molecular markers differ in LTP responses. Potentiation that depends on calcium-permeable (CP) AMPA receptors has been characterized in oriens-lacunosum moleculare (O-LM) interneurons, which express parvalbumin and somatostatin (SM). However, it is unknown how widely CP-AMPAR-dependent plasticity is expressed among different GABAergic interneuron types. Here we examine synaptic plasticity in rat hippocampal O-LM cells and two other interneuron types expressing either nitric oxide synthase (NOS) or cholecystokinin (CCK), which are known to be physiologically and developmentally distinct. We report similar CP-AMPAR-dependent LTP in NOS-immunopositive ivy cells and SM-expressing O-LM cells to afferent fiber theta burst stimulation. The potentiation in both cell types is induced at postsynaptic membrane potentials below firing threshold, and induction is blocked by intense spiking simultaneously with afferent stimulation. The strong inward rectification and calcium permeability of AMPARs is explained by a low level of GluA2 subunit mRNA expression. LTP is not elicited in CCK-expressing Schaffer collateral-associated cells, which lack CP-AMPARs and express high levels of the GluA2 subunit. The results show that CP-AMPAR-mediated synaptic potentiation is common in hippocampal interneuron types and occurs in interneurons of both feedforward and feedback inhibitory pathways.

  2. LTP enhances synaptogenesis in the developing hippocampus.

    PubMed

    Watson, Deborah J; Ostroff, Linnaea; Cao, Guan; Parker, Patrick H; Smith, Heather; Harris, Kristen M

    2016-05-01

    In adult hippocampus, long-term potentiation (LTP) produces synapse enlargement while preventing the formation of new small dendritic spines. Here, we tested how LTP affects structural synaptic plasticity in hippocampal area CA1 of Long-Evans rats at postnatal day 15 (P15). P15 is an age of robust synaptogenesis when less than 35% of dendritic spines have formed. We hypothesized that LTP might therefore have a different effect on synapse structure than in adults. Theta-burst stimulation (TBS) was used to induce LTP at one site and control stimulation was delivered at an independent site, both within s. radiatum of the same hippocampal slice. Slices were rapidly fixed at 5, 30, and 120 min after TBS, and processed for analysis by three-dimensional reconstruction from serial section electron microscopy (3DEM). All findings were compared to hippocampus that was perfusion-fixed (PF) in vivo at P15. Excitatory and inhibitory synapses on dendritic spines and shafts were distinguished from synaptic precursors, including filopodia and surface specializations. The potentiated response plateaued between 5 and 30 min and remained potentiated prior to fixation. TBS resulted in more small spines relative to PF by 30 min. This TBS-related spine increase lasted 120 min, hence, there were substantially more small spines with LTP than in the control or PF conditions. In contrast, control test pulses resulted in spine loss relative to PF by 120 min, but not earlier. The findings provide accurate new measurements of spine and synapse densities and sizes. The added or lost spines had small synapses, took time to form or disappear, and did not result in elevated potentiation or depression at 120 min. Thus, at P15 the spines formed following TBS, or lost with control stimulation, appear to be functionally silent. With TBS, existing synapses were awakened and then new spines formed as potential substrates for subsequent plasticity.

  3. LTP enhances synaptogenesis in the developing hippocampus

    PubMed Central

    Watson, Deborah J.; Ostroff, Linnaea; Cao, Guan; Parker, Patrick H.; Smith, Heather

    2015-01-01

    ABSTRACT In adult hippocampus, long‐term potentiation (LTP) produces synapse enlargement while preventing the formation of new small dendritic spines. Here, we tested how LTP affects structural synaptic plasticity in hippocampal area CA1 of Long‐Evans rats at postnatal day 15 (P15). P15 is an age of robust synaptogenesis when less than 35% of dendritic spines have formed. We hypothesized that LTP might therefore have a different effect on synapse structure than in adults. Theta‐burst stimulation (TBS) was used to induce LTP at one site and control stimulation was delivered at an independent site, both within s. radiatum of the same hippocampal slice. Slices were rapidly fixed at 5, 30, and 120 min after TBS, and processed for analysis by three‐dimensional reconstruction from serial section electron microscopy (3DEM). All findings were compared to hippocampus that was perfusion‐fixed (PF) in vivo at P15. Excitatory and inhibitory synapses on dendritic spines and shafts were distinguished from synaptic precursors, including filopodia and surface specializations. The potentiated response plateaued between 5 and 30 min and remained potentiated prior to fixation. TBS resulted in more small spines relative to PF by 30 min. This TBS‐related spine increase lasted 120 min, hence, there were substantially more small spines with LTP than in the control or PF conditions. In contrast, control test pulses resulted in spine loss relative to PF by 120 min, but not earlier. The findings provide accurate new measurements of spine and synapse densities and sizes. The added or lost spines had small synapses, took time to form or disappear, and did not result in elevated potentiation or depression at 120 min. Thus, at P15 the spines formed following TBS, or lost with control stimulation, appear to be functionally silent. With TBS, existing synapses were awakened and then new spines formed as potential substrates for subsequent plasticity. © 2015 The Authors Hippocampus

  4. Ischemic-LTP in striatal spiny neurons of both direct and indirect pathway requires the activation of D1-like receptors and NO/soluble guanylate cyclase/cGMP transmission.

    PubMed

    Arcangeli, Sara; Tozzi, Alessandro; Tantucci, Michela; Spaccatini, Cristiano; de Iure, Antonio; Costa, Cinzia; Di Filippo, Massimiliano; Picconi, Barbara; Giampà, Carmen; Fusco, Francesca Romana; Amoroso, Salvatore; Calabresi, Paolo

    2013-02-01

    Striatal medium-sized spiny neurons (MSNs) are highly vulnerable to ischemia. A brief ischemic insult, produced by oxygen and glucose deprivation (OGD), can induce ischemic long-term potentiation (i-LTP) of corticostriatal excitatory postsynaptic response. Since nitric oxide (NO) is involved in the pathophysiology of brain ischemia and the dopamine D1/D5-receptors (D1-like-R) are expressed in striatal NOS-positive interneurons, we hypothesized a relation between NOS-positive interneurons and striatal i-LTP, involving D1R activation and NO production. We investigated the mechanisms involved in i-LTP induced by OGD in corticostriatal slices and found that the D1-like-R antagonist SCH-23390 prevented i-LTP in all recorded MSNs. Immunofluorescence analysis confirmed the induction of i-LTP in both substance P-positive, (putative D1R-expressing) and adenosine A2A-receptor-positive (putative D2R-expressing) MSNs. Furthermore, i-LTP was dependent on a NOS/cGMP pathway since pharmacological blockade of NOS, guanylate-cyclase, or PKG prevented i-LTP. However, these compounds failed to prevent i-LTP in the presence of a NO donor or cGMP analog, respectively. Interestingly, the D1-like-R antagonism failed to prevent i-LTP when intracellular cGMP was pharmacologically increased. We propose that NO, produced by striatal NOS-positive interneurons via the stimulation of D1-like-R located on these cells, is critical for i-LTP induction in the entire population of MSNs involving a cGMP-dependent pathway.

  5. Ischemic-LTP in striatal spiny neurons of both direct and indirect pathway requires the activation of D1-like receptors and NO/soluble guanylate cyclase/cGMP transmission

    PubMed Central

    Arcangeli, Sara; Tozzi, Alessandro; Tantucci, Michela; Spaccatini, Cristiano; de Iure, Antonio; Costa, Cinzia; Di Filippo, Massimiliano; Picconi, Barbara; Giampà, Carmen; Fusco, Francesca Romana; Amoroso, Salvatore; Calabresi, Paolo

    2013-01-01

    Striatal medium-sized spiny neurons (MSNs) are highly vulnerable to ischemia. A brief ischemic insult, produced by oxygen and glucose deprivation (OGD), can induce ischemic long-term potentiation (i-LTP) of corticostriatal excitatory postsynaptic response. Since nitric oxide (NO) is involved in the pathophysiology of brain ischemia and the dopamine D1/D5-receptors (D1-like-R) are expressed in striatal NOS-positive interneurons, we hypothesized a relation between NOS-positive interneurons and striatal i-LTP, involving D1R activation and NO production. We investigated the mechanisms involved in i-LTP induced by OGD in corticostriatal slices and found that the D1-like-R antagonist SCH-23390 prevented i-LTP in all recorded MSNs. Immunofluorescence analysis confirmed the induction of i-LTP in both substance P-positive, (putative D1R-expressing) and adenosine A2A-receptor-positive (putative D2R-expressing) MSNs. Furthermore, i-LTP was dependent on a NOS/cGMP pathway since pharmacological blockade of NOS, guanylate-cyclase, or PKG prevented i-LTP. However, these compounds failed to prevent i-LTP in the presence of a NO donor or cGMP analog, respectively. Interestingly, the D1-like-R antagonism failed to prevent i-LTP when intracellular cGMP was pharmacologically increased. We propose that NO, produced by striatal NOS-positive interneurons via the stimulation of D1-like-R located on these cells, is critical for i-LTP induction in the entire population of MSNs involving a cGMP-dependent pathway. PMID:23149555

  6. The facilitating effect of systemic administration of Kv7/M channel blocker XE991 on LTP induction in the hippocampal CA1 area independent of muscarinic activation.

    PubMed

    Song, Ming-Ke; Cui, Yong-Yao; Zhang, Wei-Wei; Zhu, Liang; Lu, Yang; Chen, Hong-Zhuan

    2009-09-11

    A large amount of in vitro studies demonstrate suppression of M-current in hippocampal neurons by Kv7/M channel blocker results in depolarization of membrane potential and release of neurotransmitters, such as acetylcholine and glutamate, suggesting that Kv7/M channel may play important roles in regulating synaptic plasticity. In the present study, we examined the in vivo effect of Kv7/M channel inhibition on the long-term potentiation (LTP) induction at basal dendrites in hippocampal CA1 area of urethane-anaesthetized rats. The Kv7/M channel was inhibited by intraperitoneal injection of XE991 (10mg/kg) and the LTP of field excitatory postsynaptic potential (fEPSP) was induced by supra-threshold high frequency stimulation (S1 HFS). A weak protocol which was just below the threshold for evoking LTP was used as sub-threshold high frequency stimulation (S2 HFS). XE991 did not significantly alter the slope of fEPSP and the magnitude of LTP induced by S1 HFS, suggesting that Kv7/M channel inhibition had little or no effect on glutamatergic transmission under basal conditions. However, XE991 could make S2 HFS evoke LTP even after the application of the muscarinic cholinergic (mACh) receptor antagonist scopolamine, suggesting that Kv7/M channel inhibition lowered the threshold for LTP induction and the effect was independent of muscarinic activation. Based on the above findings, we concluded that the facilitating effect of XE991 on LTP induction is not mediated by its ability to enhance the release of acetylcholine; therefore, Kv7/M channel blockers may provide a therapeutic benefit to cholinergic deficiency-related cognitive impairment, e.g., Alzheimer's disease.

  7. Postsynaptic potentiation of corticospinal projecting neurons in the anterior cingulate cortex after nerve injury

    PubMed Central

    2014-01-01

    Long-term potentiation (LTP) is the key cellular mechanism for physiological learning and pathological chronic pain. In the anterior cingulate cortex (ACC), postsynaptic recruitment or modification of AMPA receptor (AMPAR) GluA1 contribute to the expression of LTP. Here we report that pyramidal cells in the deep layers of the ACC send direct descending projecting terminals to the dorsal horn of the spinal cord (lamina I-III). After peripheral nerve injury, these projection cells are activated, and postsynaptic excitatory responses of these descending projecting neurons were significantly enhanced. Newly recruited AMPARs contribute to the potentiated synaptic transmission of cingulate neurons. PKA-dependent phosphorylation of GluA1 is important, since enhanced synaptic transmission was abolished in GluA1 phosphorylation site serine-845 mutant mice. Our findings provide strong evidence that peripheral nerve injury induce long-term enhancement of cortical-spinal projecting cells in the ACC. Direct top-down projection system provides rapid and profound modulation of spinal sensory transmission, including painful information. Inhibiting cortical top-down descending facilitation may serve as a novel target for treating neuropathic pain. PMID:24890933

  8. Pre- and postsynaptic twists in BDNF secretion and action in synaptic plasticity.

    PubMed

    Edelmann, Elke; Lessmann, Volkmar; Brigadski, Tanja

    2014-01-01

    Overwhelming evidence collected since the early 1990's strongly supports the notion that BDNF is among the key regulators of synaptic plasticity in many areas of the mammalian central nervous system. Still, due to the extremely low expression levels of endogenous BDNF in most brain areas, surprisingly little data i) pinpointing pre- and postsynaptic release sites, ii) unraveling the time course of release, and iii) elucidating the physiological levels of synaptic activity driving this secretion are available. Likewise, our knowledge regarding pre- and postsynaptic effects of endogenous BDNF at the single cell level in mediating long-term potentiation still is sparse. Thus, our review will discuss the data currently available regarding synaptic BDNF secretion in response to physiologically relevant levels of activity, and will discuss how endogenously secreted BDNF affects synaptic plasticity, giving a special focus on spike timing-dependent types of LTP and on mossy fiber LTP. We will attempt to open up perspectives how the remaining challenging questions regarding synaptic BDNF release and action might be addressed by future experiments. This article is part of the Special Issue entitled 'BDNF Regulation of Synaptic Structure, Function, and Plasticity'.

  9. Myosin IXa Binds AMPAR and Regulates Synaptic Structure, LTP, and Cognitive Function

    PubMed Central

    Folci, Alessandra; Murru, Luca; Vezzoli, Elena; Ponzoni, Luisa; Gerosa, Laura; Moretto, Edoardo; Longo, Fabiana; Zapata, Jonathan; Braida, Daniela; Pistillo, Francesco; Bähler, Martin; Francolini, Maura; Sala, Mariaelvina; Bassani, Silvia

    2016-01-01

    Myosin IXa (Myo9a) is a motor protein that is highly expressed in the brain. However, the role of Myo9a in neurons remains unknown. Here, we investigated Myo9a function in hippocampal synapses. In rat hippocampal neurons, Myo9a localizes to the postsynaptic density (PSD) and binds the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) GluA2 subunit. Myo9a+/- mice displayed a thicker PSD and increased levels of PSD95 and surface AMPAR expression. Furthermore, synaptic transmission, long-term potentiation (LTP) and cognitive functions were impaired in Myo9a+/- mice. Together, these results support a key role for Myo9a in controlling the molecular structure and function of hippocampal synapses. PMID:26834556

  10. Enhanced intrinsic excitability and EPSP-spike coupling accompany enriched environment-induced facilitation of LTP in hippocampal CA1 pyramidal neurons.

    PubMed

    Malik, Ruchi; Chattarji, Sumantra

    2012-03-01

    Environmental enrichment (EE) is a well-established paradigm for studying naturally occurring changes in synaptic efficacy in the hippocampus that underlie experience-induced modulation of learning and memory in rodents. Earlier research on the effects of EE on hippocampal plasticity focused on long-term potentiation (LTP). Whereas many of these studies investigated changes in synaptic weight, little is known about potential contributions of neuronal excitability to EE-induced plasticity. Here, using whole-cell recordings in hippocampal slices, we address this gap by analyzing the impact of EE on both synaptic plasticity and intrinsic excitability of hippocampal CA1 pyramidal neurons. Consistent with earlier reports, EE increased contextual fear memory and dendritic spine density on CA1 cells. Furthermore, EE facilitated LTP at Schaffer collateral inputs to CA1 pyramidal neurons. Analysis of the underlying causes for enhanced LTP shows EE to increase the frequency but not amplitude of miniature excitatory postsynaptic currents. However, presynaptic release probability, assayed using paired-pulse ratios and use-dependent block of N-methyl-d-aspartate receptor currents, was not affected. Furthermore, CA1 neurons fired more action potentials (APs) in response to somatic depolarization, as well as during the induction of LTP. EE also reduced spiking threshold and after-hyperpolarization amplitude. Strikingly, this EE-induced increase in excitability caused the same-sized excitatory postsynaptic potential to fire more APs. Together, these findings suggest that EE may enhance the capacity for plasticity in CA1 neurons, not only by strengthening synapses but also by enhancing their efficacy to fire spikes-and the two combine to act as an effective substrate for amplifying LTP.

  11. Effects of Relative Hypoglycemia on LTP and NADH Imaging in Rat Hippocampal Slices

    PubMed Central

    Sadgrove, Matthew P.; Beaver, Christopher J.; Turner, Dennis A.

    2007-01-01

    Cognitive and neuronal impairment in diabetes may be associated with iatrogenic hypoglycemia, particularly at low serum glucose levels (< 3 mM). To evaluate cellular impairment, we assessed acute hippocampal slice functioning during decreased ambient glucose, by monitoring evoked field excitatory post-synaptic potentials (fEPSP), and slice nicotinamide adenine dinucleotide (NADH) fluorescence. The effects of lowered glucose levels (60 min) were analyzed by examining the induction and maintenance of long-term potentiation (LTP), and NADH metabolic imaging in the CA1 region. The basal fEPSP response was reduced by lowered ambient glucose, an effect that was reversible in 2.5 mM glucose, partially reversible in 1.25 mM glucose and irreversible in 0 mM glucose, after 25 min recovery. LTP induction and maintenance declined during glucose restriction, demonstrating reversibly failed maintenance in 5 mM and 2.5 mM ambient glucose, and absent induction in 1.25 mM glucose. Peak NADH levels observed during train-induced biphasic transients were significantly reduced during 1.25 mM and 2.5 mM glucose. Significant functional compromise in our slice model occurred at 2.5 mM ambient glucose, equivalent to <1mM tissue glucose in the slice center, due to diffusion limitations and active glucose utilization. This tissue glucose level correlates with human observations of a serum threshold of <3mM for cognitive impairment, since brain tissue glucose is approximately one third of serum levels. The physiological effects of hypoglycemia in our slice model, assessed through fEPSP, LTP, and NADH responses, replicate closely the in vivo situation, confirming the usefulness of this model in assessing consequences of relative hypoglycemia. PMID:17651706

  12. Temporal dynamics of cerebellar and motor cortex physiological processes during motor skill learning

    PubMed Central

    Spampinato, D.; Celnik, P.

    2017-01-01

    Learning motor tasks involves distinct physiological processes in the cerebellum (CB) and primary motor cortex (M1). Previous studies have shown that motor learning results in at least two important neurophysiological changes: modulation of cerebellar output mediated in-part by long-term depression of parallel fiber-Purkinje cell synapse and induction of long-term plasticity (LTP) in M1, leading to transient occlusion of additional LTP-like plasticity. However, little is known about the temporal dynamics of these two physiological mechanisms during motor skill learning. Here we use non-invasive brain stimulation to explore CB and M1 mechanisms during early and late motor skill learning in humans. We predicted that early skill acquisition would be proportional to cerebellar excitability (CBI) changes, whereas later stages of learning will result in M1 LTP-like plasticity modifications. We found that early, and not late into skill training, CBI changed. Whereas, occlusion of LTP-like plasticity over M1 occurred only during late, but not early training. These findings indicate a distinct temporal dissociation in the physiological role of the CB and M1 when learning a novel skill. Understanding the role and temporal dynamics of different brain regions during motor learning is critical to device optimal interventions to augment learning. PMID:28091578

  13. Enhanced LTP in aged rats: Detrimental or compensatory?

    PubMed

    Pinho, Júlia; Vale, Ruben; Batalha, Vânia L; Costenla, Ana Rita; Dias, Raquel; Rombo, Diogo; Sebastião, Ana M; de Mendonça, Alexandre; Diógenes, Maria José

    2017-03-01

    Age-dependent memory deterioration has been well documented and yet an increase in rat hippocampal LTP upon aging has been reported. This poses the question of whether the enhanced LTP is a cause or an attempt to compensate the memory deficits described in aged rats. Hippocampal slices from young, adult and aged Wistar rats were pre-incubated, with an NMDA receptor (NMDAR) antagonist, memantine (1 μM, 4 h), and hippocampal LTP was evaluated. The results show that memantine significantly decreases the larger LTP magnitude recorded in hippocampal slices from aged rats without compromising LTP recorded in slices from young and adult animals. To unveil the impact of in vivo administration of memantine, different doses (1, 5 and 10 mg/kg/day) or saline vehicle solution were intraperitoneally administered, for 15-20 days, to both young and aged animals. Memantine did not significantly affect neither the place learning of young animals, evaluated by Morris Water Maze, nor LTP recorded from hippocampal slices from the same group of animals. However, memantine (5 and 10 mg/kg/day) significantly decreased the large LTP recorded in hippocampal slices from aged animals. Moreover, aged animals treated with memantine (10 mg/kg/day) showed a significantly compromised place learning when compared to aged control animals. Overall, these results suggest that the larger LTP observed in aged animals is a compensatory phenomenon, rather than pathological. The finding that age-dependent blockade of LTP by a NMDAR antagonist leads to learning deficits, implies that the increased LTP observed upon aging may be playing an important role in the learning process.

  14. Iatrogenic postoperative cerebellar cyst.

    PubMed

    Sharif, Robin; Moscovici, Samuel; Wygoda, Marc; Eliahou, Ruth; Spektor, Sergey

    2016-12-01

    Cerebellar cyst is a known but uncommon entity. It is congenital in most cases, or may develop after brain parenchyma injuries or interventions. To our knowledge, de novo cerebellar cyst after extra-axial tumor excision, has not been described in the literature. We present the first reported case of a de novo cerebellar cyst developing in a 70-year-old woman following retrosigmoid craniotomy for vestibular schwannoma excision, and discuss the possible causes. Following cyst fenestration, there was no clinical or radiological evidence of a residual cyst.

  15. Critical involvement of postsynaptic protein kinase activation in long-term potentiation at hippocampal mossy fiber synapses on CA3 interneurons.

    PubMed

    Galván, Emilio J; Cosgrove, Kathleen E; Mauna, Jocelyn C; Card, J Patrick; Thiels, Edda; Meriney, Stephen D; Barrionuevo, Germán

    2010-02-24

    Hippocampal mossy fiber (MF) synapses on area CA3 lacunosum-moleculare (L-M) interneurons are capable of undergoing a Hebbian form of NMDA receptor (NMDAR)-independent long-term potentiation (LTP) induced by the same type of high-frequency stimulation (HFS) that induces LTP at MF synapses on pyramidal cells. LTP of MF input to L-M interneurons occurs only at synapses containing mostly calcium-impermeable (CI)-AMPA receptors (AMPARs). Here, we demonstrate that HFS-induced LTP at these MF-interneuron synapses requires postsynaptic activation of protein kinase A (PKA) and protein kinase C (PKC). Brief extracellular stimulation of PKA with forskolin (FSK) alone or in combination with 1-Methyl-3-isobutylxanthine (IBMX) induced a long-lasting synaptic enhancement at MF synapses predominantly containing CI-AMPARs. However, the FSK/IBMX-induced potentiation in cells loaded with the specific PKA inhibitor peptide PKI(6-22) failed to be maintained. Consistent with these data, delivery of HFS to MFs synapsing onto L-M interneurons loaded with PKI(6-22) induced posttetanic potentiation (PTP) but not LTP. Hippocampal sections stained for the catalytic subunit of PKA revealed abundant immunoreactivity in interneurons located in strata radiatum and L-M of area CA3. We also found that extracellular activation of PKC with phorbol 12,13-diacetate induced a pharmacological potentiation of the isolated CI-AMPAR component of the MF EPSP. However, HFS delivered to MF synapses on cells loaded with the PKC inhibitor chelerythrine exhibited PTP followed by a significant depression. Together, our data indicate that MF LTP in L-M interneurons at synapses containing primarily CI-AMPARs requires some of the same signaling cascades as does LTP of glutamatergic input to CA3 or CA1 pyramidal cells.

  16. Acute cerebellar ataxia

    MedlinePlus

    ... Alcohol, medications, and insecticides Bleeding into the cerebellum Multiple sclerosis Strokes of the cerebellum Vaccination ... swelling (inflammation) of the cerebellum (such as from multiple sclerosis) Cerebellar ataxia caused by a recent viral infection ...

  17. [Autosomal recessive cerebellar ataxias].

    PubMed

    Tranchant, Christine; Anheim, Mathieu

    2009-12-01

    Friedreich ataxia is the most frequent recessive cerebral ataxia d should always be researched first. Ataxia with isolated vitamin E deficiency and abetalipoproteinemia have a specific treatment. Associated neurological signs such polyneuroapthy, ophtalmologic or oculomotor signs, pyramidal signs, and cerebellar MRI can lead to the etiological diagnosis. Biological tests should be: vitamin E, cholesterol, alpha-fetoprotein levels, acanthocytes, than phytanic acid, cholestanol, lysosomal enzymes. Numerous autosomal recessive cerebellar ataxia remain without etiology.

  18. Cerebellar Development and Disease

    PubMed Central

    Gleeson, Joseph G.

    2008-01-01

    Recent Advances The molecular control of cell type specification within the developing cerebellum as well as the genetic causes of the most common human developmental cerebellar disorders have long remained mysterious. Recent genetic lineage and loss-of-function data from mice have revealed unique and non-overlapping anatomical origins for GABAergic neurons from ventricular zone precursors and glutamatergic cell from rhombic lip precursors, mirroring distinct origins for these neurotransmitter-specific cell types in the cerebral cortex. Mouse studies elucidating the role of Ptf1a as a cerebellar ventricular zone GABerigic fate switch were actually preceded by the recognition that PTF1A mutations in humans cause cerebellar agenesis, a birth defect of the human cerebellum. Indeed, several genes for congenital human cerebellar malformations have recently been identified, including genes causing Joubert syndrome, Dandy-Walker malformation and Ponto-cerebellar hypoplasia. These studies have pointed to surprisingly complex roles for transcriptional regulation, mitochondrial function and neuronal cilia in patterning, homeostasis and cell proliferation during cerebellar development. Together mouse and human studies are synergistically advancing our understanding of the developmental mechanisms that generate the uniquely complex mature cerebellum. PMID:18513948

  19. TrkB signalling pathways in LTP and learning.

    PubMed

    Minichiello, Liliana

    2009-12-01

    Understanding the mechanisms that underlie learning is one of the most fascinating and central aims of neurobiological research. Hippocampal long-term potentiation (LTP) is widely regarded as a prime candidate for the cellular mechanism of learning. The receptor tyrosine kinase TrkB (also known as NTRK2), known primarily for its function during PNS and CNS development, has emerged in recent years as a potent regulator of hippocampal LTP. Here I describe efforts to understand the signalling pathways and molecular mechanisms that underlie the involvement of TrkB in LTP and learning.

  20. Differential effects of pentylenetetrazol-kindling on long-term potentiation of population excitatory postsynaptic potentials and population spikes in the CA1 region of rat hippocampus.

    PubMed

    Palizvan, M R; Fathollahi, Y; Semnanian, S; Hajezadeh, S; Mirnajafizadh, J

    2001-04-13

    The effects of pentylenetetrazol-kindling on synaptic transmission and the effectiveness of θ pattern primed-bursts (PBs) for the induction of long-term potentiation (LTP) of population excitatory postsynaptic potentials and population spikes were investigated in hippocampal CA1 of pentylenetetrazol-kindled rats. Experiments were carried out in the control and kindled animals at two post-kindling periods, i.e., 48-144 h (early phase) and 30-33 days (long lasting phase). Field potentials (population excitatory postsynaptic potentials, pEPSPs; and population spikes, PSs) were recorded at the stratum radiatum and the stratum pyramidale following stimulation of the stratum fibers, respectively. PBs were delivered to stratum fibers and PB potentiation was assessed. The results showed that 48-144 h after kindling there was no significant difference for pEPSP slope and PS amplitude between two groups. But at 30-33 days after kindling, the pEPSP slope in the stratum radiatum of kindled animals decreased, whereas the amplitude of PSs increased compared to those of controls. Shortly after kindling, control animals had normal LTP of pEPSP slope and PS amplitude in response to PBs, but kindled rats lack LTP of pEPSP slope and PBs induced LTP of PS amplitude in most of kindled animals. In 30-33 days after kindling, PB potentiation was not observed in the stratum radiatum of kindled animals but PBs induced LTP of PS amplitude, which was significantly greater than that of control animals. The effect is compatible with the hypothesis, which postulates kindling-associated functional deficit in hippocampus, especially CA1, as an explanation for the behavioral deficits seen with the kindling model of epilepsy.

  1. Synaptic potentiation of dual-component excitatory postsynaptic currents in the rat hippocampus.

    PubMed Central

    Clark, K A; Collingridge, G L

    1995-01-01

    1. Whole-cell patch-clamp recording has been used to study tetanus-induced synaptic potentiation of dual-component excitatory postsynaptic currents (EPSCs) in the CA1 region of rat hippocampal slices, following blockade of GABAA and GABAB receptor-mediated synaptic inhibition. 2. At a holding potential of -60 mV, the initial slope of the EPSC (between 10 and 60% of maximum amplitude) provided an accurate measurement of the AMPA receptor-mediated component, and the amplitude of the EPSC at a latency of 100 ms provided the best estimate of the size of the NMDA receptor-mediated component. 3. Neurons were voltage clamped for at least 45 min prior to delivery of a tetanus (test intensity, 100 Hz, 1 s). Measurements at 10 and 30 min following the tetanus were used as indications of short-term potentiation (STP) and long-term potentiation (LTP), respectively. One set of neurons were voltage clamped at -60 mV throughout. These neurons could be subdivided into two populations on the basis of whether or not there was LTP (n = 9), or only STP (n = 6), of the AMPA receptor-mediated component. A second set of neurons were voltage clamped at -60 mV for 30 min and then at -50 mV for 15 min before, during and for 30 min following tetanization. In these experiments there was STP but not LTP (n = 8). 4. In all neurons (n = 23), the time course of the potentiation of the NMDA receptor-mediated component paralleled that of the AMPA receptor-mediated component. In addition, potentiation of the NMDA and AMPA receptor-mediated components were of a similar magnitude. 5. These data demonstrate that it is possible to induce LTP by high frequency stimulation after 45 min of whole-cell recording. Under these conditions, there is a parallel potentiation of the AMPA and NMDA receptor-mediated components of dual-component EPSCs. This constitutes the first evidence, from studies of dual-component synaptic responses, which is consistent with a presynaptic locus of expression of tetanus

  2. Intra-cerebellar infusion of the protein kinase Mzeta (PKMζ) inhibitor ZIP disrupts eyeblink classical conditioning

    PubMed Central

    Chihabi, Kutibh; Morielli, Anthony D.; Green, John T.

    2016-01-01

    PKM-ζ, a constitutively active N-terminal truncated form of PKC-ζ, has long been implicated in a cellular correlate of learning, long-term potentiation (LTP). Inhibition of PKM-ζ with Zeta-inhibitory peptide (ZIP) has been shown in many brain structures to disrupt maintenance of AMPA receptors, irreversibly disrupting numerous forms of learning and memory that have been maintained for weeks. Delay eyeblink conditioning (EBC) is an established model for the assessment of cerebellar learning; here, we show that PKC-ζ and PKM-ζ are highly expressed in the cerebellar cortex, with highest expression found in Purkinje cell (PC) nuclei. Despite being highly expressed in the cerebellar cortex, no studies have examined how regulation of cerebellar PKM-ζ may affect cerebellar-dependent learning and memory. Given its disruption of learning in other brain structures, we hypothesized that ZIP would also disrupt delay EBC. We have shown that infusion of ZIP into the lobulus simplex of the rat cerebellar cortex can indeed significantly disrupt delay EBC. PMID:26949968

  3. CYLINDER LENS ALIGNMENT IN THE LTP

    SciTech Connect

    TAKACS, P.Z.

    2005-07-26

    The Long Trace Profiler (LTP), is well-suited for the measurement of the axial figure of cylindrical mirrors that usually have a long radius of curvature in the axial direction but have a short radius of curvature in the sagittal direction. The sagittal curvature causes the probe beam to diverge in the transverse direction without coming to a focus on the detector, resulting in a very weak signal. It is useful to place a cylinder lens into the optical system above the mirror under test to refocus the sagittal divergence and increase the signal level. A positive cylinder lens can be placed at two positions above the surface: the Cat's Eye reflection position and the Wavefront-Matching position. The Cat's Eye position, is very tolerant to mirror misalignment, which is not good if absolute axial radius of curvature is to be measured. Lateral positioning and rotational misalignments of lens and the mirror combine to produce unusual profile results. This paper looks at various alignment issues with measurements and by raytrace simulations to determine the best strategy to minimize radius of curvature errors in the measurement of cylindrical aspheres.

  4. Neuroligins Are Selectively Essential for NMDAR Signaling in Cerebellar Stellate Interneurons

    PubMed Central

    Südhof, Thomas C.

    2016-01-01

    Neuroligins are postsynaptic cell-adhesion molecules that contribute to synapse specification. However, many other postsynaptic cell-adhesion molecules are known and the relative contributions of neuroligins versus other such molecules in different types of synapses and neurons remains largely unknown. Here, we have studied the role of neuroligins in cerebellar stellate interneurons that participate in a well defined circuit that converges on Purkinje cells as the major output neurons of cerebellar cortex. By crossing triple conditional knock-out (cKO) mice targeting all three major neuroligins [neuroligin-1 to neuroligin-3 (NL123)] with parvalbumin-Cre (PV-Cre) transgenic mice, we deleted neuroligins from inhibitory cerebellar interneurons and Purkinje cells, allowing us to study the effects of neuroligin deletions on cerebellar stellate cell synapses by electrophysiology in acute slices. PV-Cre/NL123 cKO mice did not exhibit gross alterations of cerebellar structure or cerebellar interneuron morphology. Strikingly, electrophysiological recordings in stellate cells from these PV-Cre/NL123 cKO mice revealed a large decrease in NMDAR-mediated excitatory synaptic responses, which, in stellate cells, are largely extrasynaptic, without a change in AMPA-receptor-mediated responses. Parallel analyses in PV-Cre/NL1 mice that are single NL1 cKO mice uncovered the same phenotype, demonstrating that NL1 is responsible for recruiting extrasynaptic NMDARs. Moreover, we observed only a modest impairment in inhibitory synaptic responses in stellate cells lacking NL123 despite a nearly complete suppression of inhibitory synaptic transmission in Purkinje cells by the same genetic manipulation. Our results suggest that, unlike other types of neurons investigated, neuroligins are selectively essential in cerebellar stellate interneurons for enabling the function of extrasynaptic NMDARs. SIGNIFICANCE STATEMENT Neuroligins are postsynaptic cell-adhesion molecules genetically linked to

  5. The Isolation, Primacy, and Recency Effects Predicted by an Adaptive LTD/LTP Threshold in Postsynaptic Cells

    ERIC Educational Resources Information Center

    Sikstrom, Sverker

    2006-01-01

    An item that stands out (is isolated) from its context is better remembered than an item consistent with the context. This isolation effect cannot be accounted for by increased attention, because it occurs when the isolated item is presented as the first item, or by impoverished memory of nonisolated items, because the isolated item is better…

  6. Active decay of composite excitatory postsynaptic potentials in hippocampal slices from young rats.

    PubMed

    Dozmorov, Mikhail; Niu, Yin-Ping; Xu, Hui-Ping; Xiao, Min-Yi; Li, Rui; Sandberg, Mats; Wigström, Holger

    2003-05-23

    NMDA receptor dependent synaptic plasticity was examined in hippocampal slices using a novel pharmacological pairing procedure. Field excitatory postsynaptic potentials (EPSPs) were recorded from the CA1 area of slices maintained in a low Mg(2+) solution using a stimulus rate of 0.1-0.2 Hz. The NMDA receptor antagonist 2-amino-5-phosphonovalerate (AP5) was initially included in the perfusion solution to establish baseline recording of isolated AMPA EPSPs. Washing out AP5 led to the expression of composite EPSPs, containing both AMPA and NMDA receptor mediated components. Following an initial, transient potentiation of the AMPA component, the composite responses gradually decayed for several hours, involving AMPA and NMDA components to a similar extent. This decay was input specific and could be terminated at any stage by reapplication of AP5. Subsequent long-term potentiation (LTP) reversed the effect to an extent inversely related to the degree of depression. Experiments to test the interaction with long-term depression (LTD) revealed a significant but incomplete overlap between the two depression processes. In conclusion, pairing synaptic activation at test stimulus frequency with pharmacological unblocking of NMDA receptors allows for expression of composite EPSPs that decay substantially, due to an active mechanism. The underlying process appears to be at least partly distinct from those involved in homosynaptic LTP and LTD.

  7. Metaplastic up-regulation of LTP in the rat visual cortex by monocular visual training: requirement of task mastery, hemispheric specificity, and NMDA-GluN2B involvement.

    PubMed

    Hager, A M; Gagolewicz, P J; Rodier, S; Kuo, M-C; Dumont, É C; Dringenberg, H C

    2015-05-07

    "Metaplasticity" is defined as an alteration of synaptic plasticity properties or mechanisms by a priming event without actual changes in synaptic strength. For example, visual discrimination training of rats leads to a facilitation of the subsequent induction of long-term potentiation (LTP) between the lateral geniculate nucleus (LGN) and the primary visual cortex (V1). Here, rats received visual discrimination training in a modified water maze, with one eye occluded during training to create monocular viewing conditions; 63% of rats acquired the task under these conditions. Following training, in vivo electrophysiology was used to examine LTP of field postsynaptic potentials (fPSPs) in V1 elicited by LGN stimulation. Rats that had successfully learned the task showed significantly greater LTP in the "trained V1" (contralateral to the open, trained eye) relative to the "untrained" hemisphere. Rats that underwent training but failed to acquire the task did not show this lateralized plasticity enhancement and had similar levels of LTP in both cerebral hemispheres. Cortical application of the NMDA receptor-GluN2B subunit antagonist Ro 25-6981 (2 mM) reversed the training-induced LTP facilitation without affecting LTP in the untrained V1. Whole-cell patch clamp recordings of V1 (layers II/III) pyramidal cells in vitro demonstrated that pharmacologically isolated NMDA currents exhibit a greater sensitivity to GluN2B blockade in the trained relative to the untrained V1. Together, these experiments reveal a surprising degree of anatomical (only in the hemisphere contralateral to the trained eye) and behavioral specificity (only in rats that mastered the task) for the effect of visual training to enhance LTP in V1. Further, cortical GluN2B subunits appear to be directly involved in this metaplastic facilitation of thalamocortical plasticity, suggesting that NMDA subunit composition or functioning is, at least in part, regulated by the exposure to behaviorally significant

  8. Optimised purification and characterisation of lipid transfer protein 1 (LTP1) and its lipid-bound isoform LTP1b from barley malt.

    PubMed

    Nieuwoudt, Melanie; Lombard, Nicolaas; Rautenbach, Marina

    2014-08-15

    In beer brewing, brewers worldwide strive to obtain product consistency in terms of flavour, colour and foam. Important proteins contributing to beer foam are lipid transfer proteins (LTPs), in particular LTP1 and its lipid-bound isoform LTP1b, which are known to transport lipids in vivo and prevent lipids from destabilising the beer foam. LTP1 and LTP1b were successfully purified using only five purification steps with a high purified protein yield (160 mg LTP1 and LTP1b from 200 g barley). Circular dichroism of LTP1 and LTP1b confirmed that both proteins are highly tolerant to high temperatures (>90 °C) and are pH stable, particularly at a neutral to a more basic pH. Only LTP1 exhibited antiyeast and thermo-stable lytic activity, while LTP1b was inactive, indicating that the fatty acid moiety compromised the antimicrobial activity of LTP1. This lack in antiyeast activity and the positive foam properties of LTP1b would benefit beer fermentation and quality.

  9. Perinatal undernutrition attenuates field excitatory postsynaptic potentials and influences dendritic spine density and morphology in hippocampus of male rat offspring.

    PubMed

    Zhang, Y; Wei, J; Yang, Z

    2013-08-06

    Perinatal undernutrition affects the hippocampus, a brain region crucial for learning and memory. However, far less is known about the changes of dendritic spine density and morphology related to hippocampal synaptic plasticity. As dendritic spines are dynamic structures essential for synaptic plasticity and serve as the primary post-synaptic location of the excitatory neurotransmission that underlies learning and memory, the aim of the present study was to investigate whether the perinatal undernutrition affected hippocampal synaptic plasticity accompanied by the change of dendritic spines in anesthetized rats. An input-output curve was first determined using the measurements of field excitatory postsynaptic potential (fEPSP) slope in response to a series of stimulation intensities. Long-term potentiation (LTP) induced by high-frequency stimulation was recorded in the Schaffer collateral-CA1 pathway. Post-tetanic potentiation derived from the fEPSP slope was also measured immediately after LTP induction. Quantitative data of dendritic spines from hippocampal CA1 pyramidal cells were obtained using Golgi staining. The results showed that 50% perinatal food restriction (FR50) impaired the magnitude of LTP of the fEPSP slope in the Schaffer collateral-CA1 pathway. Additionally, FR50 reduced overall spine densities in both basal dendrites and apical dendrites of hippocampal CA1 pyramidal cells. Moreover, FR50 reduced type densities of thin and mushroom spines in apical dendrites, whereas a reduction in the type of mushroom spines was only observed in the basal dendrites of hippocampal CA1 pyramidal cells. These findings suggested that perinatal undernutrition decreased excitatory synaptic input and further affected the processing of information in a given network by selectively reducing the number of special dendritic spines. Thus, these changes in the density and the types of dendritic spines in CA1 pyramidal neurons may partly explain the impaired hippocampal

  10. Input Specificity and Dependence of Spike Timing–Dependent Plasticity on Preceding Postsynaptic Activity at Unitary Connections between Neocortical Layer 2/3 Pyramidal Cells

    PubMed Central

    Holmgren, Carl; Shemer, Isaac; Silberberg, Gilad; Grillner, Sten; Harkany, Tibor

    2009-01-01

    Layer 2/3 (L2/3) pyramidal cells receive excitatory afferent input both from neighbouring pyramidal cells and from cortical and subcortical regions. The efficacy of these excitatory synaptic inputs is modulated by spike timing–dependent plasticity (STDP). Here we report that synaptic connections between L2/3 pyramidal cell pairs are located proximal to the soma, at sites overlapping those of excitatory inputs from other cortical layers. Nevertheless, STDP at L2/3 pyramidal to pyramidal cell connections showed fundamental differences from known STDP rules at these neighbouring contacts. Coincident low-frequency pre- and postsynaptic activation evoked only LTD, independent of the order of the pre- and postsynaptic cell firing. This symmetric anti-Hebbian STDP switched to a typical Hebbian learning rule if a postsynaptic action potential train occurred prior to the presynaptic stimulation. Receptor dependence of LTD and LTP induction and their pre- or postsynaptic loci also differed from those at other L2/3 pyramidal cell excitatory inputs. Overall, we demonstrate a novel means to switch between STDP rules dependent on the history of postsynaptic activity. We also highlight differences in STDP at excitatory synapses onto L2/3 pyramidal cells which allow for input specific modulation of synaptic gain. PMID:19193711

  11. Thrombin induces ischemic LTP (iLTP): implications for synaptic plasticity in the acute phase of ischemic stroke

    PubMed Central

    Stein, Efrat Shavit; Itsekson-Hayosh, Zeev; Aronovich, Anna; Reisner, Yair; Bushi, Doron; Pick, Chaim G.; Tanne, David; Chapman, Joab; Vlachos, Andreas; Maggio, Nicola

    2015-01-01

    Acute brain ischemia modifies synaptic plasticity by inducing ischemic long-term potentiation (iLTP) of synaptic transmission through the activation of N-Methyl-D-aspartate receptors (NMDAR). Thrombin, a blood coagulation factor, affects synaptic plasticity in an NMDAR dependent manner. Since its activity and concentration is increased in brain tissue upon acute stroke, we sought to clarify whether thrombin could mediate iLTP through the activation of its receptor Protease-Activated receptor 1 (PAR1). Extracellular recordings were obtained in CA1 region of hippocampal slices from C57BL/6 mice. In vitro ischemia was induced by acute (3 minutes) oxygen and glucose deprivation (OGD). A specific ex vivo enzymatic assay was employed to assess thrombin activity in hippocampal slices, while OGD-induced changes in prothrombin mRNA levels were assessed by (RT)qPCR. Upon OGD, thrombin activity increased in hippocampal slices. A robust potentiation of excitatory synaptic strength was detected, which occluded the ability to induce further LTP. Inhibition of either thrombin or its receptor PAR1 blocked iLTP and restored the physiological, stimulus induced LTP. Our study provides important insights on the early changes occurring at excitatory synapses after ischemia and indicates the thrombin/PAR1 pathway as a novel target for developing therapeutic strategies to restore synaptic function in the acute phase of ischemic stroke. PMID:25604482

  12. KCNQ/Kv7 channel activator flupirtine protects against acute stress-induced impairments of spatial memory retrieval and hippocampal LTP in rats.

    PubMed

    Li, C; Huang, P; Lu, Q; Zhou, M; Guo, L; Xu, X

    2014-11-07

    Spatial memory retrieval and hippocampal long-term potentiation (LTP) are impaired by stress. KCNQ/Kv7 channels are closely associated with memory and the KCNQ/Kv7 channel activator flupirtine represents neuroprotective effects. This study aims to test whether KCNQ/Kv7 channel activation prevents acute stress-induced impairments of spatial memory retrieval and hippocampal LTP. Rats were placed on an elevated platform in the middle of a bright room for 30 min to evoke acute stress. The expression of KCNQ/Kv7 subunits was analyzed at 1, 3 and 12 h after stress by Western blotting. Spatial memory was examined by the Morris water maze (MWM) and the field excitatory postsynaptic potential (fEPSP) in the hippocampal CA1 area was recorded in vivo. Acute stress transiently decreased the expression of KCNQ2 and KCNQ3 in the hippocampus. Acute stress impaired the spatial memory retrieval and hippocampal LTP, the KCNQ/Kv7 channel activator flupirtine prevented the impairments, and the protective effects of flupirtine were blocked by XE-991 (10,10-bis(4-Pyridinylmethyl)-9(10H)-anthracenone), a selective KCNQ channel blocker. Furthermore, acute stress decreased the phosphorylation of glycogen synthase kinase-3β (GSK-3β) at Ser9 in the hippocampus, and flupirtine inhibited the reduction. These results suggest that the KCNQ/Kv7 channels may be a potential target for protecting both hippocampal synaptic plasticity and spatial memory retrieval from acute stress influences.

  13. Genetics Home Reference: lissencephaly with cerebellar hypoplasia

    MedlinePlus

    ... Conditions lissencephaly with cerebellar hypoplasia lissencephaly with cerebellar hypoplasia Enable Javascript to view the expand/collapse boxes. ... Open All Close All Description Lissencephaly with cerebellar hypoplasia (LCH) affects brain development, resulting in the brain ...

  14. New operational mode of the pencil beam interferometry based LTP

    NASA Astrophysics Data System (ADS)

    Centers, Gary; Smith, Brian V.; Yashchuk, Valeriy V.

    2016-09-01

    The advent of fully coherent free electron laser and diffraction limited synchrotron storage ring sources of x-rays is catalyzing the development of new ultra-high accuracy metrology methods. To fully exploit the potential of these sources, metrology needs to be capable of determining the figure of an optical element with sub-nanometer height accuracy. Currently, the two most prevalent slope measuring instruments used for characterization of x-ray optics are the auto-collimator based nanometer optical measuring device (NOM) and the long trace profiler (LTP) using pencil beam interferometry. These devices have been consistently improved upon by the x-ray optics metrology community, but appear to be approaching their metrological limits. Here, we consider a novel operational mode for the LTP. The fundamental measuring principle of the LTP is reviewed, and a suggested mode of operation is analytically derived. This mode of operation leads to significant suppression of the instrumental systematic errors. Via cross-comparison measurement with the LTP in old and new modes, the performance of the profiler in the new mode is investigated. We also discuss potential areas of further development, including the possibility for local curvature measurement.

  15. Presynaptic GluN2D receptors detect glutamate spillover and regulate cerebellar GABA release

    PubMed Central

    Dubois, Christophe J.; Lachamp, Philippe M.; Sun, Lu; Mishina, Masayoshi

    2015-01-01

    Glutamate directly activates N-methyl-d-aspartate (NMDA) receptors on presynaptic inhibitory interneurons and enhances GABA release, altering the excitatory-inhibitory balance within a neuronal circuit. However, which class of NMDA receptors is involved in the detection of glutamate spillover is not known. GluN2D subunit-containing NMDA receptors are ideal candidates as they exhibit a high affinity for glutamate. We now show that cerebellar stellate cells express both GluN2B and GluN2D NMDA receptor subunits. Genetic deletion of GluN2D subunits prevented a physiologically relevant, stimulation-induced, lasting increase in GABA release from stellate cells [long-term potentiation of inhibitory transmission (I-LTP)]. NMDA receptors are tetramers composed of two GluN1 subunits associated to either two identical subunits (di-heteromeric receptors) or to two different subunits (tri-heteromeric receptors). To determine whether tri-heteromeric GluN2B/2D NMDA receptors mediate I-LTP, we tested the prediction that deletion of GluN2D converts tri-heteromeric GluN2B/2D to di-heteromeric GluN2B NMDA receptors. We find that prolonged stimulation rescued I-LTP in GluN2D knockout mice, and this was abolished by GluN2B receptor blockers that failed to prevent I-LTP in wild-type mice. Therefore, NMDA receptors that contain both GluN2D and GluN2B mediate the induction of I-LTP. Because these receptors are not present in the soma and dendrites, presynaptic tri-heteromeric GluN2B/2D NMDA receptors in inhibitory interneurons are likely to mediate the cross talk between excitatory and inhibitory transmission. PMID:26510761

  16. [Cerebellar cognitive affective syndrome secondary to a cerebellar tumour].

    PubMed

    Domínguez-Carral, J; Carreras-Sáez, I; García-Peñas, J J; Fournier-Del Castillo, C; Villalobos-Reales, J

    2015-01-01

    Cerebellar cognitive affective syndrome is characterized by disturbances of executive function, impaired spatial cognition, linguistic difficulties, and personality change. The case of an 11 year old boy is presented, with behavior problems, learning difficulties and social interaction problems. In the physical examination he had poor visual contact, immature behavior, reduced expressive language and global motor disability with gait dyspraxia, with no defined cerebellar motor signs. In the neuropsychological evaluation he has a full scale overall intellectual quotient of 84, with signs of cerebellar cognitive affective syndrome. A tumour affecting inferior cerebellar vermis was observed in the magnetic resonance imaging, which had not significantly grown during 5 years of follow up. The cerebellum participates in controlling cognitive and affective functions. Cerebellar pathology must be considered in the differential diagnosis of children with cognitive or learning disorder with associated behavioral and emotional components.

  17. Flavoprotein imaging in the cerebellar cortex in vivo: cellular and metabolic basis and insights into cerebellar function

    NASA Astrophysics Data System (ADS)

    Gao, Wangcai; Chen, Gang; Ebner, Timothy J.

    2009-02-01

    Flavoprotein autofluorescence is an activity dependent intrinsic signal. Flavoproteins are involved in the electron transport chain and change their fluorescence according to the cellular redox state. We have been using flavoprotein autofluorescence in the cerebellum to examine properties of cerebellar circuits. Studies have also focused on understanding the cellular and metabolic origins of this intrinsic optical signal. Parallel fiber stimulation evokes a beamlike response intersected by bands of decreased fluorescence. The beam response is biphasic, with an early fluorescence increase (light phase) followed by a slower decrease (dark phase). We show this signal originates from flavoproteins as determined by its wavelength selectivity and sensitivity to blockers of the electron transport chain. Selectively blocking glutamate receptors abolished the on-beam light phase with the dark phase remaining intact. This demonstrates that the light phase is due to postsynaptic neuronal activation and suggests the dark phase is primarily due to glial activation. The bands of reduced fluorescence intersecting the beam are primarily neuronal in origin, mediated by GABAergic transmission, and due to the inhibitory action of molecular layer interneurons on Purkinje cells and the interneurons themselves. This parasagittally organized molecular layer inhibition differentially modulates the spatial pattern of cerebellar cortical activity. Flavoprotein imaging also reveals the functional architectures underlying the responses to inferior olive and peripheral whisker pad stimulation. Therefore, flavoprotein autofluorescence imaging is providing new insights into cerebellar cortical function and neurometabolic coupling.

  18. At immature mossy-fiber-CA3 synapses, correlated presynaptic and postsynaptic activity persistently enhances GABA release and network excitability via BDNF and cAMP-dependent PKA.

    PubMed

    Sivakumaran, Sudhir; Mohajerani, Majid H; Cherubini, Enrico

    2009-02-25

    In the adult rat hippocampus, the axons of granule cells in the dentate gyrus, the mossy fibers (MF), form excitatory glutamatergic synapses with CA3 principal cells. In neonates, MF release into their targets mainly GABA, which at this developmental stage is depolarizing. Here we tested the hypothesis that, at immature MF-CA3 synapses, correlated presynaptic [single fiber-evoked GABA(A)-mediated postsynaptic potentials (GPSPs)] and postsynaptic activity (back propagating action potentials) may exert a critical control on synaptic efficacy. This form of plasticity, called spike-timing-dependent plasticity (STDP), is a Hebbian type form of learning extensively studied at the level of glutamatergic synapses. Depending on the relative timing, pairing postsynaptic spiking and single MF-GPSPs induced bidirectional changes in synaptic efficacy. In case of positive pairing, spike-timing-dependent-long-term potentiation (STD-LTP) was associated with a persistent increase in GPSP slope and in the probability of cell firing. The transduction pathway involved a rise of calcium in the postsynaptic cell and the combined activity of cAMP-dependent PKA (protein kinase A) and brain-derived neurotrophic factor (BDNF). Retrograde signaling via BDNF and presynaptic TrkB receptors led to a persistent increase in GABA release. In "presynaptically" silent neurons, the enhanced probability of GABA release induced by the pairing protocol, unsilenced these synapses. Shifting E(GABA) from the depolarizing to the hyperpolarizing direction with bumetanide failed to modify synaptic strength. Thus, STD-LTP of GPSPs provides a reliable way to convey information from granule cells to the CA3 associative network at a time when glutamatergic synapses are still poorly developed.

  19. Endogenous opioid peptides contribute to associative LTP in the hippocampal CA3 region.

    PubMed

    Martinez, Carlo O; Do, Viet H; Derrick, Brian E

    2011-09-01

    The medial and lateral perforant path projections to the hippocampal CA3 region display distinct mechanisms of long-term potentiation (LTP) induction, N-methyl-d-aspartate (NMDA) and opioid receptor dependent, respectively. However, medial and lateral perforant path projections to the CA3 region display associative LTP with coactivation, suggesting that while they differ in receptors involved in LTP induction they may share common downstream mechanisms of LTP induction. Here we address this interaction of LTP induction mechanisms by evaluating the contribution of opioid receptors to the induction of associative LTP among the medial and lateral perforant path projections to the CA3 region in vivo. Local application of the opioid receptor antagonists naloxone or Cys2-Tyr3-Orn5-Pen7-amide (CTOP) normally block induction of lateral perforant path-CA3 LTP. However, these opioid receptor antagonists failed to block associative LTP in lateral perforant path-CA3 synapses when it was induced by strong coactivation of the medial perforant pathway which displays NMDAR-dependent LTP. Thus strong activation of non-opioidergic afferents can substitute for the opioid receptor activation required for lateral perforant path LTP induction. Conversely, medial perforant path-CA3 associative LTP was blocked by opioid receptor antagonists when induced by strong coactivation of the opioidergic lateral perforant path. These data indicate endogenous opioid peptides contribute to associative LTP at coactive synapses when induced by strong coactivation of an opioidergic afferent system. These data further suggest that associative LTP induction is regulated by the receptor mechanisms of the strongly stimulated pathway. Thus, while medial and lateral perforant path synapses differ in their mechanisms of LTP induction, associative LTP at these synapses share common downstream mechanisms of induction.

  20. Childhood Cerebellar Ataxia

    PubMed Central

    Fogel, Brent L.

    2012-01-01

    Childhood presentations of ataxia, an impairment of balance and coordination caused by damage to or dysfunction of the cerebellum, can often be challenging to diagnose. Presentations tend to be clinically heterogeneous but key considerations may vary based on the child's age at onset, the course of illness, and subtle differences in phenotype. Systematic investigation is recommended for efficient diagnosis. In this review, we outline common etiologies and describe a comprehensive approach to the evaluation of both acquired and genetic cerebellar ataxia in children. PMID:22764177

  1. Postsynaptic Signal Transduction Models for Long-Term Potentiation and Depression

    PubMed Central

    Manninen, Tiina; Hituri, Katri; Kotaleski, Jeanette Hellgren; Blackwell, Kim T.; Linne, Marja-Leena

    2010-01-01

    More than a hundred biochemical species, activated by neurotransmitters binding to transmembrane receptors, are important in long-term potentiation (LTP) and long-term depression (LTD). To investigate which species and interactions are critical for synaptic plasticity, many computational postsynaptic signal transduction models have been developed. The models range from simple models with a single reversible reaction to detailed models with several hundred kinetic reactions. In this study, more than a hundred models are reviewed, and their features are compared and contrasted so that similarities and differences are more readily apparent. The models are classified according to the type of synaptic plasticity that is modeled (LTP or LTD) and whether they include diffusion or electrophysiological phenomena. Other characteristics that discriminate the models include the phase of synaptic plasticity modeled (induction, expression, or maintenance) and the simulation method used (deterministic or stochastic). We find that models are becoming increasingly sophisticated, by including stochastic properties, integrating with electrophysiological properties of entire neurons, or incorporating diffusion of signaling molecules. Simpler models continue to be developed because they are computationally efficient and allow theoretical analysis. The more complex models permit investigation of mechanisms underlying specific properties and experimental verification of model predictions. Nonetheless, it is difficult to fully comprehend the evolution of these models because (1) several models are not described in detail in the publications, (2) only a few models are provided in existing model databases, and (3) comparison to previous models is lacking. We conclude that the value of these models for understanding molecular mechanisms of synaptic plasticity is increasing and will be enhanced further with more complete descriptions and sharing of the published models. PMID:21188161

  2. Crossed Cerebellar Diaschisis

    PubMed Central

    Han, Shuguang; Wang, Xiaopeng; Xu, Kai; Hu, Chunfeng

    2016-01-01

    Abstract Crossed cerebellar diaschisis (CCD) describes a depression of oxidative metabolism glucose and blood flow in the cerebellum secondary to a supratentorial lesion in the contralateral cerebral hemisphere. PET/MR has the potential to become a powerful tool for demonstrating and imaging intracranial lesions .We herein report 3 cases of CCD imaging using a tri-modality PET/CT–MR set-up for investigating the value of adding MRI rather than CT to PET in clinical routine. We describe 3 patients with CCD and neurological symptoms in conjunction with abnormal cerebral fluorodeoxyglucose (FDG) positron emission tomography/computed tomography-magnetic resonance imaging (PET/CT–MR) manifestations including arterial spin-labeling (ASL) and T2-weighted images. In all, 18FDG-PET/CT detected positive FDG uptake in supratentorial lesions, and hypometabolism with atrophy in the contralateral cerebellum. More than that, hybrid PET/MRI provided a more accurate anatomic localization and ASL indicated disruption of the cortico-ponto-cerebellar pathway. Using pathology or long-term clinical follow-up to confirm the PET and ASL findings, the supratentorial lesions of the 3 patients were respectively diagnosed with cerebral infarction, recurrent glioma, and metastasis. The reports emphasize the significance of multimodality radiological examinations. Multimodality imaging contributes to proper diagnosis, management, and follow-up of supratentorial lesions with CCD. PMID:26765477

  3. Nicotine recruits glutamate receptors to postsynaptic sites.

    PubMed

    Duan, Jing-Jing; Lozada, Adrian F; Gou, Chen-Yu; Xu, Jing; Chen, Yuan; Berg, Darwin K

    2015-09-01

    Cholinergic neurons project throughout the nervous system and activate nicotinic receptors to modulate synaptic function in ways that shape higher order brain function. The acute effects of nicotinic signaling on long-term synaptic plasticity have been well-characterized. Less well understood is how chronic exposure to low levels of nicotine, such as those encountered by habitual smokers, can alter neural connections to promote addiction and other lasting behavioral effects. We show here that chronic exposure of hippocampal neurons in culture to low levels of nicotine recruits AMPA and NMDA receptors to the cell surface and sequesters them at postsynaptic sites. The receptors include GluA2-containing AMPA receptors, which are responsible for most of the excitatory postsynaptic current mediated by AMPA receptors on the neurons, and include NMDA receptors containing GluN1 and GluN2B subunits. Moreover, we find that the nicotine treatment also increases expression of the presynaptic component synapsin 1 and arranges it in puncta juxtaposed to the additional AMPA and NMDA receptor puncta, suggestive of increases in synaptic contacts. Consistent with increased synaptic input, we find that the nicotine treatment leads to an increase in the excitatory postsynaptic currents mediated by AMPA and NMDA receptors. Further, the increases skew the ratio of excitatory-to-inhibitory input that the cell receives, and this holds both for pyramidal neurons and inhibitory neurons in the hippocampal CA1 region. The GluN2B-containing NMDA receptor redistribution at synapses is associated with a significant increase in GluN2B phosphorylation at Tyr1472, a site known to prevent GluN2B endocytosis. These results suggest that chronic exposure to low levels of nicotine not only alters functional connections but also is likely to change excitability levels across networks. Further, it may increase the propensity for synaptic plasticity, given the increase in synaptic NMDA receptors.

  4. Nicotine Recruits Glutamate Receptors to Postsynaptic Sites

    PubMed Central

    Duan, Jing-jing; Lozada, Adrian F.; Gou, Chen-yu; Xu, Jing; Chen, Yuan; Berg, Darwin K.

    2015-01-01

    Cholinergic neurons project throughout the nervous system and activate nicotinic receptors to modulate synaptic function in ways that shape higher order brain function. The acute effects of nicotinic signaling on long-term synaptic plasticity have been well-characterized. Less well understood is how chronic exposure to low levels of nicotine, such as those encountered by habitual smokers, can alter neural connections to promote addiction and other lasting behavioral effects. We show here that chronic exposure of hippocampal neurons in culture to low levels of nicotine recruits AMPA and NMDA receptors to the cell surface and sequesters them at postsynaptic sites. The receptors include GluA2-containing AMPA receptors, which are responsible for most of the excitatory postsynaptic current mediated by AMPA receptors on the neurons, and include NMDA receptors containing GluN1 and GluN2B subunits. Moreover, we find that the nicotine treatment also increases expression of the presynaptic component synapsin 1 and arranges it in puncta juxtaposed to the additional AMPA and NMDA receptor puncta, suggestive of increases in synaptic contacts. Consistent with increased synaptic input, we find that the nicotine treatment leads to an increase in the excitatory postsynaptic currents mediated by AMPA and NMDA receptors. Further, the increases skew the ratio of excitatory-to-inhibitory input the cell receives, and this holds both for pyramidal neurons and inhibitory neurons in the hippocampal CA1 region. The GluN2B-containing NMDA receptor redistribution at synapses is associated with a significant increase in GluN2B phosphorylation at Tyr1472, a site known to prevent GluN2B endocytosis. These results suggest that chronic exposure to low levels of nicotine not only alters functional connections but also is likely to change excitability levels across networks. Further, it may increase the propensity for synaptic plasticity, given the increase in synaptic NMDA receptors. PMID:26365992

  5. Dopamine Induces LTP Differentially in Apical and Basal Dendrites through BDNF and Voltage-Dependent Calcium Channels

    ERIC Educational Resources Information Center

    Navakkode, Sheeja; Sajikumar, Sreedharan; Korte, Martin; Soong, Tuck Wah

    2012-01-01

    The dopaminergic modulation of long-term potentiation (LTP) has been studied well, but the mechanism by which dopamine induces LTP (DA-LTP) in CA1 pyramidal neurons is unknown. Here, we report that DA-LTP in basal dendrites is dependent while in apical dendrites it is independent of activation of L-type voltage-gated calcium channels (VDCC).…

  6. Distinct Single but Not Necessarily Repeated Tetanization Is Required to Induce Hippocampal Late-LTP in the Rat CA1

    ERIC Educational Resources Information Center

    Sajikumar, Sreedharan; Navakkode, Sheeja; Frey, Julietta U.

    2008-01-01

    The protein synthesis-dependent form of hippocampal long-term potentiation (late-LTP) is thought to underlie memory. Its induction requires a distinct stimulation strength, and the common opinion is that only repeated tetani result in late-LTP whereas as single tetanus only reveals a transient early-LTP. Properties of LTP induction were compared…

  7. Early Disruption of Extracellular Pleiotrophin Distribution Alters Cerebellar Neuronal Circuit Development and Function.

    PubMed

    Hamza, M M; Rey, S A; Hilber, P; Arabo, A; Collin, T; Vaudry, D; Burel, D

    2016-10-01

    The cerebellum is a structure of the central nervous system involved in balance, motor coordination, and voluntary movements. The elementary circuit implicated in the control of locomotion involves Purkinje cells, which receive excitatory inputs from parallel and climbing fibers, and are regulated by cerebellar interneurons. In mice as in human, the cerebellar cortex completes its development mainly after birth with the migration, differentiation, and synaptogenesis of granule cells. These cellular events are under the control of numerous extracellular matrix molecules including pleiotrophin (PTN). This cytokine has been shown to regulate the morphogenesis of Purkinje cells ex vivo and in vivo via its receptor PTPζ. Since Purkinje cells are the unique output of the cerebellar cortex, we explored the consequences of their PTN-induced atrophy on the function of the cerebellar neuronal circuit in mice. Behavioral experiments revealed that, despite a normal overall development, PTN-treated mice present a delay in the maturation of their flexion reflex. Moreover, patch clamp recording of Purkinje cells revealed a significant increase in the frequency of spontaneous excitatory postsynaptic currents in PTN-treated mice, associated with a decrease of climbing fiber innervations and an abnormal perisomatic localization of the parallel fiber contacts. At adulthood, PTN-treated mice exhibit coordination impairment on the rotarod test associated with an alteration of the synchronization gait. Altogether these histological, electrophysiological, and behavior data reveal that an early ECM disruption of PTN composition induces short- and long-term defaults in the establishment of proper functional cerebellar circuit.

  8. IL1RAPL1 controls inhibitory networks during cerebellar development in mice.

    PubMed

    Gambino, Frédéric; Kneib, Marie; Pavlowsky, Alice; Skala, Henriette; Heitz, Stéphane; Vitale, Nicolas; Poulain, Bernard; Khelfaoui, Malik; Chelly, Jamel; Billuart, Pierre; Humeau, Yann

    2009-10-01

    Abnormalities in the formation and function of cerebellar circuitry potentially contribute to cognitive deficits in humans. In the adult, the activity of the sole output neurons of the cerebellar cortex - the Purkinje cells (PCs) - is shaped by the balance of activity between local excitatory and inhibitory circuits. However, how this balance is established during development remains poorly understood. Here, we investigate the role of interleukin-1 receptor accessory protein-like 1 (IL1RAPL1), a protein linked to cognitive function which interacts with neuronal calcium sensor 1 (NCS-1) in the development of mouse cerebellum. Using Il1rapl1-deficient mice, we found that absence of IL1RAPL1 causes a transient disinhibition of deep cerebellar nuclei neurons between postnatal days 10 and 14 (P10/P14). Upstream, in the cerebellar cortex, we found developmental perturbations in the activity level of molecular layer interneurons (MLIs), resulting in the premature appearance of giant GABAA-mediated inhibitory post-synaptic currents capable of silencing PCs. Examination of feed-forward recruitment of MLIs by parallel fibres shows that during this P10/P14 time window, MLIs were more responsive to incoming excitatory drive. Thus, we conclude that IL1RAPL1 exerts a key function during cerebellar development in establishing local excitation/inhibition balance.

  9. Unexpected Magnetic Domain Behavior in LTP-MnBi

    SciTech Connect

    Nguyen, PK; Jin, S; Berkowitz, AE

    2013-07-01

    Low-temperature-phase MnBi (LTP-MnBi) has attracted much interest as a potential rare-earth-free permanent magnet material because of its high uniaxial magnetocrystalline anisotropy at room temperature, K approximate to 10(7) ergs/cc, and the unusual increase of anisotropy with increasing temperature, with an accompanying increasing coercive force (H-C) with temperature. However, due to the complex Mn-Bi phase diagram, bulk samples of LTP-MnBi with the optimum saturation moment, similar to 75-76 emu/g have been achieved only with zone-refined single crystals. We have prepared polycrystalline samples of LTP-MnBi by induction melting and annealing at 300 degrees C. The moment in 70 kOe is 73.5 emu/g, but H-C is only 50 Oe. This is quite surprising-the high saturation moment indicates the dominating presence of LTP-MnBi. Therefore, an H-C c of some significant fraction of 2K/M-S approximate to 30 kOe would seem reasonable in this polycrystalline sample. By examining "Bitter" patterns, we show that the sample is composed of similar to 50 - 100 mu m crystallites. The randomly oriented crystallites exhibit the variety of magnetic domain structures and orientations expected from the hexagonal-structured MnBi with its strong uniaxial anisotropy. Clearly, the reversal of magnetization in the sample proceeds by the low-field nucleation of reversed magnetization in each crystallite, rather than by a wall-pinning mechanism. When the annealed sample was milled into fine particles, H-C increased by several orders of magnitude, as expected.

  10. Sex differences in hippocampal long-term potentiation (LTP) and Pavlovian fear conditioning in rats: positive correlation between LTP and contextual learning.

    PubMed

    Maren, S; De Oca, B; Fanselow, M S

    1994-10-24

    Three experiments investigated sex differences in hippocampal long-term potentiation (LTP) and Pavlovian fear conditioning in rats. Experiment 1 revealed a robust sex difference in the magnitude of LTP induced at perforant path synapses in the dentate gyrus of pentobarbital-anesthetized rats. This sex difference in LTP was evident in rats of 35 and 60 days of age and was not the result of pre-LTP sex differences in perforant path synaptic transmission; 20-day-old rats did not show LTP. An analysis of field potentials evoked during LTP induction revealed a sex difference in the magnitude of N-methyl-D-aspartate (NMDA) receptor activation that was highly correlated with the magnitude of LTP. Experiment 2 showed that males condition more fear, measured as freezing, to the contextual conditional stimuli (CSs) of a conditioning chamber compared to their female counterparts. This sex difference in conditional freezing was apparent with both low and high unconditional stimulus (US, footshock) intensities. Experiment 3 revealed that the enhanced fear conditioning in males was specific to contextual CSs, and consisted of a more rapid rate of conditioning. Together, these experiments reveal a positive correlation between the magnitude of hippocampal LTP and a form of learning that depends on the hippocampus. Furthermore, they suggest a neural basis for sex differences in hippocampus-dependent learning tasks.

  11. Autosomal recessive cerebellar ataxias

    PubMed Central

    Palau, Francesc; Espinós, Carmen

    2006-01-01

    Autosomal recessive cerebellar ataxias (ARCA) are a heterogeneous group of rare neurological disorders involving both central and peripheral nervous system, and in some case other systems and organs, and characterized by degeneration or abnormal development of cerebellum and spinal cord, autosomal recessive inheritance and, in most cases, early onset occurring before the age of 20 years. This group encompasses a large number of rare diseases, the most frequent in Caucasian population being Friedreich ataxia (estimated prevalence 2–4/100,000), ataxia-telangiectasia (1–2.5/100,000) and early onset cerebellar ataxia with retained tendon reflexes (1/100,000). Other forms ARCA are much less common. Based on clinicogenetic criteria, five main types ARCA can be distinguished: congenital ataxias (developmental disorder), ataxias associated with metabolic disorders, ataxias with a DNA repair defect, degenerative ataxias, and ataxia associated with other features. These diseases are due to mutations in specific genes, some of which have been identified, such as frataxin in Friedreich ataxia, α-tocopherol transfer protein in ataxia with vitamin E deficiency (AVED), aprataxin in ataxia with oculomotor apraxia (AOA1), and senataxin in ataxia with oculomotor apraxia (AOA2). Clinical diagnosis is confirmed by ancillary tests such as neuroimaging (magnetic resonance imaging, scanning), electrophysiological examination, and mutation analysis when the causative gene is identified. Correct clinical and genetic diagnosis is important for appropriate genetic counseling and prognosis and, in some instances, pharmacological treatment. Due to autosomal recessive inheritance, previous familial history of affected individuals is unlikely. For most ARCA there is no specific drug treatment except for coenzyme Q10 deficiency and abetalipoproteinemia. PMID:17112370

  12. MULTIPLE FUNCTIONS LONG TRACE PROFILER (LTP-MF) FOR NATIONAL SYNCHROTRON RADIATION LABORATORY OF CHINA.

    SciTech Connect

    QIAN, S.; WANG, Q.; HONG, Y.; TAKACS, P.

    2005-07-31

    The Long Trace Profiler (LTP) is a useful optical metrology instrument for measuring the figure and slope error of cylindrical aspheres commonly used as synchrotron radiation (SR) optics. It is used extensively at a number of synchrotron radiation laboratories around the world. In order to improve SR beam line quality and resolution, the National Synchrotron Radiation Laboratory (NSRL) of China is developing a versatile LTP that can be used to measure both SR optics and more conventional ''normal'' optical surfaces. The optical metrology laboratories at Brookhaven National Laboratory (BNL) and NSRL are collaborating in developing a multiple functions LTP (LTP-MF). Characteristics of the LTP-MF are: a very compact and lightweight optical head, a large angular test range ({+-} 16 mad) and high accuracy. The LTP-MF can be used in various configurations: as a laboratory-based LTP, an in-situ LTP or penta-prism LTP, as an angle monitor, a portable LTP, and a small radius of curvature test instrument. The schematic design of the compact optical head and a new compact slide are introduced. Analysis of different measurements modes and systematic error correction methods are introduced.

  13. Regulatory function of Arabidopsis lipid transfer protein 1 (LTP1) in ethylene response and signaling.

    PubMed

    Wang, Honglin; Sun, Yue; Chang, Jianhong; Zheng, Fangfang; Pei, Haixia; Yi, Yanjun; Chang, Caren; Dong, Chun-Hai

    2016-07-01

    Ethylene as a gaseous plant hormone is directly involved in various processes during plant growth and development. Much is known regarding the ethylene receptors and regulatory factors in the ethylene signal transduction pathway. In Arabidopsis thaliana, REVERSION-TO-ETHYLENE SENSITIVITY1 (RTE1) can interact with and positively regulates the ethylene receptor ETHYLENE RESPONSE1 (ETR1). In this study we report the identification and characterization of an RTE1-interacting protein, a putative Arabidopsis lipid transfer protein 1 (LTP1) of unknown function. Through bimolecular fluorescence complementation, a direct molecular interaction between LTP1 and RTE1 was verified in planta. Analysis of an LTP1-GFP fusion in transgenic plants and plasmolysis experiments revealed that LTP1 is localized to the cytoplasm. Analysis of ethylene responses showed that the ltp1 knockout is hypersensitive to 1-aminocyclopropanecarboxylic acid (ACC), while LTP1 overexpression confers insensitivity. Analysis of double mutants etr1-2 ltp1 and rte1-3 ltp1 demonstrates a regulatory function of LTP1 in ethylene receptor signaling through the molecular association with RTE1. This study uncovers a novel function of Arabidopsis LTP1 in the regulation of ethylene response and signaling.

  14. Hippocampal and cerebellar mossy fibre boutons – same name, different function

    PubMed Central

    Delvendahl, Igor; Weyhersmüller, Annika; Ritzau-Jost, Andreas; Hallermann, Stefan

    2013-01-01

    Over a century ago, the Spanish anatomist Ramón y Cajal described ‘mossy fibres’ in the hippocampus and the cerebellum, which contain several presynaptic boutons. Technical improvements in recent decades have allowed direct patch-clamp recordings from both hippocampal and cerebellar mossy fibre boutons (hMFBs and cMFBs, respectively), making them ideal models to study fundamental properties of synaptic transmission. hMFBs and cMFBs have similar size and shape, but each hMFB contacts one postsynaptic hippocampal CA3 pyramidal neuron, while each cMFB contacts ∼50 cerebellar granule cells. Furthermore, hMFBs and cMFBs differ in terms of their functional specialization. At hMFBs, a large number of release-ready vesicles and low release probability (<0.1) contribute to marked synaptic facilitation. At cMFBs, a small number of release-ready vesicles, high release probability (∼0.5) and rapid vesicle reloading result in moderate frequency-dependent synaptic depression. These presynaptic mechanisms, in combination with faster postsynaptic currents of cerebellar granule cells compared with hippocampal CA3 pyramidal neurons, enable much higher transmission frequencies at cMFB compared with hMFB synapses. Analysing the underling mechanisms of synaptic transmission and information processing represents a fascinating challenge and may reveal insights into the structure–function relationship of the human brain. PMID:23297303

  15. Redistribution of crossed cerebellar diaschisis

    SciTech Connect

    Kim, S.M.; Park, C.H.; Intenzo, C.M.; Bell, R.

    1989-04-01

    Crossed cerebellar diaschisis refers to a functional decrease in blood flow to the cerebellar hemisphere contralateral to the infarcted or ischemic cerebral hemisphere. This phenomenon can be depicted using PET as well as using SPECT. This condition, seen on early I-123 IMP brain scans, can show redistribution on the three hour delayed scan, presumably due to normal non-specific amine receptor sites of the affected cerebellum. One such case is reported.

  16. Speech prosody in cerebellar ataxia

    NASA Astrophysics Data System (ADS)

    Casper, Maureen

    The present study sought an acoustic signature for the speech disturbance recognized in cerebellar degeneration. Magnetic resonance imaging was used for a radiological rating of cerebellar involvement in six cerebellar ataxic dysarthric speakers. Acoustic measures of the [pap] syllables in contrastive prosodic conditions and of normal vs. brain-damaged patients were used to further our understanding both of the speech degeneration that accompanies cerebellar pathology and of speech motor control and movement in general. Pair-wise comparisons of the prosodic conditions within the normal group showed statistically significant differences for four prosodic contrasts. For three of the four contrasts analyzed, the normal speakers showed both longer durations and higher formant and fundamental frequency values in the more prominent first condition of the contrast. The acoustic measures of the normal prosodic contrast values were then used as a model to measure the degree of speech deterioration for individual cerebellar subjects. This estimate of speech deterioration as determined by individual differences between cerebellar and normal subjects' acoustic values of the four prosodic contrasts was used in correlation analyses with MRI ratings. Moderate correlations between speech deterioration and cerebellar atrophy were found in the measures of syllable duration and f0. A strong negative correlation was found for F1. Moreover, the normal model presented by these acoustic data allows for a description of the flexibility of task- oriented behavior in normal speech motor control. These data challenge spatio-temporal theory which explains movement as an artifact of time wherein longer durations predict more extreme movements and give further evidence for gestural internal dynamics of movement in which time emerges from articulatory events rather than dictating those events. This model provides a sensitive index of cerebellar pathology with quantitative acoustic

  17. A Study of the Spatial Protein Organization of the Postsynaptic Density Isolated from Porcine Cerebral Cortex and Cerebellum

    PubMed Central

    Yun-Hong, Yen; Chih-Fan, Chuang; Chia-Wei, Chang; Yen-Chung, Chang

    2011-01-01

    Postsynaptic density (PSD) is a protein supramolecule lying underneath the postsynaptic membrane of excitatory synapses and has been implicated to play important roles in synaptic structure and function in mammalian central nervous system. Here, PSDs were isolated from two distinct regions of porcine brain, cerebral cortex and cerebellum. SDS-PAGE and Western blotting analyses indicated that cerebral and cerebellar PSDs consisted of a similar set of proteins with noticeable differences in the abundance of various proteins between these samples. Subsequently, protein localization in these PSDs was analyzed by using the Nano-Depth-Tagging method. This method involved the use of three synthetic reagents, as agarose beads whose surface was covalently linked with a fluorescent, photoactivable, and cleavable chemical crosslinker by spacers of varied lengths. After its application was verified by using a synthetic complex consisting of four layers of different proteins, the Nano-Depth-Tagging method was used here to yield information concerning the depth distribution of various proteins in the PSD. The results indicated that in both cerebral and cerebellar PSDs, glutamate receptors, actin, and actin binding proteins resided in the peripheral regions within ∼10 nm deep from the surface and that scaffold proteins, tubulin subunits, microtubule-binding proteins, and membrane cytoskeleton proteins found in mammalian erythrocytes resided in the interiors deeper than 10 nm from the surface in the PSD. Finally, by using the immunoabsorption method, binding partner proteins of two proteins residing in the interiors, PSD-95 and α-tubulin, and those of two proteins residing in the peripheral regions, elongation factor-1α and calcium, calmodulin-dependent protein kinase II α subunit, of cerebral and cerebellar PSDs were identified. Overall, the results indicate a striking similarity in protein organization between the PSDs isolated from porcine cerebral cortex and cerebellum. A

  18. The initiation of post-synaptic protrusions

    PubMed Central

    Hotulainen, Pirta; Saarikangas, Juha

    2016-01-01

    ABSTRACT The post-synaptic spines of neuronal dendrites are highly elaborate membrane protrusions. Their anatomy, stability and density are intimately linked to cognitive performance. The morphological transitions of spines are powered by coordinated polymerization of actin filaments against the plasma membrane, but how the membrane-associated polymerization is spatially and temporally regulated has remained ill defined. Here, we discuss our recent findings showing that dendritic spines can be initiated by direct membrane bending by the I-BAR protein MIM/Mtss1. This lipid phosphatidylinositol (PI(4,5)P2) signaling-activated membrane bending coordinated spatial actin assembly and promoted spine formation. From recent advances, we formulate a general model to discuss how spatially concentrated protein-lipid microdomains formed by multivalent interactions between lipids and actin/membrane regulatory proteins might launch cell protrusions. PMID:27489575

  19. The Characteristics of LTP Induced in Hippocampal Slices Are Dependent on Slice-Recovery Conditions

    ERIC Educational Resources Information Center

    Godaux, Emile; Ris, Laurence; Capron, Brigitte; Sindic, Christian

    2006-01-01

    In area CA1 of hippocampal slices which are allowed to recover from slicing "in interface" and where recordings are carried out in interface, a single 1-sec train of 100-Hz stimulation triggers a short-lasting long-term potentiation (S-LTP), which lasts 1-2 h, whereas multiple 1-sec trains induce a long-lasting LTP (L-LTP), which lasts several…

  20. Agonist-Dependent Postsynaptic Effects of Opioids on Miniature Excitatory Postsynaptic Currents in Cultured Hippocampal Neurons

    PubMed Central

    Liao, Dezhi; Grigoriants, Olga O.; Loh, Horace H.; Law, Ping-Yee

    2006-01-01

    Although chronic treatment with morphine is known to alter the function and morphology of excitatory synapses, the effects of other opioids on these synapses are not clear. Here we report distinct effects of several opioids (morphine, DAMGO and etorphine) on miniature excitatory postsynaptic currents (mEPSCs) in cultured hippocampal neurons: (1) Chronic treatment with morphine for > 3 days decreased the amplitude, frequency, rise time and decay time of mEPSCs. In contrast, “internalizing” opioids such as etorphine and DAMGO increased the frequency of mEPSCs and had no significant effect on the amplitude and kinetics of mEPSCs. These results demonstrate that different opioids can have distinct effects on the function of excitatory synapses. (2) MOR-GFP is clustered in dendritic spines in most hippocampal neurons but is concentrated in axon-like processes in striatal and corticostriatal non-spiny neurons. It suggests that MORs might mediate pre- or post-synaptic effects depending upon cell types. (3) Neurons were cultured from MOR knock-out mice and were exogenously transfected with GFP-tagged MORs (MOR-GFP). Chronic treatment with morphine suppressed mEPSCs only in neurons that contained postsynaptic MOR-GFP, indicating thatopioids can modulate excitatory synaptic transmission postsynaptically. (4) Morphine acutely decreased mEPSC amplitude in neurons expressing exogenous MOR-GFP, but had no effect on neurons expressing GFP. It indicates that the low level of endogenous MORs could only allow slow opioid-induced plasticity of excitatory synapses under normal conditions. (5) A theoretical model suggests that morphine might affect the function of spines by decreasing the electrotonic distance from synaptic inputs to the soma. PMID:17122315

  1. Delayed release of neurotransmitter from cerebellar granule cells.

    PubMed

    Atluri, P P; Regehr, W G

    1998-10-15

    At fast chemical synapses the rapid release of neurotransmitter that occurs within a few milliseconds of an action potential is followed by a more sustained elevation of release probability, known as delayed release. Here we characterize the role of calcium in delayed release and test the hypothesis that facilitation and delayed release share a common mechanism. Synapses between cerebellar granule cells and their postsynaptic targets, stellate cells and Purkinje cells, were studied in rat brain slices. Presynaptic calcium transients were measured with calcium-sensitive fluorophores, and delayed release was detected with whole-cell recordings. Calcium influx, presynaptic calcium dynamics, and the number of stimulus pulses were altered to assess their effect on delayed release and facilitation. Following single stimuli, delayed release can be separated into two components: one lasting for tens of milliseconds that is steeply calcium-dependent, the other lasting for hundreds of milliseconds that is driven by low levels of calcium with a nearly linear calcium dependence. The amplitude, calcium dependence, and magnitude of delayed release do not correspond to those of facilitation, indicating that these processes are not simple reflections of a shared mechanism. The steep calcium dependence of delayed release, combined with the large calcium transients observed in these presynaptic terminals, suggests that for physiological conditions delayed release provides a way for cells to influence their postsynaptic targets long after their own action potential activity has subsided.

  2. NsLTP1 and NsLTP2 isoforms in soft wheat (Triticum aestivum Cv. Centauro) and farro (Triticum dicoccon Schrank) bran.

    PubMed

    Capocchi, Antonella; Fontanini, Debora; Muccilli, Vera; Cunsolo, Vincenzo; Saviozzi, Franco; Saletti, Rosaria; Lorenzi, Roberto; Foti, Salvatore; Galleschi, Luciano

    2005-10-05

    Isoforms of nonspecific lipid-transfer protein 1 (nsLTP1) and nonspecific lipid-transfer protein 2 (nsLTP2) were investigated in bran tissues isolated from caryopses of two cereal crops quite relevant for the Italian market, the cultivar Centauro of soft wheat (Triticum aestivum) and Italian emmer or farro (Triticum dicoccon Schrank). By sequential separation of the bran extracts on cation-exchange and gel filtration chromatographies, fractions containing only proteins belonging to the nsLTP1 and nsLTP2 classes were obtained. The proteins were roughly identified by SDS-PAGE and by immunoreactions in Western blotting experiments. By MALDI-MS and RP-HPLC/ESI-MS analyses we were able to show the presence of several LTP1 and LTP2 isoforms in the investigated species. Bioinformatic searches based on the determined Mr indicated that (i) two nsLTP1s already identified in T. aestivum have Mr and number of Cys residues identical to that of a 9.6 kDa protein present both in soft wheat cv. Centauro and in farro; (ii) two isoforms of nsLTP2 detected in T. aestivum have the same Mr and number of Cys residues of two 7 kDa proteins found in Centauro; and (iii) a nsLTP1 detected in Ambrosia artemisiifolia has Mr and number of Cys residues coincident to that of a 9.9 kDa protein found both in soft wheat cv. Centauro and in farro.

  3. Calcium as a trigger for cerebellar long-term synaptic depression.

    PubMed

    Finch, Elizabeth A; Tanaka, Keiko; Augustine, George J

    2012-09-01

    Cerebellar long-term depression (LTD) is a form of long-term synaptic plasticity that is triggered by calcium(Ca2+) signals in the postsynaptic Purkinje cell. This Ca2+comes both from IP3-mediated release from intracellular Ca2+ stores, as well as from Ca2+ influx through voltage-gated Ca2+ channels. The Ca2+ signal that triggers LTD occurs locally within dendritic spines and is due to supralinear summation of signals coming from these two Ca2+ sources. The properties of this postsynaptic Ca2+signal can explain several features of LTD, such as its associativity, synapse specificity, and dependence on thetiming of synaptic activity, and can account for the slow kinetics of LTD expression. Thus, from a Ca2+ signaling perspective, LTD is one of the best understood forms of synaptic plasticity.

  4. Temperate Streptococcus thermophilus phages expressing superinfection exclusion proteins of the Ltp type

    PubMed Central

    Ali, Yahya; Koberg, Sabrina; Heßner, Stefanie; Sun, Xingmin; Rabe, Björn; Back, Angela; Neve, Horst; Heller, Knut J.

    2014-01-01

    Lipoprotein Ltp encoded by temperate Streptococcus thermophilus phage TP-J34 is the prototype of the wide-spread family of host cell surface-exposed lipoproteins involved in superinfection exclusion (sie). When screening for other S. thermophilus phages expressing this type of lipoprotein, three temperate phages—TP-EW, TP-DSM20617, and TP-778—were isolated. In this communication we present the total nucleotide sequences of TP-J34 and TP-778L. For TP-EW, a phage almost identical to TP-J34, besides the ltp gene only the two regions of deviation from TP-J34 DNA were analyzed: the gene encoding the tail protein causing an assembly defect in TP-J34 and the gene encoding the lysin, which in TP-EW contains an intron. For TP-DSM20617 only the sequence of the lysogeny module containing the ltp gene was determined. The region showed high homology to the same region of TP-778. For TP-778 we could show that absence of the attR region resulted in aberrant excision of phage DNA. The amino acid sequence of mature LtpTP-EW was shown to be identical to that of mature LtpTP-J34, whereas the amino acid sequence of mature LtpTP-778 was shown to differ from mature LtpTP-J34 in eight amino acid positions. LtpTP-DSM20617 was shown to differ from LtpTP-778 in just one amino acid position. In contrast to LtpTP-J34, LtpTP-778 did not affect infection of lactococcal phage P008 instead increased activity against phage P001 was noticed. PMID:24659988

  5. APP and APLP2 are essential at PNS and CNS synapses for transmission, spatial learning and LTP

    PubMed Central

    Weyer, Sascha W; Klevanski, Maja; Delekate, Andrea; Voikar, Vootele; Aydin, Dorothee; Hick, Meike; Filippov, Mikhail; Drost, Natalia; Schaller, Kristin L; Saar, Martina; Vogt, Miriam A; Gass, Peter; Samanta, Ayan; Jäschke, Andres; Korte, Martin; Wolfer, David P; Caldwell, John H; Müller, Ulrike C

    2011-01-01

    Despite its key role in Alzheimer pathogenesis, the physiological function(s) of the amyloid precursor protein (APP) and its proteolytic fragments are still poorly understood. Previously, we generated APPsα knock-in (KI) mice expressing solely the secreted ectodomain APPsα. Here, we generated double mutants (APPsα-DM) by crossing APPsα-KI mice onto an APLP2-deficient background and show that APPsα rescues the postnatal lethality of the majority of APP/APLP2 double knockout mice. Surviving APPsα-DM mice exhibited impaired neuromuscular transmission, with reductions in quantal content, readily releasable pool, and ability to sustain vesicle release that resulted in muscular weakness. We show that these defects may be due to loss of an APP/Mint2/Munc18 complex. Moreover, APPsα-DM muscle showed fragmented post-synaptic specializations, suggesting impaired postnatal synaptic maturation and/or maintenance. Despite normal CNS morphology and unaltered basal synaptic transmission, young APPsα-DM mice already showed pronounced hippocampal dysfunction, impaired spatial learning and a deficit in LTP that could be rescued by GABAA receptor inhibition. Collectively, our data show that APLP2 and APP are synergistically required to mediate neuromuscular transmission, spatial learning and synaptic plasticity. PMID:21522131

  6. Direct Cortical Inputs Erase LTP at Schaffer Collateral Synapses

    PubMed Central

    Izumi, Yukitoshi; Zorumski, Charles F.

    2008-01-01

    Long-term potentiation (LTP), a synaptic mechanism thought to underlie memory formation, has been studied extensively at hippocampal Schaffer collateral (SC) synapses. The SC pathway transmits information to area CA1 that originates in entorhinal cortex and is processed by the dentate gyrus and area CA3. CA1 also receives direct excitatory input from entorhinal cortex via the perforant path (PP), but the role of this cortical input is less certain. Here we report that low frequency stimulation of PP inputs to CA1 has no lasting effect on basal SC transmission, but effectively depotentiates SC synapses that have undergone LTP in a fashion that can be reversed by subsequent high frequency stimulation of SC inputs. This depotentiation does not require N-methyl-D-aspartate receptors, Group I metabotropic glutamate receptors or L-type calcium channels, but involves adenosine acting at A1 receptors. Given the limited storage capacity of the hippocampus, these observations provide a mechanism by which input from cortex can help to reset synaptic transmission in the hippocampus and facilitate further information processing. PMID:18799687

  7. Dysfunctional cerebellar Purkinje cells contribute to autism-like behaviour in Shank2-deficient mice

    PubMed Central

    Peter, Saša; ten Brinke, Michiel M.; Stedehouder, Jeffrey; Reinelt, Claudia M.; Wu, Bin; Zhou, Haibo; Zhou, Kuikui; Boele, Henk-Jan; Kushner, Steven A.; Lee, Min Goo; Schmeisser, Michael J.; Boeckers, Tobias M.; Schonewille, Martijn; Hoebeek, Freek E.; De Zeeuw, Chris I.

    2016-01-01

    Loss-of-function mutations in the gene encoding the postsynaptic scaffolding protein SHANK2 are a highly penetrant cause of autism spectrum disorders (ASD) involving cerebellum-related motor problems. Recent studies have implicated cerebellar pathology in the aetiology of ASD. Here we evaluate the possibility that cerebellar Purkinje cells (PCs) represent a critical locus of ASD-like pathophysiology in mice lacking Shank2. Absence of Shank2 impairs both PC intrinsic plasticity and induction of long-term potentiation at the parallel fibre to PC synapse. Moreover, inhibitory input onto PCs is significantly enhanced, most prominently in the posterior lobe where simple spike (SS) regularity is most affected. Using PC-specific Shank2 knockouts, we replicate alterations of SS regularity in vivo and establish cerebellar dependence of ASD-like behavioural phenotypes in motor learning and social interaction. These data highlight the importance of Shank2 for PC function, and support a model by which cerebellar pathology is prominent in certain forms of ASD. PMID:27581745

  8. Orexins excite neurons of the rat cerebellar nucleus interpositus via orexin 2 receptors in vitro.

    PubMed

    Yu, Lei; Zhang, Xiao-Yang; Zhang, Jun; Zhu, Jing-Ning; Wang, Jian-Jun

    2010-03-01

    Orexins are newfound hypothalamic neuropeptides implicated in the regulation of feeding behavior, sleep-wakefulness cycle, nociception, addiction, emotions, as well as narcolepsy. However, little is known about roles of orexins in motor control. Therefore, the present study was designed to investigate the effect of orexins on neuronal activity in the cerebellum, an important subcortical center for motor control. In this study, perfusing slices with orexin A (100 nM-1 microM) or orexin B (100 nM-1 microM) both produced neurons in the rat cerebellar interpositus nucleus (IN) a concentration-dependent excitatory response (96/143, 67.1%). Furthermore, both of the excitations induced by orexin A and B were not blocked by the low-Ca(2+)/high-Mg(2+) medium (n = 8), supporting a direct postsynaptic action of the peptides. Highly selective orexin 1 receptor antagonist SB-334867 did not block the excitatory response of cerebellar IN neurons to orexins (n = 22), but [Ala(11), D-Leu(15)] orexin B, a highly selective orexin 2 receptor (OX(2)R) agonist, mimicked the excitatory effect of orexins on the cerebellar neurons (n = 18). These results demonstrate that orexins excite the cerebellar IN neurons through OX(2)R and suggest that the central orexinergic nervous system may actively participate in motor control through its modulation on one of the final outputs of the spinocerebellum.

  9. Alcohol Withdrawal and Cerebellar Mitochondria.

    PubMed

    Jung, Marianna E

    2015-08-01

    Cerebellar disorders trigger the symptoms of movement problems, imbalance, incoordination, and frequent fall. Cerebellar disorders are shown in various CNS illnesses including a drinking disorder called alcoholism. Alcoholism is manifested as an inability to control drinking in spite of adverse consequences. Human and animal studies have shown that cerebellar symptoms persist even after complete abstinence from drinking. In particular, the abrupt termination (ethanol withdrawal) of long-term excessive ethanol consumption has shown to provoke a variety of neuronal and mitochondrial damage to the cerebellum. Upon ethanol withdrawal, excitatory neurotransmitter molecules such as glutamate are overly released in brain areas including cerebellum. This is particularly relevant to the cerebellar neuronal network as glutamate signals are projected to Purkinje neurons through granular cells that are the most populated neuronal type in CNS. This excitatory neuronal signal may be elevated by ethanol withdrawal stress, which promotes an increase in intracellular Ca(2+) level and a decrease in a Ca(2+)-binding protein, both of which result in the excessive entry of Ca(2+) to the mitochondria. Subsequently, mitochondria undergo a prolonged opening of mitochondrial permeability transition pore and the overproduction of harmful free radicals, impeding adenosine triphosphate (ATP)-generating function. This in turn provokes the leakage of mitochondrial molecule cytochrome c to the cytosol, which triggers a cascade of adverse cytosol reactions. Upstream to this pathway, cerebellum under the condition of ethanol withdrawal has shown aberrant gene modifications through altered DNA methylation, histone acetylation, or microRNA expression. Interplay between these events and molecules may result in functional damage to cerebellar mitochondria and consequent neuronal degeneration, thereby contributing to motoric deficit. Mitochondria-targeting research may help develop a powerful new

  10. Kalirin and Trio proteins serve critical roles in excitatory synaptic transmission and LTP

    PubMed Central

    Herring, Bruce E.; Nicoll, Roger A.

    2016-01-01

    The molecular mechanism underlying long-term potentiation (LTP) is critical for understanding learning and memory. CaMKII, a key kinase involved in LTP, is both necessary and sufficient for LTP induction. However, how CaMKII gives rise to LTP is currently unknown. Recent studies suggest that Rho GTPases are necessary for LTP. Rho GTPases are activated by Rho guanine exchange factors (RhoGEFs), but the RhoGEF(s) required for LTP also remain unknown. Here, using a combination of molecular, electrophysiological, and imaging techniques, we show that the RhoGEF Kalirin and its paralog Trio play critical and redundant roles in excitatory synapse structure and function. Furthermore, we show that CaMKII phosphorylation of Kalirin is sufficient to enhance synaptic AMPA receptor expression, and that preventing CaMKII signaling through Kalirin and Trio prevents LTP induction. Thus, our data identify Kalirin and Trio as the elusive targets of CaMKII phosphorylation responsible for AMPA receptor up-regulation during LTP. PMID:26858404

  11. Kalirin and Trio proteins serve critical roles in excitatory synaptic transmission and LTP.

    PubMed

    Herring, Bruce E; Nicoll, Roger A

    2016-02-23

    The molecular mechanism underlying long-term potentiation (LTP) is critical for understanding learning and memory. CaMKII, a key kinase involved in LTP, is both necessary and sufficient for LTP induction. However, how CaMKII gives rise to LTP is currently unknown. Recent studies suggest that Rho GTPases are necessary for LTP. Rho GTPases are activated by Rho guanine exchange factors (RhoGEFs), but the RhoGEF(s) required for LTP also remain unknown. Here, using a combination of molecular, electrophysiological, and imaging techniques, we show that the RhoGEF Kalirin and its paralog Trio play critical and redundant roles in excitatory synapse structure and function. Furthermore, we show that CaMKII phosphorylation of Kalirin is sufficient to enhance synaptic AMPA receptor expression, and that preventing CaMKII signaling through Kalirin and Trio prevents LTP induction. Thus, our data identify Kalirin and Trio as the elusive targets of CaMKII phosphorylation responsible for AMPA receptor up-regulation during LTP.

  12. Decreased cerebellar blood flow in postinfectious acute cerebellar ataxia

    PubMed Central

    Nagamitsu, S.; Matsuishi, T.; Ishibashi, M.; Yamashita, Y.; Nishimi, T.; Ichikawa, K.; Yamanishi, K.; Kato, H.

    1999-01-01

    OBJECTIVE—The aim of the present study was to evaluate the regional cerebral blood flow (rCBF) in patients with postinfectious acute cerebellar ataxia using single photon emission computed tomography (SPECT).
METHODS—Five children with postinfectious acute cerebellar ataxia and five control subjects were examined. The distribution of rCBF was measured by SPECT imaging after intravenous administration of 123I-IMP (111 MBq). The rCBF ratio—defined as the ratio of rCBF in the region of interest (ROI) to that in the occipital cortex—was calculated for each cortical and subcortical ROI. The mean rCBF ratio of each region was then compared between the ataxic and control subjects. These patients and all control subjects were also evaluated using MRI.
RESULTS—The rCBF ratio was significantly lower in the cerebellum of the ataxic patients than in the cerebellum of the control subjects (p<0.05). No abnormal cerebellar morphology and no abnormal signal intensities were found on MRI.
CONCLUSION—123I-IMP SPECT clearly demonstrated the decreased rCBF in the cerebellum of all patients with postinfectious acute cerebellar ataxia.

 PMID:10369834

  13. Cutin monomer induces expression of the rice OsLTP5 lipid transfer protein gene.

    PubMed

    Kim, Tae Hyun; Park, Jong Ho; Kim, Moon Chul; Cho, Sung Ho

    2008-01-01

    Treatment with the cutin monomer 16-hydroxypalmitic acid (HPA), a major component of cutin, elicited the synthesis of hydrogen peroxide (H2O2) in rice leaves and induced the expression of the lipid transfer protein gene OsLTP5. Treatment with HPA also induced expression of OsLTP1, OsLTP2, and the pathogen-related PR-10 genes to a lesser extent. The OsLTP5 transcript was expressed prominently in stems and flowers, but was barely detectable in leaves. Expression of OsLTP5 was induced in shoots in response to ABA and salicylic acid. It is proposed that HPA is perceived by rice as a signal, inducing defense reactions.

  14. Sensitivity to theta-burst timing permits LTP in dorsal striatal adult brain slice

    PubMed Central

    Hawes, Sarah L.; Gillani, Fawad; Evans, Rebekah C.; Benkert, Elizabeth A.

    2013-01-01

    Long-term potentiation (LTP) of excitatory afferents to the dorsal striatum likely occurs with learning to encode new skills and habits, yet corticostriatal LTP is challenging to evoke reliably in brain slice under physiological conditions. Here we test the hypothesis that stimulating striatal afferents with theta-burst timing, similar to recently reported in vivo temporal patterns corresponding to learning, evokes LTP. Recording from adult mouse brain slice extracellularly in 1 mM Mg2+, we find LTP in dorsomedial and dorsolateral striatum is preferentially evoked by certain theta-burst patterns. In particular, we demonstrate that greater LTP is produced using moderate intraburst and high theta-range frequencies, and that pauses separating bursts of stimuli are critical for LTP induction. By altering temporal pattern alone, we illustrate the importance of burst-patterning for LTP induction and demonstrate that corticostriatal long-term depression is evoked in the same preparation. In accord with prior studies, LTP is greatest in dorsomedial striatum and relies on N-methyl-d-aspartate receptors. We also demonstrate a requirement for both Gq- and Gs/olf-coupled pathways, as well as several kinases associated with memory storage: PKC, PKA, and ERK. Our data build on previous reports of activity-directed plasticity by identifying effective values for distinct temporal parameters in variants of theta-burst LTP induction paradigms. We conclude that those variants which best match reports of striatal activity during learning behavior are most successful in evoking dorsal striatal LTP in adult brain slice without altering artificial cerebrospinal fluid. Future application of this approach will enable diverse investigations of plasticity serving striatal-based learning. PMID:23926032

  15. The late maintenance of hippocampal LTP: requirements, phases, 'synaptic tagging', 'late-associativity' and implications.

    PubMed

    Reymann, Klaus G; Frey, Julietta U

    2007-01-01

    Our review focuses on the mechanisms which enable the late maintenance of hippocampal long-term potentiation (LTP; >3h), a phenomenon which is thought to underlie prolonged memory. About 20 years ago we showed for the first time that the maintenance of LTP - like memory storage--depends on intact protein synthesis and thus, consists of at least two temporal phases. Here we concentrate on mechanisms required for the induction of the transient early-LTP and of the protein synthesis-dependent late-LTP. Our group has shown that the induction of late-LTP requires the associative activation of heterosynaptic inputs, i.e. the synergistic activation of glutamatergic and modulatory, reinforcing inputs within specific, effective time windows. The induction of late-LTP is characterized by novel, late-associative properties such as 'synaptic tagging' and 'late-associative reinforcement'. Both phenomena require the associative setting of synaptic tags as well as the availability of plasticity-related proteins (PRPs) and they are restricted to functional dendritic compartments, in general. 'Synaptic tagging' guarantees input specificity and thus the specific processing of afferent signals for the establishment of late-LTP. 'Late-associative reinforcement' describes a process where early-LTP by the co-activation of modulatory inputs can be transformed into late-LTP in activated synapses where a tag is set. Recent evidence from behavioral experiments, which studied processes of emotional and cognitive reinforcement of LTP, point to the physiological relevance of the above mechanisms during cellular and system's memory formation.

  16. Neuroligin-2 accelerates GABAergic synapse maturation in cerebellar granule cells

    PubMed Central

    Fu, Zhanyan; Vicini, Stefano

    2009-01-01

    Neuroligins (NLGs) are postsynaptic cell adhesion molecules that are thought to function in synaptogenesis. To investigate the role of NLGs on synaptic transmission once the synapse is formed, we transfected neuroligin-2(NLG2) in cultured mouse cerebellar granule cells (CGCs), and recorded GABAA (γ-aminobutyric acid) receptor mediated miniature postsynaptic currents (mISPCs). NLG2 transfected cells had mIPSCs with faster decay than matching GFP expressing controls at young culture ages (days in vitro, DIV 7-8). Down-regulation of NLG2 by the isoform specific shRNA-NLG2 resulted in an opposite effect. We and others have shown that the switch of α subunits of GABAA Rs from α2/3 to α1 underlies developmental speeding of the IPSC decay in various CNS regions, including the cerebellum. To assess whether the reduced decay time of mIPSCs by NLG2 is due to the recruitment of more α1 containing GABAARs at the synapses, we examined the prolongation of current decay by the zolpidem, which has been shown to preferentially enhance the activity of α1 subunit containing GABA channel. The application of zolpidem resulted in a significantly greater prolongation kinetics of synaptic currents in NLG2 over-expressing cells than control cells, suggesting that NLG2 over-expression accelerates synapse maturation by promoting incorporation of the α1 subunit-containing GABAARs at postsynaptic sites in immature cells. In addition, the effect of NLG2 on the speeding of decay time course of synaptic currents was abolished when we used CGC cultures from α1-/- mice. Lastly, to exclude the possibility that the fast decay of mIPSCs induced by NLG2 could be also due to the impacts of NLG2 on the GABA transient in synaptic cleft, we measured the sensitivity of mIPSCs to the fast-off competitive antagonists TPMPA. We found that TPMPA similarly inhibits mIPSCs in control and NLG2 over-expressing CGCs both at young age (DIV8) and old age (DIV14) of cultures. However, we confirm our previous

  17. High Actin Concentrations in Brain Dendritic Spines and Postsynaptic Densities

    NASA Astrophysics Data System (ADS)

    Matus, Andrew; Ackermann, Marcel; Pehling, Gundula; Randolph Byers, H.; Fujiwara, Keigi

    1982-12-01

    Antibodies against actin were used to corroborate the presence of actin as a major component protein of isolated brain postsynaptic densities. The same antibodies also were used as an immunohistochemical stain to study the distribution of actin in sections of intact brain tissue. This showed two major sites where actin is concentrated: smooth muscle cells around blood vessels and postsynaptic sites. In the postsynaptic area the highest concentration of actin occurs in postsynaptic densities and there also is intense staining in the surrounding cytoplasm, especially within dendritic spines. Antiactin staining was much weaker in other parts of neurons and in glial cells. The high concentration of actin in dendritic spines may be related to shape changes that these structures have been found to undergo in response to prolonged afferent stimulation.

  18. Predicting Presynaptic and Postsynaptic Neurotoxins by Developing Feature Selection Technique

    PubMed Central

    Yang, Yunchun; Zhang, Chunmei; Chen, Rong; Huang, Po

    2017-01-01

    Presynaptic and postsynaptic neurotoxins are proteins which act at the presynaptic and postsynaptic membrane. Correctly predicting presynaptic and postsynaptic neurotoxins will provide important clues for drug-target discovery and drug design. In this study, we developed a theoretical method to discriminate presynaptic neurotoxins from postsynaptic neurotoxins. A strict and objective benchmark dataset was constructed to train and test our proposed model. The dipeptide composition was used to formulate neurotoxin samples. The analysis of variance (ANOVA) was proposed to find out the optimal feature set which can produce the maximum accuracy. In the jackknife cross-validation test, the overall accuracy of 94.9% was achieved. We believe that the proposed model will provide important information to study neurotoxins. PMID:28303250

  19. Orthostatic tremor: a cerebellar pathology?

    PubMed

    Gallea, Cécile; Popa, Traian; García-Lorenzo, Daniel; Valabregue, Romain; Legrand, André-Pierre; Apartis, Emmanuelle; Marais, Lea; Degos, Bertrand; Hubsch, Cecile; Fernández-Vidal, Sara; Bardinet, Eric; Roze, Emmanuel; Lehéricy, Stéphane; Meunier, Sabine; Vidailhet, Marie

    2016-08-01

    SEE MUTHURAMAN ET AL DOI101093/AWW164 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Primary orthostatic tremor is characterized by high frequency tremor affecting the legs and trunk during the standing position. Cerebellar defects were suggested in orthostatic tremor without direct evidence. We aimed to characterize the anatomo-functional defects of the cerebellar motor pathways in orthostatic tremor. We used multimodal neuroimaging to compare 17 patients with orthostatic tremor and 17 age- and gender-matched healthy volunteers. Nine of the patients with orthostatic tremor underwent repetitive transcranial stimulation applied over the cerebellum during five consecutive days. We quantified the duration of standing position and tremor severity through electromyographic recordings. Compared to healthy volunteers, grey matter volume in patients with orthostatic tremor was (i) increased in the cerebellar vermis and correlated positively with the duration of the standing position; and (ii) increased in the supplementary motor area and decreased in the lateral cerebellum, which both correlated with the disease duration. Functional connectivity between the lateral cerebellum and the supplementary motor area was abnormally increased in patients with orthostatic tremor, and correlated positively with tremor severity. After repetitive transcranial stimulation, tremor severity and functional connectivity between the lateral cerebellum and the supplementary motor area were reduced. We provide an explanation for orthostatic tremor pathophysiology, and demonstrate the functional relevance of cerebello-thalamo-cortical connections in tremor related to cerebellar defects.

  20. Linking oscillations in cerebellar circuits

    PubMed Central

    Courtemanche, Richard; Robinson, Jennifer C.; Aponte, Daniel I.

    2013-01-01

    In many neuroscience fields, the study of local and global rhythmicity has been receiving increasing attention. These network influences could directly impact on how neuronal groups interact together, organizing for different contexts. The cerebellar cortex harbors a variety of such local circuit rhythms, from the rhythms in the cerebellar cortex per se, or those dictated from important afferents. We present here certain cerebellar oscillatory phenomena that have been recorded in rodents and primates. Those take place in a range of frequencies: from the more known oscillations in the 4–25 Hz band, such as the olivocerebellar oscillatory activity and the granule cell layer oscillations, to the more recently reported slow (<1 Hz oscillations), and the fast (>150 Hz) activity in the Purkinje cell layer. Many of these oscillations appear spontaneously in the circuits, and are modulated by behavioral imperatives. We review here how those oscillations are recorded, some of their modulatory mechanisms, and also identify some of the cerebellar nodes where they could interact. A particular emphasis has been placed on how these oscillations could be modulated by movement and certain neuropathological manifestations. Many of those oscillations could have a definite impact on the way information is processed in the cerebellum and how it interacts with other structures in a variety of contexts. PMID:23908606

  1. Speech Prosody in Cerebellar Ataxia

    ERIC Educational Resources Information Center

    Casper, Maureen A.; Raphael, Lawrence J.; Harris, Katherine S.; Geibel, Jennifer M.

    2007-01-01

    Persons with cerebellar ataxia exhibit changes in physical coordination and speech and voice production. Previously, these alterations of speech and voice production were described primarily via perceptual coordinates. In this study, the spatial-temporal properties of syllable production were examined in 12 speakers, six of whom were healthy…

  2. Theta Frequency Stimulation Induces a Local Form of Late Phase LTP in the CA1 Region of the Hippocampus

    ERIC Educational Resources Information Center

    Huang, Yan-You; Kandel, Eric R.

    2005-01-01

    The late phase of LTP (L-LTP) is typically induced by repeated high-frequency stimulation. This form of LTP requires activation of transcription and translation and results in the cell-wide distribution of gene products that can be captured by other marked synapses. Here we report that theta frequency stimulation (5 Hz, 30 sec) applied to the…

  3. Functional consequences of pre- and postsynaptic expression of synaptic plasticity.

    PubMed

    Costa, Rui Ponte; Mizusaki, Beatriz E P; Sjöström, P Jesper; van Rossum, Mark C W

    2017-03-05

    Growing experimental evidence shows that both homeostatic and Hebbian synaptic plasticity can be expressed presynaptically as well as postsynaptically. In this review, we start by discussing this evidence and methods used to determine expression loci. Next, we discuss the functional consequences of this diversity in pre- and postsynaptic expression of both homeostatic and Hebbian synaptic plasticity. In particular, we explore the functional consequences of a biologically tuned model of pre- and postsynaptically expressed spike-timing-dependent plasticity complemented with postsynaptic homeostatic control. The pre- and postsynaptic expression in this model predicts (i) more reliable receptive fields and sensory perception, (ii) rapid recovery of forgotten information (memory savings), and (iii) reduced response latencies, compared with a model with postsynaptic expression only. Finally, we discuss open questions that will require a considerable research effort to better elucidate how the specific locus of expression of homeostatic and Hebbian plasticity alters synaptic and network computations.This article is part of the themed issue 'Integrating Hebbian and homeostatic plasticity'.

  4. Functional consequences of pre- and postsynaptic expression of synaptic plasticity

    PubMed Central

    Mizusaki, Beatriz E. P.

    2017-01-01

    Growing experimental evidence shows that both homeostatic and Hebbian synaptic plasticity can be expressed presynaptically as well as postsynaptically. In this review, we start by discussing this evidence and methods used to determine expression loci. Next, we discuss the functional consequences of this diversity in pre- and postsynaptic expression of both homeostatic and Hebbian synaptic plasticity. In particular, we explore the functional consequences of a biologically tuned model of pre- and postsynaptically expressed spike-timing-dependent plasticity complemented with postsynaptic homeostatic control. The pre- and postsynaptic expression in this model predicts (i) more reliable receptive fields and sensory perception, (ii) rapid recovery of forgotten information (memory savings), and (iii) reduced response latencies, compared with a model with postsynaptic expression only. Finally, we discuss open questions that will require a considerable research effort to better elucidate how the specific locus of expression of homeostatic and Hebbian plasticity alters synaptic and network computations. This article is part of the themed issue ‘Integrating Hebbian and homeostatic plasticity’. PMID:28093547

  5. Integration of asynchronously released quanta prolongs the postsynaptic spike window.

    PubMed

    Iremonger, Karl J; Bains, Jaideep S

    2007-06-20

    Classically, the release of glutamate in response to a presynaptic action potential causes a brief increase in postsynaptic excitability. Previous reports indicate that at some central synapses, a single action potential can elicit multiple, asynchronous release events. This raises the possibility that the temporal dynamics of neurotransmitter release may determine the duration of altered postsynaptic excitability. In response to physiological challenges, the magnocellular neurosecretory cells (MNCs) in the paraventricular nucleus of the hypothalamus (PVN) exhibit robust and prolonged increases in neuronal activity. Although the postsynaptic conductances that may facilitate this form of activity have been investigated thoroughly, the role of presynaptic release has been largely overlooked. Because the specific patterns of activity generated by MNCs require the activation of excitatory synaptic inputs, we sought to characterize the release dynamics at these synapses and determine whether they contribute to prolonged excitability in these cells. We obtained whole-cell recordings from MNCs in brain slices of postnatal day 21-44 rats. Stimulation of glutamatergic inputs elicited large and prolonged postsynaptic events that resulted from the summation of multiple, asynchronously released quanta. Asynchronous release was selectively inhibited by the slow calcium buffer EGTA-AM and potentiated by brief high-frequency stimulus trains. These trains caused a prolonged increase in postsynaptic spike activity that could also be eliminated by EGTA-AM. Our results demonstrate that glutamatergic terminals in PVN exhibit asynchronous release, which is important in generating large postsynaptic depolarizations and prolonged spiking in response to brief, high-frequency bursts of presynaptic activity.

  6. Long-Term Spatiotemporal Reconfiguration of Neuronal Activity Revealed by Voltage-Sensitive Dye Imaging in the Cerebellar Granular Layer

    PubMed Central

    Gandolfi, Daniela; Mapelli, Jonathan; D'Angelo, Egidio

    2015-01-01

    Understanding the spatiotemporal organization of long-term synaptic plasticity in neuronal networks demands techniques capable of monitoring changes in synaptic responsiveness over extended multineuronal structures. Among these techniques, voltage-sensitive dye imaging (VSD imaging) is of particular interest due to its good spatial resolution. However, improvements of the technique are needed in order to overcome limits imposed by its low signal-to-noise ratio. Here, we show that VSD imaging can detect long-term potentiation (LTP) and long-term depression (LTD) in acute cerebellar slices. Combined VSD imaging and patch-clamp recordings revealed that the most excited regions were predominantly associated with granule cells (GrCs) generating EPSP-spike complexes, while poorly responding regions were associated with GrCs generating EPSPs only. The correspondence with cellular changes occurring during LTP and LTD was highlighted by a vector representation obtained by combining amplitude with time-to-peak of VSD signals. This showed that LTP occurred in the most excited regions lying in the core of activated areas and increased the number of EPSP-spike complexes, while LTD occurred in the less excited regions lying in the surround. VSD imaging appears to be an efficient tool for investigating how synaptic plasticity contributes to the reorganization of multineuronal activity in neuronal circuits. PMID:26294979

  7. Early postnatal nicotine exposure causes hippocampus-dependent memory impairments in adolescent mice: Association with altered nicotinic cholinergic modulation of LTP, but not impaired LTP.

    PubMed

    Nakauchi, Sakura; Malvaez, Melissa; Su, Hailing; Kleeman, Elise; Dang, Richard; Wood, Marcelo A; Sumikawa, Katumi

    2015-02-01

    Fetal nicotine exposure from smoking during pregnancy causes long-lasting cognitive impairments in offspring, yet little is known about the mechanisms that underlie this effect. Here we demonstrate that early postnatal exposure of mouse pups to nicotine via maternal milk impairs long-term, but not short-term, hippocampus-dependent memory during adolescence. At the Schaffer collateral (SC) pathway, the most widely studied synapses for a cellular correlate of hippocampus-dependent memory, the induction of N-methyl-D-aspartate receptor-dependent transient long-term potentiation (LTP) and protein synthesis-dependent long-lasting LTP are not diminished by nicotine exposure, but rather unexpectedly the threshold for LTP induction becomes lower after nicotine treatment. Using voltage sensitive dye to visualize hippocampal activity, we found that early postnatal nicotine exposure also results in enhanced CA1 depolarization and hyperpolarization after SC stimulation. Furthermore, we show that postnatal nicotine exposure induces pervasive changes to the nicotinic modulation of CA1 activity: activation of nicotinic receptors no longer increases CA1 network depolarization, acute nicotine inhibits rather than facilitates the induction of LTP at the SC pathway by recruiting an additional nicotinic receptor subtype, and acute nicotine no longer blocks LTP induction at the temporoammonic pathway. These findings reflect the pervasive impact of nicotine exposure during hippocampal development, and demonstrate an association of hippocampal memory impairments with altered nicotinic cholinergic modulation of LTP, but not impaired LTP. The implication of our results is that nicotinic cholinergic-dependent plasticity is required for long-term memory formation and that postnatal nicotine exposure disrupts this form of plasticity.

  8. Synapse-specific contribution of the variation of transmitter concentration to the decay of inhibitory postsynaptic currents.

    PubMed Central

    Nusser, Z; Naylor, D; Mody, I

    2001-01-01

    Synaptic transmission is characterized by a remarkable trial-to-trial variability in the postsynaptic response, influencing the way in which information is processed in neuronal networks. This variability may originate from the probabilistic nature of quantal transmitter release, from the stochastic behavior of the receptors, or from the fluctuation of the transmitter concentration in the cleft. We combined nonstationary noise analysis and modeling techniques to estimate the contribution of transmitter fluctuation to miniature inhibitory postsynaptic current (mIPSC) variability. A substantial variability (approximately 30%) in mIPSC decay was found in all cell types studied (neocortical layer2/3 pyramidal cells, granule cells of the olfactory bulb, and interneurons of the cerebellar molecular layer). This large variability was not solely the consequence of the expression of multiple types of GABA(A) receptors, as a similar mIPSC decay variability was observed in cerebellar interneurons that express only a single type (alpha(1)beta(2)gamma(2)) of GABA(A) receptor. At large synapses on these cells, all variance in mIPSC decay could be accounted for by the stochastic behavior of approximately 36 pS channels, consistent with the conductance of alpha(1)beta(2)gamma(2) GABA(A) receptors at physiological temperatures. In contrast, at small synapses, a significant amount of variability in the synaptic cleft GABA transient had to be present to account for the additional variance in IPSC decay over that produced by stochastic channel openings. Thus, our results suggest a synapse-specific contribution of the variation of the spatiotemporal profile of GABA to the decay of IPSCs. PMID:11222289

  9. Plasticity of NMDA receptor-mediated excitatory postsynaptic currents at perforant path inputs to dendrite-targeting interneurons.

    PubMed

    Harney, Sarah C; Anwyl, Roger

    2012-08-15

    Synaptic plasticity of NMDA receptors (NMDARs) has been recently described in a number of brain regions and we have previously characterised LTP and LTD of glutamatergic NMDA receptor-mediated EPSCs (NMDAR-EPSCs) in granule cells of dentate gyrus. The functional significance of NMDAR plasticity at perforant path synapses on hippocampal network activity depends on whether this is a common feature of perforant path synapses on all postsynaptic target cells or if this plasticity occurs only at synapses on principal cells. We recorded NMDAR-EPSCs at medial perforant path synapses on interneurons in dentate gyrus which had significantly slower decay kinetics compared to those recorded in granule cells. NMDAR pharmacology in interneurons was consistent with expression of both GluN2B- and GluN2D-containing receptors. In contrast to previously described high frequency stimulation-induced bidirectional plasticity of NMDAR-EPSCs in granule cells, only LTD of NMDAR-EPSCs was induced in interneurons in our standard experimental conditions. In interneurons, LTD of NMDAR-EPSCs was associated with a loss of sensitivity to a GluN2D-selective antagonist and was inhibited by the actin stabilising agent, jasplakinolide. While LTP of NMDAR-EPSCs can be readily induced in granule cells, this form of plasticity was only observed in interneurons when extracellular calcium was increased above physiological concentrations during HFS or when PKC was directly activated by phorbol ester, suggesting that opposing forms of plasticity at inputs to interneurons and principal cells may act to regulate granule cell dendritic integration and processing.

  10. Long-term potentiation (LTP) of human sensory-evoked potentials.

    PubMed

    Kirk, Ian J; McNair, Nicolas A; Hamm, Jeffrey P; Clapp, Wesley C; Mathalon, Daniel H; Cavus, Idil; Teyler, Timothy J

    2010-09-01

    Long-term potentiation (LTP) is the principal candidate synaptic mechanism underlying learning and memory, and has been studied extensively at the cellular and molecular level in laboratory animals. Inquiry into the functional significance of LTP has been hindered by the absence of a human model as, until recently, LTP has only been directly demonstrated in humans in isolated cortical tissue obtained from patients undergoing surgery, where it displays properties identical to those seen in non-human preparations. In this brief review, we describe the results of paradigms recently developed in our laboratory for inducing LTP-like changes in visual-, and auditory-evoked potentials. We describe how rapid, repetitive presentation of sensory stimuli leads to a persistent enhancement of components of sensory-evoked potential in normal humans. Experiments to date, investigating the locus, stimulus specificity, and NMDA receptor dependence of these LTP-like changes suggest that they have the essential characteristics of LTP seen in experimental animals. The ability to elicit LTP from non-surgical patients will provide a human model system allowing the detailed examination of synaptic plasticity in normal subjects and may have future clinical applications in the assessment of cognitive disorders. Copyright © 2010 John Wiley & Sons, Ltd. For further resources related to this article, please visit the WIREs website.

  11. CaMKII Phosphorylation of TARPγ-8 Is a Mediator of LTP and Learning and Memory.

    PubMed

    Park, Joongkyu; Chávez, Andrés E; Mineur, Yann S; Morimoto-Tomita, Megumi; Lutzu, Stefano; Kim, Kwang S; Picciotto, Marina R; Castillo, Pablo E; Tomita, Susumu

    2016-10-05

    Protein phosphorylation is an essential step for the expression of long-term potentiation (LTP), a long-lasting, activity-dependent strengthening of synaptic transmission widely regarded as a cellular mechanism underlying learning and memory. At the core of LTP is the synaptic insertion of AMPA receptors (AMPARs) triggered by the NMDA receptor-dependent activation of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). However, the CaMKII substrate that increases AMPAR-mediated transmission during LTP remains elusive. Here, we identify the hippocampus-enriched TARPγ-8, but not TARPγ-2/3/4, as a critical CaMKII substrate for LTP. We found that LTP induction increases TARPγ-8 phosphorylation, and that CaMKII-dependent enhancement of AMPAR-mediated transmission requires CaMKII phosphorylation sites of TARPγ-8. Moreover, LTP and memory formation, but not basal transmission, are significantly impaired in mice lacking CaMKII phosphorylation sites of TARPγ-8. Together, these findings demonstrate that TARPγ-8 is a crucial mediator of CaMKII-dependent LTP and therefore a molecular target that controls synaptic plasticity and associated cognitive functions.

  12. Drosophila Lipophorin Receptors Recruit the Lipoprotein LTP to the Plasma Membrane to Mediate Lipid Uptake

    PubMed Central

    Rodríguez-Vázquez, Míriam; Mejía-Morales, John E.; Culi, Joaquim

    2015-01-01

    Lipophorin, the main Drosophila lipoprotein, circulates in the hemolymph transporting lipids between organs following routes that must adapt to changing physiological requirements. Lipophorin receptors expressed in developmentally dynamic patterns in tissues such as imaginal discs, oenocytes and ovaries control the timing and tissular distribution of lipid uptake. Using an affinity purification strategy, we identified a novel ligand for the lipophorin receptors, the circulating lipoprotein Lipid Transfer Particle (LTP). We show that specific isoforms of the lipophorin receptors mediate the extracellular accumulation of LTP in imaginal discs and ovaries. The interaction requires the LA-1 module in the lipophorin receptors and is strengthened by a contiguous region of 16 conserved amino acids. Lipophorin receptor variants that do not interact with LTP cannot mediate lipid uptake, revealing an essential role of LTP in the process. In addition, we show that lipophorin associates with the lipophorin receptors and with the extracellular matrix through weak interactions. However, during lipophorin receptor-mediated lipid uptake, LTP is required for a transient stabilization of lipophorin in the basolateral plasma membrane of imaginal disc cells. Together, our data suggests a molecular mechanism by which the lipophorin receptors tether LTP to the plasma membrane in lipid acceptor tissues. LTP would interact with lipophorin particles adsorbed to the extracellular matrix and with the plasma membrane, catalyzing the exchange of lipids between them. PMID:26121667

  13. BDNF Facilitates L-LTP Maintenance in the Absence of Protein Synthesis through PKMζ

    PubMed Central

    Mei, Fan; Nagappan, Guhan; Ke, Yang; Sacktor, Todd C.; Lu, Bai

    2011-01-01

    Late-phase long term potentiation (L-LTP) is thought to be the cellular basis for long-term memory (LTM). While LTM as well as L-LTP is known to depend on transcription and translation, it is unclear why brain-derived neurotrophic factor (BDNF) could sustain L-LTP when protein synthesis is inhibited. The persistently active protein kinase ζ (PKMζ) is the only molecule implicated in perpetuating L-LTP maintenance. Here, in mouse acute brain slices, we show that inhibition of PKMζ reversed BDNF-dependent form of L-LTP. While BDNF did not alter the steady-state level of PKMζ, BDNF together with the L-LTP inducing theta-burst stimulation (TBS) increased PKMζ level even without protein synthesis. Finally, in the absence of de novo protein synthesis, BDNF maintained TBS-induced PKMζ at a sufficient level. These results suggest that BDNF sustains L-LTP through PKMζ in a protein synthesis-independent manner, revealing an unexpected link between BDNF and PKMζ. PMID:21747912

  14. LTP but not seizure is associated with up-regulation of AKAP-150.

    PubMed

    Génin, A; French, P; Doyère, V; Davis, S; Errington, M L; Maroun, M; Stean, T; Truchet, B; Webber, M; Wills, T; Richter-Levin, G; Sanger, G; Hunt, S P; Mallet, J; Laroche, S; Bliss, T V P; O'Connor, V

    2003-01-01

    We have used differential display to profile and compare the mRNAs expressed in the hippocampus of freely moving animals after the induction of long-term potentiation (LTP) at the perforant path-dentate gyrus synapse with control rats receiving low-frequency stimulation. We have combined this with in situ hybridization and have identified A-kinase anchoring protein of 150 kDa (AKAP-150) as a gene selectively up-regulated during the maintenance phase of LTP. AKAP-150 mRNA has a biphasic modulation in the dentate gyrus following the induction of LTP. The expression of AKAP-150 was 29% lower than stimulated controls 1 h after the induction of LTP. Its expression was enhanced 3 (50%), 6 (239%) and 12 h (210%) after induction, returning to control levels by 24 h postinduction. The NMDA receptor antagonist CPP blocked the tetanus-induced modulation of AKAP-150 expression. Interestingly, strong generalized stimulation produced by electroconvulsive shock did not increase the expression of AKAP-150. This implies that the AKAP-150 harbours a novel property of selective responsiveness to the stimulation patterns that trigger NMDA-dependent LTP in vivo. Its selective up-regulation during LTP and its identified functions as a scaffold for protein kinase A, protein kinase C, calmodulin, calcineurin and ionotropic glutamate receptors suggest that AKAP-150 encodes is an important effector protein in the expression of late LTP.

  15. Environmental enrichment modifies the PKA-dependence of hippocampal LTP and improves hippocampus-dependent memory.

    PubMed

    Duffy, S N; Craddock, K J; Abel, T; Nguyen, P V

    2001-01-01

    cAMP-dependent protein kinase (PKA) is critical for the expression of some forms of long-term potentiation (LTP) in area CA1 of the mouse hippocampus and for hippocampus-dependent memory. Exposure to spatially enriched environments can modify LTP and improve behavioral memory in rodents, but the molecular bases for the enhanced memory performance seen in enriched animals are undefined. We tested the hypothesis that exposure to a spatially enriched environment may alter the PKA dependence of hippocampal LTP. Hippocampal slices from enriched mice showed enhanced LTP following a single burst of 100-Hz stimulation in the Schaffer collateral pathway of area CA1. In slices from nonenriched mice, this single-burst form of LTP was less robust and was unaffected by Rp-cAMPS, an inhibitor of PKA. In contrast, the enhanced LTP in enriched mice was attenuated by Rp-cAMPS. Enriched slices expressed greater forskolin-induced, cAMP-dependent synaptic facilitation than did slices from nonenriched mice. Enriched mice showed improved memory for contextual fear conditioning, whereas memory for cued fear conditioning was unaffected following enrichment. Our data indicate that exposure of mice to spatial enrichment alters the PKA dependence of LTP and enhances one type of hippocampus-dependent memory. Environmental enrichment can transform the pharmacological profile of hippocampal LTP, possibly by altering the threshold for activity-dependent recruitment of the cAMP-PKA signaling pathway following electrical and chemical stimulation. We suggest that experience-dependent plasticity of the PKA dependence of hippocampal LTP may be important for regulating the efficacy of hippocampus-based memory.

  16. Roles of testosterone and amygdaloid LTP induction in determining sex differences in fear memory magnitude.

    PubMed

    Chen, Li-Shen; Tzeng, Wen-Yu; Chuang, Jia-Ying; Cherng, Chianfang G; Gean, Po-Wu; Yu, Lung

    2014-08-01

    Women are thought to form fear memory more robust than men do and testosterone is suspected to play a role in determining such a sex difference. Mouse cued fear freezing was used to study the sex-related susceptibility and the role of testosterone in fear memory in humans. A 75-dB tone was found to provoke weak freezing, while 0.15-mA and 0.20-mA footshock caused strong freezing responses. No sex differences were noticed in the tone- or footshock-induced (naïve fear) freezing. Following the conditionings, female mice exhibited greater tone (cued fear)-induced freezing than did male mice. Nonetheless, female mice demonstrated indistinctive cued fear freezing across the estrous phases and ovariectomy did not affect such freezing in female mice. Orchidectomy enhanced the cued fear freezing in male mice. Systemic testosterone administrations and an intra-lateral nucleus of amygdala (LA) testosterone infusion diminished the cued fear freezing in orchidectomized male mice, while pretreatment with flutamide (Flu) eradicated these effects. Long-term potentiation (LTP) magnitude in LA has been known to correlate with the strength of the cued fear conditioning. We found that LA LTP magnitude was indeed greater in female than male mice. Orchidectomy enhanced LTP magnitude in males' LA, while ovariectomy decreased LTP magnitude in females' LA. Testosterone decreased LTP magnitude in orchidectomized males' LA and estradiol enhanced LTP magnitude in ovariectomized females' LA. Finally, male mice had lower LA GluR1 expression than female mice and orchidectomy enhanced the GluR1 expression in male mice. These findings, taken together, suggest that testosterone plays a critical role in rendering the sex differences in the cued fear freezing and LA LTP. Testosterone is negatively associated with LA LTP and the cued fear memory in male mice. However, ovarian hormones and LA LTP are loosely associated with the cued fear memory in female mice.

  17. Diminished KCC2 confounds synapse-specificity of LTP during senescence

    PubMed Central

    Ferando, Isabella; Faas, Guido; Mody, Istvan

    2016-01-01

    Synapse-specificity of LTP ensures that no interference arises from inputs irrelevant to the memory to be encoded. In hippocampi of aged (21-28 months-old) mice LTP was relayed to unstimulated synapses blemishing its synapse-specificity. Diminished levels of the K+/Cl– cotransporter KCC2 and a depolarizing GABAA receptor-mediated synaptic component following LTP were the most likely causes for spreading the potentiation, unveiling novel mechanisms hindering information storage in the aged brain, and identifying KCC2 as a potential target for intervention. PMID:27500406

  18. Subcellular compartment-specific molecular diversity of pre- and postsynaptic GABAB-activated GIRK channels in Purkinje cells

    PubMed Central

    Fernández-Alacid, Laura; Aguado, Carolina; Ciruela, Francisco; Martín, Ricardo; Colón, José; Cabañero, María José; Gassmann, Martin; Watanabe, Masahiko; Shigemoto, Ryuichi; Wickman, Kevin; Bettler, Bernhard; Sánchez-Prieto, José; Luján, Rafael

    2009-01-01

    Activation of G protein-gated inwardly-rectifying K+ (GIRK or Kir3) channels by metabotropic gamma-aminobutyric acid (B) (GABAB) receptors is an essential signalling pathway controlling neuronal excitability and synaptic transmission in the brain. To investigate the relationship between GIRK channel subunits and GABAB receptors in cerebellar Purkinje cells at post- and pre-synaptic sites, we used biochemical, functional and immunohistochemical techniques. Co-immunoprecipitation analysis demonstrated that GIRK subunits are co-assembled with GABAB receptors in the cerebellum. Immunoelectron microscopy showed that the subunit composition of GIRK channels in Purkinje cell spines is compartment-dependent. Thus, at extrasynaptic sites GIRK channels are formed by GIRK1/GIRK2/GIRK3, postsynaptic densities contain GIRK2/GIRK3 and dendritic shafts contain GIRK1/GIRK3. The postsynaptic association of GIRK subunits with GABAB receptors in Purkinje cells is supported by the subcellular regulation of the ion channel and the receptor in mutant mice. At presynaptic sites, GIRK channels localized to parallel fibre terminals are formed by GIRK1/GIRK2/GIRK3 and co-localize with GABAB receptors. Consistent with this morphological evidence we demonstrate their functional interaction at axon terminals in the cerebellum by showing that GIRK channels play a role in the inhibition of glutamate release by GABAB receptors. The association of GIRK channels and GABAB receptors with excitatory synapses at both post- and presynaptic sites indicates their intimate involvement in the modulation of glutamatergic neurotransmission in the cerebellum. PMID:19558451

  19. Cochlear implantation following cerebellar surgery.

    PubMed

    Saeed, Shahad; Mawman, Deborah; Green, Kevin

    2011-08-01

    Cochlear implantation in patients with known central nervous system conditions can result in wide-ranging outcomes. The aim of this study is to report two cases of cochlear implantation outcomes in patients with acquired cerebellar ataxia following cerebellar surgery. The first is a female implanted with the Nucleus 24 implant in September 2000 and the second is a male implanted with a MED-EL Sonata Flexsoft electro-acoustic stimulation in July 2009. Programming these patients resulted in significant non-auditory stimulation which resulted in less than optimum map fittings. The patients did not gain any open set speech perception benefit although both of them gained an awareness of sound with the device. However, patient 2 elected to become a non-user because of the limited benefit.

  20. Nonsurgical cerebellar mutism (anarthria) in two children.

    PubMed

    Mewasingh, Leena D; Kadhim, Hazim; Christophe, Catherine; Christiaens, Florence J; Dan, Bernard

    2003-01-01

    Cerebellar mutism (anarthria) is a well-described complication of posterior fossa tumor resection. It is accompanied by a characteristic behavior including irritability and autistic features. This syndrome is typically reversible within days to months. Underlying pathophysiology is unknown. We describe two children who presented with a similar clinical finding after nonsurgical cerebellar involvement, hemolytic-uremic syndrome in one and cerebellitis in the other. Postmortem pathologic findings in the first patient indicated cerebellar ischemic necrosis. Single-photon emission computed tomography in the second patient revealed diffuse cerebellar hypoperfusion with no supratentorial abnormalities, refuting a phenomenon of diaschisis between cerebellar and frontal connections. These findings confirm that this clinical syndrome may occur in a nonsurgical, nontraumatic context. They are consistent with recent integrative hypotheses explaining cerebellar anarthria.

  1. Regulation of postsynaptic AMPA responses by synaptojanin 1.

    PubMed

    Gong, Liang-Wei; De Camilli, Pietro

    2008-11-11

    Endocytosis of postsynaptic AMPA receptors is a mechanism through which efficiency of neurotransmission is regulated. We have genetically tested the hypothesis that synaptojanin 1, a phosphoinositide phosphatase implicated in the endocytosis of synaptic vesicles presynaptically, may also function in the endocytosis of AMPA receptors postsynaptically. Electrophysiological recordings of cultured hippocampal neurons showed that miniature excitatory postsynaptic current amplitudes were larger in synaptojanin 1 knockout (KO) neurons because of an increase of surface-exposed AMPA receptors. This change did not represent an adaptive response to decreased presynaptic release in KO cultures and was rescued by the expression of wild type, but not catalytically inactive synaptojanin 1, in the postsynaptic neuron. NMDA-induced internalization of pHluorin-tagged AMPA receptors (GluR2) was impaired in KO neurons. These results reveal a function of synaptojanin 1 in constitutive and triggered internalization of AMPA receptors and thus indicate a role for phosphatidylinositol(4,5)-bisphosphate metabolism in the regulation of postsynaptic AMPA responses.

  2. Diffusion dynamics of synaptic molecules during inhibitory postsynaptic plasticity

    PubMed Central

    Petrini, Enrica Maria; Barberis, Andrea

    2014-01-01

    The plasticity of inhibitory transmission is expected to play a key role in the modulation of neuronal excitability and network function. Over the last two decades, the investigation of the determinants of inhibitory synaptic plasticity has allowed distinguishing presynaptic and postsynaptic mechanisms. While there has been a remarkable progress in the characterization of presynaptically-expressed plasticity of inhibition, the postsynaptic mechanisms of inhibitory long-term synaptic plasticity only begin to be unraveled. At postsynaptic level, the expression of inhibitory synaptic plasticity involves the rearrangement of the postsynaptic molecular components of the GABAergic synapse, including GABAA receptors, scaffold proteins and structural molecules. This implies a dynamic modulation of receptor intracellular trafficking and receptor surface lateral diffusion, along with regulation of the availability and distribution of scaffold proteins. This Review will focus on the mechanisms of the multifaceted molecular reorganization of the inhibitory synapse during postsynaptic plasticity, with special emphasis on the key role of protein dynamics to ensure prompt and reliable activity-dependent adjustments of synaptic strength. PMID:25294987

  3. Cbln1 downregulates the formation and function of inhibitory synapses in mouse cerebellar Purkinje cells.

    PubMed

    Ito-Ishida, Aya; Kakegawa, Wataru; Kohda, Kazuhisa; Miura, Eriko; Okabe, Shigeo; Yuzaki, Michisuke

    2014-04-01

    The formation of excitatory and inhibitory synapses must be tightly coordinated to establish functional neuronal circuitry during development. In the cerebellum, the formation of excitatory synapses between parallel fibers and Purkinje cells is strongly induced by Cbln1, which is released from parallel fibers and binds to the postsynaptic δ2 glutamate receptor (GluD2). However, Cbln1's role, if any, in inhibitory synapse formation has been unknown. Here, we show that Cbln1 downregulates the formation and function of inhibitory synapses between Purkinje cells and interneurons. Immunohistochemical analyses with an anti-vesicular GABA transporter antibody revealed an increased density of interneuron-Purkinje cell synapses in the cbln1-null cerebellum. Whole-cell patch-clamp recordings from Purkinje cells showed that both the amplitude and frequency of miniature inhibitory postsynaptic currents were increased in cbln1-null cerebellar slices. A 3-h incubation with recombinant Cbln1 reversed the increased amplitude of inhibitory currents in Purkinje cells in acutely prepared cbln1-null slices. Furthermore, an 8-day incubation with recombinant Cbln1 reversed the increased interneuron-Purkinje cell synapse density in cultured cbln1-null slices. In contrast, recombinant Cbln1 did not affect cerebellar slices from mice lacking both Cbln1 and GluD2. Finally, we found that tyrosine phosphorylation was upregulated in the cbln1-null cerebellum, and acute inhibition of Src-family kinases suppressed the increased inhibitory postsynaptic currents in cbln1-null Purkinje cells. These findings indicate that Cbln1-GluD2 signaling inhibits the number and function of inhibitory synapses, and shifts the excitatory-inhibitory balance towards excitation in Purkinje cells. Cbln1's effect on inhibitory synaptic transmission is probably mediated by a tyrosine kinase pathway.

  4. Genetics Home Reference: VLDLR-associated cerebellar hypoplasia

    MedlinePlus

    ... Conditions VLDLR-associated cerebellar hypoplasia VLDLR-associated cerebellar hypoplasia Enable Javascript to view the expand/collapse boxes. ... Open All Close All Description VLDLR -associated cerebellar hypoplasia is an inherited condition that affects the development ...

  5. Integration and regulation of glomerular inhibition in the cerebellar granular layer circuit

    PubMed Central

    Mapelli, Lisa; Solinas, Sergio; D'Angelo, Egidio

    2014-01-01

    Inhibitory synapses can be organized in different ways and be regulated by a multitude of mechanisms. One of the best known examples is provided by the inhibitory synapses formed by Golgi cells onto granule cells in the cerebellar glomeruli. These synapses are GABAergic and inhibit granule cells through two main mechanisms, phasic and tonic. The former is based on vesicular neurotransmitter release, the latter on the establishment of tonic γ-aminobutyric acid (GABA) levels determined by spillover and regulation of GABA uptake. The mechanisms of post-synaptic integration have been clarified to a considerable extent and have been shown to differentially involve α1 and α6 subunit-containing GABA-A receptors. Here, after reviewing the basic mechanisms of GABAergic transmission in the cerebellar glomeruli, we examine how inhibition controls signal transfer at the mossy fiber-granule cell relay. First of all, we consider how vesicular release impacts on signal timing and how tonic GABA levels control neurotransmission gain. Then, we analyze the integration of these inhibitory mechanisms within the granular layer network. Interestingly, it turns out that glomerular inhibition is just one element in a large integrated signaling system controlled at various levels by metabotropic receptors. GABA-B receptor activation by ambient GABA regulates glutamate release from mossy fibers through a pre-synaptic cross-talk mechanisms, GABA release through pre-synaptic auto-receptors, and granule cell input resistance through post-synaptic receptor activation and inhibition of a K inward-rectifier current. Metabotropic glutamate receptors (mGluRs) control GABA release from Golgi cell terminals and Golgi cell input resistance and autorhythmic firing. This complex set of mechanisms implements both homeostatic and winner-take-all processes, providing the basis for fine-tuning inhibitory neurotransmission and for optimizing signal transfer through the cerebellar cortex. PMID:24616663

  6. Augmenting LTP-Like Plasticity in Human Motor Cortex by Spaced Paired Associative Stimulation.

    PubMed

    Müller-Dahlhaus, Florian; Lücke, Caroline; Lu, Ming-Kuei; Arai, Noritoshi; Fuhl, Anna; Herrmann, Eva; Ziemann, Ulf

    2015-01-01

    Paired associative stimulation (PASLTP) of the human primary motor cortex (M1) can induce LTP-like plasticity by increasing corticospinal excitability beyond the stimulation period. Previous studies showed that two consecutive PASLTP protocols interact by homeostatic metaplasticity, but animal experiments provided evidence that LTP can be augmented by repeated stimulation protocols spaced by ~30 min. Here we tested in twelve healthy selected PASLTP responders the possibility that LTP-like plasticity can be augmented in the human M1 by systematically varying the interval between two consecutive PASLTP protocols. The first PASLTP protocol (PAS1) induced strong LTP-like plasticity lasting for 30-60 min. The effect of a second identical PASLTP protocol (PAS2) critically depended on the time between PAS1 and PAS2. At 10 min, PAS2 prolonged the PAS1-induced LTP-like plasticity. At 30 min, PAS2 augmented the LTP-like plasticity induced by PAS1, by increasing both magnitude and duration. At 60 min and 180 min, PAS2 had no effect on corticospinal excitability. The cumulative LTP-like plasticity after PAS1 and PAS2 at 30 min exceeded significantly the effect of PAS1 alone, and the cumulative PAS1 and PAS2 effects at 60 min and 180 min. In summary, consecutive PASLTP protocols interact in human M1 in a time-dependent manner. If spaced by 30 min, two consecutive PASLTP sessions can augment LTP-like plasticity in human M1. Findings may inspire further research on optimized therapeutic applications of non-invasive brain stimulation in neurological and psychiatric diseases.

  7. Effects of antiepileptic drugs on associative LTP-like plasticity in human motor cortex.

    PubMed

    Heidegger, Tonio; Krakow, Karsten; Ziemann, Ulf

    2010-10-01

    Antiepileptic drugs (AEDs) are used extensively in clinical practice but relatively little is known on their specific effects at the systems level of human cortex. Here we tested, using a double-blind randomized placebo-controlled crossover design in healthy subjects, the effects of a single therapeutic oral dose of seven AEDs with different modes of action (tiagabine, diazepam, gabapentin, lamotrigine, topiramate, levetiracetam and piracetam) on long-term potentiation (LTP)-like motor cortical plasticity induced by paired associative transcranial magnetic stimulation (PAS). PAS-induced LTP-like plasticity was assessed from the increase in motor evoked potential amplitude in a hand muscle contralateral to the stimulated motor cortex. Levetiracetam significantly reduced LTP-like plasticity when compared to the placebo condition. Tiagabine, diazepam, lamotrigine and piracetam resulted in nonsignificant trends towards reduction of LTP-like plasticity while gabapentin and topiramate had no effect. The particularly depressant effect of levetiracetam is probably explained by its unique mode of action through binding at the vesicle membrane protein SV2A. Enhancement of gamma-amino butyric acid-dependent cortical inhibition by tiagabine, diazepam and possibly levetiracetam, and blockage of voltage-gated sodium channels by lamotrigine, may also depress PAS-induced LTP-like plasticity but these mechanisms appear to be less relevant. Findings may inform about AED-related adverse effects on important LTP-dependent central nervous systems processes such as learning or memory formation. The particular depressant effect of levetiracetam on LTP-like plasticity may also relate to the unique properties of this drug to inhibit epileptogenesis, a potentially LTP-associated process.

  8. Synaptic pathology in the cerebellar dentate nucleus in chronic multiple sclerosis.

    PubMed

    Albert, Monika; Barrantes-Freer, Alonso; Lohrberg, Melanie; Antel, Jack P; Prineas, John W; Palkovits, Miklós; Wolff, Joachim R; Brück, Wolfgang; Stadelmann, Christine

    2016-10-05

    In multiple sclerosis, cerebellar symptoms are associated with clinical impairment and an increased likelihood of progressive course. Cortical atrophy and synaptic dysfunction play a prominent role in cerebellar pathology and although the dentate nucleus is a predilection site for lesion development, structural synaptic changes in this region remain largely unexplored. Moreover, the mechanisms leading to synaptic dysfunction have not yet been investigated at an ultrastructural level in multiple sclerosis. Here, we report on synaptic changes of dentate nuclei in post-mortem cerebella of 16 multiple sclerosis patients and eight controls at the histological level as well as an electron microscopy evaluation of afferent synapses of the cerebellar dentate and pontine nuclei of one multiple sclerosis patient and one control. We found a significant reduction of afferent dentate synapses in multiple sclerosis, irrespective of the presence of demyelination, and a close relationship between glial processes and dentate synapses. Ultrastructurally, we show autophagosomes containing degradation products of synaptic vesicles within dendrites, residual bodies within intact-appearing axons and free postsynaptic densities opposed to astrocytic appendages. Our study demonstrates loss of dentate afferent synapses and provides, for the first time, ultrastructural evidence pointing towards neuron-autonomous and neuroglia-mediated mechanisms of synaptic degradation in chronic multiple sclerosis.

  9. Simulated Responses of Cerebellar Purkinje Cells are Independent of the Dendritic Location of Granule Cell Synaptic Inputs

    NASA Astrophysics Data System (ADS)

    de Schutter, Erik; Bower, James M.

    1994-05-01

    Cerebellar Purkinje cell responses to granule cell synaptic inputs were examined with a computer model including active dendritic conductances. Dendritic P-type Ca2+ channels amplified postsynaptic responses when the model was firing at a physiological rate. Small synchronous excitatory inputs applied distally on the large dendritic tree resulted in somatic responses of similar size to those generated by more proximal inputs. In contrast, in a passive model the somatic postsynaptic potentials to distal inputs were 76% smaller. The model predicts that the somatic firing response of Purkinje cells is relatively insensitive to the exact dendritic location of synaptic inputs. We describe a mechanism of Ca2+-mediated synaptic amplification, based on the subspiking threshold recruitment of P-type Ca2+ channels in the dendritic branches surrounding the input site.

  10. LTP requires a reserve pool of glutamate receptors independent of subunit type.

    PubMed

    Granger, Adam J; Shi, Yun; Lu, Wei; Cerpas, Manuel; Nicoll, Roger A

    2013-01-24

    Long-term potentiation (LTP) of synaptic transmission is thought to be an important cellular mechanism underlying memory formation. A widely accepted model posits that LTP requires the cytoplasmic carboxyl tail (C-tail) of the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor subunit GluA1. To find the minimum necessary requirement of the GluA1 C-tail for LTP in mouse CA1 hippocampal pyramidal neurons, we used a single-cell molecular replacement strategy to replace all endogenous AMPA receptors with transfected subunits. In contrast to the prevailing model, we found no requirement of the GluA1 C-tail for LTP. In fact, replacement with the GluA2 subunit showed normal LTP, as did an artificially expressed kainate receptor not normally found at these synapses. The only conditions under which LTP was impaired were those with markedly decreased AMPA receptor surface expression, indicating a requirement for a reserve pool of receptors. These results demonstrate the synapse's remarkable flexibility to potentiate with a variety of glutamate receptor subtypes, requiring a fundamental change in our thinking with regard to the core molecular events underlying synaptic plasticity.

  11. Neonatal isolation alters LTP in freely moving juvenile rats: sex differences.

    PubMed

    Bronzino, J D; Kehoe, P; Austin-LaFrance, R J; Rushmore, R J; Kurdian, J

    1996-01-01

    We have previously reported that neonatal isolation significantly enhanced the magnitude of hippocampal long-term potentiation (LTP) recorded from freely moving male rats tested at 30 days of age. The present study extends this work to examine the effects of neonatal isolation on hippocampal LTP in male and female juvenile rats. Changes in dentate granule cell population measures, i.e., EPSP slope and population spike amplitude (PSA), evoked by tetanization of the medial perforant pathway were used to assess the effects of neonatal isolation on LTP over a period of 96 hrs. Prior to tetanization, significant sex differences were obtained for input/output (I/O) response measures of EPSP slope and PSA, with males showing consistently higher values than females. No significant effect of treatment was obtained within either sex for baseline measures. Following tetanization significant sex differences were also obtained for both measures, with males showing significantly greater enhancement than females. Comparisons made at 1 hr post-tetanization (establishment of LTP) indicated that isolated males showed significantly greater enhancement than any other group. On the other hand, treatment differences were not obtained from females. At 96 hrs (maintenance of LTP), however, both neonatally isolated males and females showed significantly greater enhancement than either non-isolated siblings or unhandled controls. These results indicate that males and females exhibit different enhancement profiles with respect to both the magnitude and duration of LTP, and that neonatal isolation alters these profiles in a sex-specific manner.

  12. Aromatase inhibition abolishes LTP generation in female but not in male mice.

    PubMed

    Vierk, Ricardo; Glassmeier, Günter; Zhou, Lepu; Brandt, Nicola; Fester, Lars; Dudzinski, Danuta; Wilkars, Wiebke; Bender, Roland A; Lewerenz, Martha; Gloger, Simon; Graser, Lucas; Schwarz, Jürgen; Rune, Gabriele M

    2012-06-13

    Inhibitors of aromatase, the final enzyme of estradiol synthesis, are suspected of inducing memory deficits in women. In previous experiments, we found hippocampal spine synapse loss in female mice that had been treated with letrozole, a potent aromatase inhibitor. In this study, we therefore focused on the effects of letrozole on long-term potentiation (LTP), which is an electrophysiological parameter of memory and is known to induce spines, and on phosphorylation of cofilin, which stabilizes the spine cytoskeleton and is required for LTP in mice. In acute slices of letrozole-treated female mice with reduced estradiol serum concentrations, impairment of LTP started as early as after 6 h of treatment and progressed further, together with dephosphorylation of cofilin in the same slices. Theta-burst stimulation failed to induce LTP after 1 week of treatment. Impairment of LTP was followed by spine and spine synapse loss. The effects were confirmed in vitro by using hippocampal slice cultures of female mice. The sequence of effects in response to letrozole were similar in ovariectomized female and male mice, with, however, differences as to the degree of downregulation. Our data strongly suggest that impairment of LTP, followed by loss of mushroom spines and spine synapses in females, may have implications for memory deficits in women treated with letrozole.

  13. Late-associativity, synaptic tagging, and the role of dopamine during LTP and LTD.

    PubMed

    Sajikumar, Sreedharan; Frey, Julietta U

    2004-07-01

    Protein synthesis-dependent, synapse input-specific late phases of long-term potentiation (LTP) and depression (LTD) may underlie memory formation at the cellular level. Recently, it was described that the induction of LTP can mark a specifically activated synapse by a synaptic tag to capture synapse non-specific plasticity-related proteins (PRPs) and thus maintaining input-specific LTP for prolonged periods. Here we show in rat hippocampal slices in vitro, that the induction of protein synthesis-dependent late-LTD is also characterized by synaptic tagging and that heterosynaptic induction of either LTD or LTP on two sets of independent synaptic inputs S1 and S2 can lead to late-associative interactions: early-LTD in S2 was transformed into a late-LTD, if late-LTP was induced in S1. The synthesis of process-independent PRPs by late-LTP in S1 was sufficient to transform early- into late-LTD in S2 when process-specific synaptic tags were set. We name this new associative property of cellular information processing 'cross-tagging.'

  14. Effects of Ketamine on Neuronal Spontaneous Excitatory Postsynaptic Currents and Miniature Excitatory Postsynaptic Currents in the Somatosensory Cortex of Rats

    PubMed Central

    Yuan, Chengdong; Zhang, Yajun; Zhang, Yu; Cao, Song; Wang, Yuan; Fu, Bao; Yu, Tian

    2016-01-01

    Background: Ketamine is a commonly used intravenous anesthetic which produces dissociation anesthesia, analgesia, and amnesia. The mechanism of ketamine-induced synaptic inhibition in high-level cortical areas is still unknown. We aimed to elucidate the effects of different concentrations of ketamine on the glutamatergic synaptic transmission of the neurons in the primary somatosensory cortex by using the whole-cell patch-clamp method. Methods: Sprague-Dawley rats (11–19 postnatal days, n=36) were used to obtain brain slices (300 μM). Spontaneous excitatory postsynaptic currents (data from 40 neurons) were recorded at a command potential of -70 mV in the presence of bicuculline (a competitive antagonist of GABAA receptors, 30 μM) and strychnine (glycine receptor antagonist, 30 μM). Miniature excitatory postsynaptic currents (data from 40 neurons) were also recorded when 1 μM of tetrodotoxin was added into the artificial cerebrospinal fluid. We used GraphPad Prism5for statistical analysis. Significant differences in the mean amplitude and frequency were tested using the Student paired 2-tailed t test. Values of P<0.05 were considered significant. Results: Different concentrations of ketamine inhibited the frequency and amplitude of the spontaneous excitatory postsynaptic currents as well as the amplitude of the miniature excitatory postsynaptic currents in a concentration-dependent manner, but they exerted no significant effect on the frequency of the miniature excitatory postsynaptic currents. Conclusion: Ketamine inhibited the excitatory synaptic transmission of the neurons in the primary somatosensory cortex. The inhibition may have been mediated by a reduction in the sensitivity of the postsynaptic glutamatergic receptors. PMID:27365548

  15. Prenatal melamine exposure impairs spatial cognition and hippocampal synaptic plasticity by presynaptic and postsynaptic inhibition of glutamatergic transmission in adolescent offspring.

    PubMed

    An, Lei; Sun, Wei

    2017-03-05

    Our previous studies showed that prenatal melamine exposure (PME) could impair spatial cognition and hippocampal long-term potentiation (LTP). More importantly, the synaptic dysfunction induced by PME was associated with the probability of presynaptic glutamate release. Considering the crucial role of the other form of synaptic plasticity, long-term depression (LTD), in some types of learning and memory process, the aim of present study was to investigate if the hippocampal LTD and cognitive flexibility were affected. And then we attempted to explore the underlying mechanism. The animal model was produced by melamine exposure throughout gestational period with 400mg/kg bodyweight, the male offspring rats were used in the study. Morris water maze (MWM) test was performed, and then LTD was recorded from Schaffer collaterals to CA1 region in the hippocampus. Behavioral test showed that learning, reference memory and re-acquisition learning abilities were impaired significantly by PME. The field excitatory postsynaptic potentials (fEPSPs) slopes of LTD were significantly higher after PME. Furthermore, the data of whole-cell patch-clamp experiments showed that PME markedly diminished the frequencies of spontaneous EPSCs (sEPSCs) and simultaneously reduced the amplitude of sEPSCs. In conclusion, PME inhibited glutamate transmission presynaptically and postsynaptically which could contribute importantly to the depressed hippocampal synaptic plasticity and further induced cognitive deficits in MWM tests.

  16. Destabilization of the Postsynaptic Density by PSD-95 Serine 73 Phosphorylation Inhibits Spine Growth and Synaptic Plasticity

    PubMed Central

    Steiner, Pascal; Higley, Michael J.; Xu, Weifeng; Czervionke, Brian L.; Malenka, Robert C.; Sabatini, Bernardo L.

    2009-01-01

    SUMMARY Long-term potentiation (LTP) is accompanied by dendritic spine growth and changes in the composition of the postsynaptic density (PSD). We find that activity-dependent growth of apical spines of CA1 pyramidal neurons is accompanied by destabilization of the PSD that results in transient loss and rapid replacement of PSD-95 and SHANK2. Signaling through PSD-95 is required for activity-dependent spine growth and trafficking of SHANK2. N-terminal PDZ and C-terminal guanylate kinase domains of PSD-95 are required for both processes, indicating that PSD-95 coordinates multiple signals to regulate morphological plasticity. Activity-dependent trafficking of PSD-95 is triggered by phosphorylation at serine 73, a conserved calcium/calmodulin-dependent protein kinase II (CaMKII) consensus phosphorylation site, which negatively regulates spine growth and potentiation of synaptic currents. We propose that PSD-95 and CaMKII act at multiple steps during plasticity induction to initially trigger and later terminate spine growth by trafficking growth-promoting PSD proteins out of the active spine. PMID:19081375

  17. Altered cerebellar feedback projections in Asperger syndrome.

    PubMed

    Catani, Marco; Jones, Derek K; Daly, Eileen; Embiricos, Nitzia; Deeley, Quinton; Pugliese, Luca; Curran, Sarah; Robertson, Dene; Murphy, Declan G M

    2008-07-15

    It has been proposed that the biological basis of autism spectrum disorder includes cerebellar 'disconnection'. However, direct in vivo evidence in support of this is lacking. Here, the microstructural integrity of cerebellar white matter in adults with Asperger syndrome was studied using diffusion tensor magnetic resonance tractography. Fifteen adults with Asperger syndrome and 16 age-IQ-gender-matched healthy controls underwent diffusion tensor magnetic resonance imaging. For each subject, tract-specific measurements of mean diffusivity and fractional anisotropy were made within the inferior, middle, superior cerebellar peduncles and short intracerebellar fibres. No group differences were observed in mean diffusivity. However, people with Asperger syndrome had significantly lower fractional anisotropy in the short intracerebellar fibres (p<0.001) and right superior cerebellar (output) peduncle (p<0.001) compared to controls; but no difference in the input tracts. Severity of social impairment, as measured by the Autistic Diagnostic Interview, was negatively correlated with diffusion anisotropy in the fibres of the left superior cerebellar peduncle. These findings suggest a vulnerability of specific cerebellar neural pathways in people with Asperger syndrome. The localised abnormalities in the main cerebellar outflow pathway may prevent the cerebral cortex from receiving those cerebellar feedback inputs necessary for a successful adaptive social behaviour.

  18. Learning of Sensory Sequences in Cerebellar Patients

    ERIC Educational Resources Information Center

    Frings, Markus; Boenisch, Raoul; Gerwig, Marcus; Diener, Hans-Christoph; Timmann, Dagmar

    2004-01-01

    A possible role of the cerebellum in detecting and recognizing event sequences has been proposed. The present study sought to determine whether patients with cerebellar lesions are impaired in the acquisition and discrimination of sequences of sensory stimuli of different modalities. A group of 26 cerebellar patients and 26 controls matched for…

  19. Acute cerebellar ataxia and infectious mononucleosis.

    PubMed Central

    Wadhwa, N. K.; Ghose, R. R.

    1983-01-01

    A 28-year-old man, who presented with acute cerebellar ataxia, was found to have haematological features of infectious mononucleosis. There was serological evidence of recent infection with Epstein-Barr virus. It is speculated that cerebellar dysfunction results from virus-induced inflammatory changes within the central nervous system. PMID:6312442

  20. Consensus Paper: Management of Degenerative Cerebellar Disorders

    PubMed Central

    Ilg, W.; Bastian, A. J.; Boesch, S.; Burciu, R. G.; Celnik, P.; Claaßen, J.; Feil, K.; Kalla, R.; Miyai, I.; Nachbauer, W.; Schöls, L.; Strupp, M.; Synofzik, M.; Teufel, J.

    2015-01-01

    Treatment of motor symptoms of degenerative cerebellar ataxia remains difficult. Yet there are recent developments that are likely to lead to significant improvements in the future. Most desirable would be a causative treatment of the underlying cerebellar disease. This is currently available only for a very small subset of cerebellar ataxias with known metabolic dysfunction. However, increasing knowledge of the pathophysiology of hereditary ataxia should lead to an increasing number of medically sensible drug trials. In this paper, data from recent drug trials in patients with recessive and dominant cerebellar ataxias will be summarized. There is consensus that up to date, no medication has been proven effective. Aminopyridines and acetazolamide are the only exception, which are beneficial in patients with episodic ataxia type 2. Aminopyridines are also effective in a subset of patients presenting with downbeat nystagmus. As such, all authors agreed that the mainstays of treatment of degenerative cerebellar ataxia are currently physiotherapy, occupational therapy, and speech therapy. For many years, well-controlled rehabilitation studies in patients with cerebellar ataxia were lacking. Data of recently published studies show that coordinative training improves motor function in both adult and juvenile patients with cerebellar degeneration. Given the well-known contribution of the cerebellum to motor learning, possible mechanisms underlying improvement will be outlined. There is consensus that evidence-based guidelines for the physiotherapy of degenerative cerebellar ataxia need to be developed. Future developments in physiotherapeutical interventions will be discussed including application of non-invasive brain stimulation. PMID:24222635

  1. Metronidazole-Induced Cerebellar Toxicity

    PubMed Central

    Agarwal, Amit; Kanekar, Sangam; Sabat, Shyam; Thamburaj, Krishnamurthy

    2016-01-01

    Metronidazole is a very common antibacterial and antiprotozoal with wide usage across the globe, including the least developed countries. It is generally well-tolerated with a low incidence of serious side-effects. Neurological toxicity is fairly common with this drug, however majority of these are peripheral neuropathy with very few cases of central nervous toxicity reported. We report the imaging findings in two patients with cerebellar dysfunction after Metronidazole usage. Signal changes in the dentate and red nucleus were seen on magnetic resonance imaging in these patients. Most of the cases reported in literature reported similar findings, suggesting high predilection for the dentate nucleus in metronidazole induced encephalopathy. PMID:27127600

  2. Ethanol affects NMDA receptor signaling at climbing fiber-Purkinje cell synapses in mice and impairs cerebellar LTD.

    PubMed

    He, Qionger; Titley, Heather; Grasselli, Giorgio; Piochon, Claire; Hansel, Christian

    2013-03-01

    Ethanol profoundly influences cerebellar circuit function and motor control. It has recently been demonstrated that functional N-methyl-(D)-aspartate (NMDA) receptors are postsynaptically expressed at climbing fiber (CF) to Purkinje cell synapses in the adult cerebellum. Using whole cell patch-clamp recordings from mouse cerebellar slices, we examined whether ethanol can affect NMDA receptor signaling in mature Purkinje cells. NMDA receptor-mediated currents were isolated by bath application of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoylbenzol[f]quinoxaline (NBQX). The remaining (D)-2-amino-5-phosphonovaleric acid ((D)-APV)-sensitive current was reduced by ethanol at concentrations as low as 10 mM. At a concentration of 50 mM ethanol, the blockade of (D)-APV-sensitive CF-excitatory postsynaptic currents was significantly stronger. Ethanol also altered the waveform of CF-evoked complex spikes by reducing the afterdepolarization. This effect was not seen when NMDA receptors were blocked by (D)-APV before ethanol wash-in. In contrast to CF synaptic transmission, parallel fiber (PF) synaptic inputs were not affected by ethanol. Finally, ethanol (10 mM) impaired long-term depression (LTD) at PF to Purkinje cell synapses as induced under control conditions by paired PF and CF activity. However, LTD induced by pairing PF stimulation with depolarizing voltage steps (substituting for CF activation) was not blocked by ethanol. These observations suggest that the sensitivity of cerebellar circuit function and plasticity to low concentrations of ethanol may be caused by an ethanol-mediated impairment of NMDA receptor signaling at CF synapses onto cerebellar Purkinje cells.

  3. Cooperation of taurine uptake and dopamine D1 receptor activation facilitates the induction of protein synthesis-dependent late LTP.

    PubMed

    Suárez, Luz M; Bustamante, Julián; Orensanz, Luís M; Martín del Río, Rafael; Solís, José M

    2014-04-01

    Co-activation of NMDA and dopamine receptors is required for the induction of the late phase of LTP (L-LTP) that is dependent on new protein synthesis. Other neuromodulatory substances may also contribute to this process. Here, we examined whether taurine is one of the neuromodulators contributing to L-LTP induction, since it is known that taurine uptake induces a long-lasting synaptic potentiation dependent on protein synthesis, and taurine uptake inhibition blocks L-LTP induced by tetanization. Experiments were conducted using rat hippocampal slices where field synaptic potentials were evoked and recorded in CA3-CA1 synapses. Taurine (1 mM) applied 10 min before a high frequency stimulation (HFS) train converted a transitory early-LTP (E-LTP) into an L-LTP dependent on protein synthesis. This taurine effect was blocked by a taurine uptake inhibitor. A facilitation of L-LTP induction was also obtained by pre-application of SKF38393, a D1/D5 dopamine receptor (D1R) agonist. In this case, LTP facilitation was not affected by the taurine uptake inhibitor. Nevertheless, when taurine and SKF38393 were simultaneously pre-applied at a concentration that individually did not modify E-LTP, they produced a synergistic mechanism that facilitated the induction of L-LTP with a sole HFS train. This facilitation of L-LTP was blocked by inhibiting either taurine uptake or D1R activation. Taurine and SKF38393 activated different signaling pathways to transform E-LTP into L-LTP. Taurine-induced L-LTP facilitation required MAPK activation, while D1R-agonist-induced facilitation depended mainly on PKA activation and partially on MAPK activation. On the other hand, the synergistic mechanisms induced by the cooperative action of taurine and SKF38393 were impaired by inhibitors against MAPK, PKA and PI3-K. This pharmacological profile resembles that displayed by L-LTP induced by three HFS trains at 10-min intervals. These results indicate that taurine uptake is necessary and

  4. Remodeling of the postsynaptic plasma membrane during neural development

    PubMed Central

    Tulodziecka, Karolina; Diaz-Rohrer, Barbara B.; Farley, Madeline M.; Chan, Robin B.; Di Paolo, Gilbert; Levental, Kandice R.; Waxham, M. Neal; Levental, Ilya

    2016-01-01

    Neuronal synapses are the fundamental units of neural signal transduction and must maintain exquisite signal fidelity while also accommodating the plasticity that underlies learning and development. To achieve these goals, the molecular composition and spatial organization of synaptic terminals must be tightly regulated; however, little is known about the regulation of lipid composition and organization in synaptic membranes. Here we quantify the comprehensive lipidome of rat synaptic membranes during postnatal development and observe dramatic developmental lipidomic remodeling during the first 60 postnatal days, including progressive accumulation of cholesterol, plasmalogens, and sphingolipids. Further analysis of membranes associated with isolated postsynaptic densities (PSDs) suggests the PSD-associated postsynaptic plasma membrane (PSD-PM) as one specific location of synaptic remodeling. We analyze the biophysical consequences of developmental remodeling in reconstituted synaptic membranes and observe remarkably stable microdomains, with the stability of domains increasing with developmental age. We rationalize the developmental accumulation of microdomain-forming lipids in synapses by proposing a mechanism by which palmitoylation of the immobilized scaffold protein PSD-95 nucleates domains at the postsynaptic plasma membrane. These results reveal developmental changes in lipid composition and palmitoylation that facilitate the formation of postsynaptic membrane microdomains, which may serve key roles in the function of the neuronal synapse. PMID:27535429

  5. Postsynaptic Deregulation in GAP-43 Heterozygous Mouse Barrel Cortex

    PubMed Central

    Kelly, Emily A.; Tremblay, Marie-Ève; McCasland, James S.

    2010-01-01

    Formation of whisker-related barrels in primary somatosensory cortex (S1) requires communication between presynaptic thalamocortical afferents (TCAs) and postsynaptic cortical neurons. GAP-43 is crucially involved in targeting TCAs to postsynaptic S1 neurons but its influence on the interactions between these 2 elements has not been explored. Here, we tested the hypothesis that reduced early expression of presynaptic GAP-43 (GAP-43 heterozygous [HZ] mice) alters postsynaptic differentiation of barrel cells. We found a transient increase in cytochrome oxidase staining between P6 and P14 in HZ animals, indicative of increased metabolic activity in barrel cortex during this time. Golgi impregnation and microtubule-associated protein 2 immunohistochemistry showed anomalous dendritic patterning in GAP-43 HZ cortex at P5, with altered dendritic length and branching and abnormal retention of dendrites that extend into developing septa. This deficiency was no longer apparent at P7, suggesting partial recovery of dendritic pruning processes. Finally, we showed early defects in synaptogenesis from P4 to P5 with increased colocalization of NR1 and GluR1 staining in HZ mice. By P7, this colocalization had normalized to wild type levels. Taken together, our findings suggest abnormal postsynaptic differentiation in GAP-43 HZ cortex during early barrel development, followed by adaptive compensation and partial phenotypic rescue. PMID:19915093

  6. Cerebellar Stroke-manifesting as Mania

    PubMed Central

    Jagadesan, Venkatesan; Thiruvengadam, Kannapiran R.; Muralidharan, Rengarajalu

    2014-01-01

    Secondary mania resulting from cerebral Cortex are described commonly. But secondary mania produced by cerebellar lesions are relatively uncommon. This case report describes a patient who developed cerebellar stoke and manic features simultaneously. 28 years old male developed giddiness and projectile vomiting. Then he would lie down for about an hour only to find that he could not walk. He became quarrelsome. His Psycho motor activities and speech were increased. He was euphoric and was expressing grandiose ideas. Bender Gestalt Test showed signs of organicity. Score in Young mania relating scale was 32; productivity was low in Rorschach. Neurological examination revealed left cerebellar signs like ataxia and slurring of speech. Computed tomography of brain showed left cerebellar infarct. Relationship between Psychiatric manifestations and cerebellar lesion are discussed. PMID:25035567

  7. Postsynaptic membrane shifts during frequency potentiation of the hippocampal EPSP.

    PubMed

    Pitler, T A; Landfield, P W

    1987-10-01

    1. In some classes of central neurons, repetitive synaptic stimulation induces substantial changes in the postsynaptic membrane, in conjunction with robust frequency potentiation of the excitatory postsynaptic potential (EPSP). However, the nature and time course of these postsynaptic membrane shifts, or their possible contributions to EPSP frequency potentiation (e.g., by altering driving force or current pathways), have not been examined extensively. We therefore studied the simultaneous patterns of change in composite EPSP amplitude, postsynaptic input resistance (Rin), and postsynaptic membrane potential during a 4-min train of 10-Hz monosynaptic stimulation in CA1 neurons of hippocampal slices. Slices were maintained in media containing either control (4 mM) or high (6.5 mM) concentrations of K+. 2. Potentiation of the EPSP, hyperpolarization of the membrane, and a decline of Rin, all developed rapidly during 10-Hz synaptic stimulation; these responses reached maximal levels by 5-15 s of the stimulation train. In most cells, a membrane depolarization phase occurred between 15 and 45 s of stimulation, followed by rehyperpolarization by 1 min of stimulation. During the depolarization phase, both EPSP potentiation and the decline in Rin remained near maximal. No significant differences were seen as a function of K+ concentrations. 3. These results show that hyperpolarization is not invariably associated temporally with EPSP frequency potentiation. Moreover, if driving force and membrane conductance changes are assumed to be approximately similar in large dendrites and soma, then the increase in driving force due to membrane hyperpolarization was not sufficient to account for the three- and fourfold increases in EPSP amplitude seen during frequency potentiation. Further, based on similar assumptions and on dendritic models of EPSP attenuation, the decline in Rin should reduce EPSP amplitude at the dendritic synaptic site and, to a proportionately greater extent

  8. Deleterious effects of a low amount of ethanol on LTP-like plasticity in human cortex.

    PubMed

    Lücke, Caroline; Heidegger, Tonio; Röhner, Mirjam; Toennes, Stefan W; Krivanekova, Lucia; Müller-Dahlhaus, Florian; Ziemann, Ulf

    2014-05-01

    Ingesting ethanol (EtOH) at low doses during social drinking is a common human behavior for its facilitating effects on social interactions. However, low-dose EtOH may have also detrimental effects that so far are underexplored. Here we sought to test the effects of low-dose EtOH on long-term potentiation (LTP)-like plasticity in human motor cortex. Previous cellular experiments showed that low-dose EtOH potentiates extrasynaptic GABAAR and reduces NMDAR-mediated currents, processes that would limit the expression of LTP. Paired associative transcranial magnetic stimulation (PASLTP) was employed in nine healthy subjects for induction of LTP-like plasticity, indexed by a long-term increase in motor-evoked potential input-output curves. Synaptic α1-GABAAR function was measured by saccadic peak velocity (SPV). Very low doses of EtOH (resulting in blood concentrations of <5 mM) suppressed LTP-like plasticity but did not affect SPV when compared with a placebo condition. In contrast, 1 mg of alprazolam, a classical benzodiazepine, or 10 mg of zolpidem, a non-benzodiazepine hypnotic, decreased SPV but did not significantly affect LTP-like plasticity when compared with placebo. This double dissociation of low-dose EtOH vs alprazolam/zolpidem effects is best explained by the putatively high affinity of EtOH but not alprazolam/zolpidem to extrasynaptic GABAARs and to NMDARs. Findings suggest that enhancement of extrasynaptic GABAAR-mediated tonic inhibition and/or reduction of NMDAR-mediated neurotransmission by EtOH blocks LTP-like plasticity in human cortex at very low doses that are easily reached during social drinking. Therefore, low-dose EtOH may jeopardize LTP-dependent processes, such as learning and memory formation.

  9. Afferent Input Selects NMDA Receptor Subtype to Determine the Persistency of Hippocampal LTP in Freely Behaving Mice

    PubMed Central

    Ballesteros, Jesús J.; Buschler, Arne; Köhr, Georg; Manahan-Vaughan, Denise

    2016-01-01

    The glutamatergic N-methyl-D-aspartate receptor (NMDAR) is critically involved in many forms of hippocampus-dependent memory that may be enabled by synaptic plasticity. Behavioral studies with NMDAR antagonists and NMDAR subunit (GluN2) mutants revealed distinct contributions from GluN2A- and GluN2B-containing NMDARs to rapidly and slowly acquired memory performance. Furthermore, studies of synaptic plasticity, in genetically modified mice in vitro, suggest that GluN2A and GluN2B may contribute in different ways to the induction and longevity of synaptic plasticity. In contrast to the hippocampal slice preparation, in behaving mice, the afferent frequencies that induce synaptic plasticity are very restricted and specific. In fact, it is the stimulus pattern and not variations in afferent frequency that determine the longevity of long-term potentiation (LTP) in vivo. Here, we explored the contribution of GluN2A and GluN2B to LTP of differing magnitudes and persistence in freely behaving mice. We applied differing high-frequency stimulation (HFS) patterns at 100 Hz to the hippocampal CA1 region, to induce NMDAR-dependent LTP in wild-type (WT) mice, that endured for <1 h (early (E)-LTP), (LTP, 2–4 h) or >24 h (late (L)-LTP). In GluN2A-knockout (KO) mice, E-LTP (HFS, 50 pulses) was significantly reduced in magnitude and duration, whereas LTP (HFS, 2 × 50 pulses) and L-LTP (HFS, 4 × 50 pulses) were unaffected compared to responses in WT animals. By contrast, pharmacological antagonism of GluN2B in WT had no effect on E-LTP but significantly prevented LTP. E-LTP and LTP were significantly impaired by GluN2B antagonism in GluN2A-KO mice. These data indicate that the pattern of afferent stimulation is decisive for the recruitment of distinct GluN2A and GluN2B signaling pathways that in turn determine the persistency of hippocampal LTP. Whereas brief bursts of patterned stimulation preferentially recruit GluN2A and lead to weak and short-lived forms of LTP, prolonged

  10. Translating LTP from animals to humans: A novel method for non-invasive assessment of cortical plasticity

    PubMed Central

    Clapp, Wesley C.; Hamm, Jeff P.; Kirk, Ian J.; Teyler, Timothy J.

    2011-01-01

    Long-term potentiation (LTP) is a synaptic mechanism underlying learning and memory that has been studied extensively in laboratory animals. The study of LTP recently has been extended into humans using repetitive sensory stimulation to induce cortical LTP. In this review paper we will discuss past results from our group demonstrating that repetitive sensory stimulation (visual or auditory) induces LTP within the sensory cortex (visual/auditory, respectively) and can be measured non-invasively using EEG or fMRI. We will discuss a number of studies that indicate that this form of LTP shares several characteristics with the synaptic LTP described in animals: it is frequency dependent, long-lasting (>1 hour), input specific, depotentiates with low-frequency stimulation, and is blocked by NMDA receptor blockers in rats. In this paper we also present new data regarding the behavioral significance of human sensory LTP. These advances will permit enquiry into the functional significance of LTP that has been hindered by the absence of a human model. The ability to elicit LTP using a natural sensory stimulus non-invasively will provide a model system allowing the detailed examination of synaptic plasticity in normal subjects and may have future clinical applications in the diagnosis and assessment of neuropsychiatric and neurocognitive disorders. PMID:21974785

  11. Wnt signaling: role in LTP, neural networks and memory.

    PubMed

    Oliva, Carolina A; Vargas, Jessica Y; Inestrosa, Nibaldo C

    2013-06-01

    Wnt components are key regulators of a variety of developmental processes, including embryonic patterning, cell specification, and cell polarity. The Wnt signaling pathway participates in the development of the central nervous system and growing evidence indicates that Wnts also regulates the function of the adult nervous system. In fact, most of the key components including Wnts and Frizzled receptors are expressed in the adult brain. Wnt ligands have been implicated in the regulation of synaptic assembly as well as in neurotransmission and synaptic plasticity. Deregulation of Wnt signaling has been associated with several pathologies, and more recently has been related to neurodegenerative diseases and to mental and mood disorders. In this review, we focus our attention on the Wnt signaling cascade in postnatal life and we review in detail the presence of Wnt signaling components in pre- and postsynaptic regions. Due to the important role of Wnt proteins in wiring neural circuits, we discuss recent findings about the role of Wnt pathways both in basal spontaneous activities as well as in activity-dependent processes that underlie synaptic plasticity. Finally, we review the role of Wnt in vivo and we finish with the most recent data in literature that involves the effect of components of the Wnt signaling pathway in neurological and mental disorders, including a special emphasis on in vivo studies that relate behavioral abnormalities to deficiencies in Wnt signaling, as well as the data that support a neuroprotective role of Wnt proteins in relation to the pathogenesis of Alzheimer's disease.

  12. Active integration of glutamatergic input to the inferior olive generates bidirectional postsynaptic potentials

    PubMed Central

    Garden, Derek L. F.; Rinaldi, Arianna

    2016-01-01

    Key points We establish experimental preparations for optogenetic investigation of glutamatergic input to the inferior olive.Neurones in the principal olivary nucleus receive monosynaptic extra‐somatic glutamatergic input from the neocortex.Glutamatergic inputs to neurones in the inferior olive generate bidirectional postsynaptic potentials (PSPs), with a fast excitatory component followed by a slower inhibitory component.Small conductance calcium‐activated potassium (SK) channels are required for the slow inhibitory component of glutamatergic PSPs and oppose temporal summation of inputs at intervals ≤ 20 ms.Active integration of synaptic input within the inferior olive may play a central role in control of olivo‐cerebellar climbing fibre signals. Abstract The inferior olive plays a critical role in motor coordination and learning by integrating diverse afferent signals to generate climbing fibre inputs to the cerebellar cortex. While it is well established that climbing fibre signals are important for motor coordination, the mechanisms by which neurones in the inferior olive integrate synaptic inputs and the roles of particular ion channels are unclear. Here, we test the hypothesis that neurones in the inferior olive actively integrate glutamatergic synaptic inputs. We demonstrate that optogenetically activated long‐range synaptic inputs to the inferior olive, including projections from the motor cortex, generate rapid excitatory potentials followed by slower inhibitory potentials. Synaptic projections from the motor cortex preferentially target the principal olivary nucleus. We show that inhibitory and excitatory components of the bidirectional synaptic potentials are dependent upon AMPA (GluA) receptors, are GABAA independent, and originate from the same presynaptic axons. Consistent with models that predict active integration of synaptic inputs by inferior olive neurones, we find that the inhibitory component is reduced by blocking large conductance

  13. The dendritic branch is the preferred integrative unit for protein synthesis-dependent LTP

    PubMed Central

    Govindarajan, Arvind; Israely, Inbal; Huang, Shu-Ying; Tonegawa, Susumu

    2011-01-01

    Summary The late-phase of long-term potentiation (L-LTP), the cellular correlate of long-term memory, induced at some synapses facilitates L-LTP expression at other synapses receiving stimulation too weak to induce L-LTP by itself. Using glutamate uncaging and two-photon imaging, we demonstrate that the efficacy of this facilitation decreases with increasing time between stimulations, increasing distance between stimulated spines and with the spines being on different dendritic branches. Paradoxically, stimulated spines compete for L-LTP expression if stimulated too closely together in time. Furthermore, the facilitation is temporally bidirectional but asymmetric. Additionally, L-LTP formation is itself biased towards occurring on spines within a branch. These data support the Clustered Plasticity Hypothesis which states that such spatial and temporal limits lead to stable engram formation, preferentially at synapses clustered within dendritic branches rather than dispersed throughout the dendritic arbor. Thus, dendritic branches rather than individual synapses are the primary functional units for long-term memory storage. PMID:21220104

  14. MGluR5 mediates the interaction between late-LTP, network activity, and learning.

    PubMed

    Bikbaev, Arthur; Neyman, Sergey; Ngomba, Richard Teke; Conn, P Jeffrey; Conn, Jeffrey; Nicoletti, Ferdinando; Manahan-Vaughan, Denise

    2008-05-14

    Hippocampal synaptic plasticity and learning are strongly regulated by metabotropic glutamate receptors (mGluRs) and particularly by mGluR5. Here, we investigated the mechanisms underlying mGluR5-modulation of these phenomena. Prolonged pharmacological blockade of mGluR5 with MPEP produced a profound impairment of spatial memory. Effects were associated with 1) a reduction of mGluR1a-expression in the dentate gyrus; 2) impaired dentate gyrus LTP; 3) enhanced CA1-LTP and 4) suppressed theta (5-10 Hz) and gamma (30-100 Hz) oscillations in the dentate gyrus. Allosteric potentiation of mGluR1 after mGluR5 blockade significantly ameliorated dentate gyrus LTP, as well as suppression of gamma oscillatory activity. CA3-lesioning prevented MPEP effects on CA1-LTP, suggesting that plasticity levels in CA1 are driven by mGluR5-dependent synaptic and network activity in the dentate gyrus. These data support the hypothesis that prolonged mGluR5-inactivation causes altered hippocampal LTP levels and network activity, which is mediated in part by impaired mGluR1-expression in the dentate gyrus. The consequence is impairment of long-term learning.

  15. The efficacy of low temperature plasma (LTP) sterilization, a new sterilization technique.

    PubMed

    Höller, C; Martiny, H; Christiansen, B; Rüden, H; Gundermann, K O

    1993-07-01

    The efficacy of low temperature plasma (LTP) sterilization, a newly developed sterilization procedure was tested. Following experiments were carried out: Determination of the most resistant test organism, influence of 10% and 20% defibrinated sheep blood or varying salt concentrations on the efficacy of the sterilization process, influence of the carrier position in the sterilization chamber and in the sterilization pouches, influence of a loaded sterilization chamber, comparative efficacy of EO and LTP, steel carriers with a blood burden of 0%, 5% and 10%, comparative efficacy of EO and LTP, strip carriers in endoscopes, blood burden 0% and 10%, with and without adaptors, evaluation of two bioindicator models. B. pumilus was the test spore that overall seemed to be most resistant to the sterilization procedure. Supplementation of the test suspension with blood or saline crystals resulted in significantly reduced efficacy and has to be avoided in practical operation. The fully loaded sterilization chamber or the position of germ carriers on the shelves had no negative influence on the effectivity of the sterilization process. There were no significant differences between EO and LTP, the blood burden not exceeding 5%. 10% blood burden resulted in a significantly weaker action of LTP. For sterilization of long lumens adaptors containing hydrogen peroxide are necessary. An appropriate bioindicator tube model is introduced.

  16. [Memory transfer in cerebellar motor learning].

    PubMed

    Nagao, Soichi

    2012-01-01

    Most of our motor skills are acquired through learning. Experiments of gain adaptation of ocular reflexes have consistently suggested that the memory of adaptation is initially formed in the cerebellar cortex, and is transferred to the cerebellar (vestibular) nuclei for consolidation to long-term memory after repetitions of training. We have recently developed a new system to evaluate the motor learning in human subjects using prism adaptation of hand reaching movement, by referring to the prism adaptation of dart throwing of Martin et al. (1996). In our system, the subject views the small target presented in the touch-panel screen, and touches it with his/her finger without direct visual feedback. After 15-30 trials of touching wearing prisms, an adaptation occurs in healthy subjects: they became able to touch the target correctly. Meanwhile, such an adaptation was impaired in patients of cerebellar disease. We have proposed a model of human prism adaptation that the memory of adaptation is initially encoded in the cerebellar cortex, and is later transferred to the cerebellar nuclei after repetitions of training. The memory in the cerebellar cortex may be formed and extinguished independently of the memory maintained in the cerebellar nuclei, and these two memories work cooperatively.

  17. Sonic hedgehog patterning during cerebellar development.

    PubMed

    De Luca, Annarita; Cerrato, Valentina; Fucà, Elisa; Parmigiani, Elena; Buffo, Annalisa; Leto, Ketty

    2016-01-01

    The morphogenic factor sonic hedgehog (Shh) actively orchestrates many aspects of cerebellar development and maturation. During embryogenesis, Shh signaling is active in the ventricular germinal zone (VZ) and represents an essential signal for proliferation of VZ-derived progenitors. Later, Shh secreted by Purkinje cells sustains the amplification of postnatal neurogenic niches: the external granular layer and the prospective white matter, where excitatory granule cells and inhibitory interneurons are produced, respectively. Moreover, Shh signaling affects Bergmann glial differentiation and promotes cerebellar foliation during development. Here we review the most relevant functions of Shh during cerebellar ontogenesis, underlying its role in physiological and pathological conditions.

  18. Dynamic properties of corticothalamic excitatory postsynaptic potentials and thalamic reticular inhibitory postsynaptic potentials in thalamocortical neurons of the guinea-pig dorsal lateral geniculate nucleus.

    PubMed

    von Krosigk, M; Monckton, J E; Reiner, P B; McCormick, D A

    1999-01-01

    The properties of postsynaptic potentials evoked by stimulation of cortical, retinal and GABAergic thalamic afferents were examined in vitro in thalamocortical neurons of the guinea-pig dorsal lateral geniculate nucleus. Brief trains of stimulation (2-10 stimuli) delivered to corticothalamic fibers led to a frequency-dependent increase in excitatory postsynaptic potential amplitude associated with an increase in activation of both N-methyl-D-aspartate and non-N-methyl-D-aspartate glutamate receptors. In addition, repetitive stimulation of corticothalamic fibers also gave rise to a slow excitatory postsynaptic potential that was blocked by local application of the glutamate metabotropic receptor antagonist alpha-methyl-4-carboxyphenylglycine. In contrast, repetitive stimulation of optic tract fibers resulted in monosynaptic excitatory postsynaptic potentials that did not potentiate and were not followed by the generation of a slow excitatory postsynaptic potential. Repetitive activation of the optic radiation also evoked both GABA(A) and GABA(B) receptor-mediated inhibitory postsynaptic potentials. These inhibitory postsynaptic potentials exhibited frequency-dependent depression during repetitive activation. The presence of frequency-dependent facilitation of corticothalamic excitatory postsynaptic potentials and frequency-dependent decrement of inhibitory postsynaptic potentials, as well as the ability of corticothalamic fibers to activate glutamate metabotropic receptors, suggests that sustained activation of corticothalamic afferents in vivo may result in postsynaptic responses in thalamocortical cells that are initially dominated by GABAergic inhibitory postsynaptic potentials followed by prominent monosynaptic excitatory postsynaptic potentials as well as a slow depolarization of the membrane potential.Therefore, the corticothalamic system may inhibit or enhance the excitability and responsiveness of thalamocortical neurons, based both on the spatial and

  19. Cystic cerebellar astrocytomas in childhood.

    PubMed

    Griffin, T W; Beaufait, D; Blasko, J C

    1979-07-01

    Thirty-nine patients with low grade cystic cerebellar astrocytomas were treated at the University of Washington and Children's Orthopedic Hospital in Seattle, Washington, between 1955 and 1977; 29 were treated with partial or complete resection alone, and 10 received radiation therapy after various types of surgical procedures. With a mean follow-up time of 7 years, the survival rate for patients who had complete resections of their primary disease was 100%. The relapse-free survival rate was 82%. The relapse-free survival rate for patients treated primarily with partial resection alone was 36%. Postoperative irradiation after partial resection for both primary and recurrent disease resulted in a relapse-free survival rate of 83%. If complete tumor excision is not possible, postoperative radiation therapy is recommended following partial resection.

  20. The Postsynaptic Density: There Is More than Meets the Eye

    PubMed Central

    Dosemeci, Ayse; Weinberg, Richard J.; Reese, Thomas S.; Tao-Cheng, Jung-Hwa

    2016-01-01

    The postsynaptic density (PSD), apparent in electron micrographs as a dense lamina just beneath the postsynaptic membrane, includes a deeper layer, the “pallium”, containing a scaffold of Shank and Homer proteins. Though poorly defined in traditionally prepared thin-section electron micrographs, the pallium becomes denser and more conspicuous during intense synaptic activity, due to the reversible addition of CaMKII and other proteins. In this Perspective article, we review the significance of CaMKII-mediated recruitment of proteins to the pallium with respect to both the trafficking of receptors and the remodeling of spine shape that follow synaptic stimulation. We suggest that the level and duration of CaMKII translocation and activation in the pallium will shape activity-induced changes in the spine. PMID:27594834

  1. Strain-dependent differences in LTP and hippocampus-dependent memory in inbred mice.

    PubMed

    Nguyen, P V; Abel, T; Kandel, E R; Bourtchouladze, R

    2000-01-01

    Many studies have used "reverse" genetics to produce "knock-out" and transgenic mice to explore the roles of various molecules in long-term potentiation (LTP) and spatial memory. The existence of a variety of inbred strains of mice provides an additional way of exploring the genetic bases of learning and memory. We examined behavioral memory and LTP expression in area CA1 of hippocampal slices prepared from four different inbred strains of mice: C57BL/6J, CBA/J, DBA/2J, and 129/SvEms-+(Ter?)/J. We found that LTP induced by four 100-Hz trains of stimulation was robust and long-lasting in C57BL/6J and DBA/2J mice but decayed in CBA/J and 129/SvEms-+(Ter?)/J mice. LTP induced by one 100-Hz train was significantly smaller after 1 hr in the 129/SvEms-+(Ter?)/J mice than in the other three strains. Theta-burst LTP was shorter lasting in CBA/J, DBA/2J, and 129/SvEms-+(Ter?)/J mice than in C57BL/6J mice. We also observed specific memory deficits, among particular mouse strains, in spatial and nonspatial tests of hippocampus-dependent memory. CBA/J mice showed defective learning in the Morris water maze, and both DBA/2J and CBA/J strains displayed deficient long-term memory in contextual and cued fear conditioning tests. Our findings provide strong support for a genetic basis for some forms of synaptic plasticity that are linked to behavioral long-term memory and suggest that genetic background can influence the electrophysiological and behavioral phenotypes observed in genetically modified mice generated for elucidating the molecular bases of learning, memory, and LTP.

  2. Developmental restoration of LTP deficits in heterozygous CaMKIIα KO mice.

    PubMed

    Goodell, Dayton J; Benke, Tim A; Bayer, K Ulrich

    2016-11-01

    The Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is a major mediator of long-term potentiation (LTP) and depression (LTD), two opposing forms of synaptic plasticity underlying learning, memory and cognition. The heterozygous CaMKIIα isoform KO (CaMKIIα(+/-)) mice have a schizophrenia-related phenotype, including impaired working memory. Here, we examined synaptic strength and plasticity in two brain areas implicated in working memory, hippocampus CA1 and medial prefrontal cortex (mPFC). Young CaMKIIα(+/-) mice (postnatal days 12-16; corresponding to a developmental stage well before schizophrenia manifestation in humans) showed impaired hippocampal CA1 LTP. However, this LTP impairment normalized over development and was no longer detected in older CaMKIIα(+/-) mice (postnatal weeks 9-11; corresponding to young adults). By contrast, the CaMKIIα(+/-) mice failed to show the developmental increase of basal synaptic transmission in the CA1 seen in wild-type (WT) mice, resulting in impaired basal synaptic transmission in the older CaMKIIα(+/-) mice. Other electrophysiological parameters were normal, including mPFC basal transmission, LTP, and paired-pulse facilitation, as well as CA1 LTD, depotentiation, and paired-pulse facilitation at either age tested. Hippocampal CaMKIIα levels were ∼60% of WT in both the older CaMKIIα(+/-) mice and in the younger WT mice, resulting in ∼30% of adult WT expression in the younger CaMKIIα(+/-) mice; levels in frontal cortex were the same as in hippocampus. Thus, in young mice, ∼30% of adult CaMKIIα expression is sufficient for normal LTD and depotentiation, while normal LTP requires higher levels, with ∼60% of CaMKIIα expression sufficient for normal LTP in adult mice.

  3. Cocaine- or stress-induced metaplasticity of LTP in the dorsal and ventral hippocampus.

    PubMed

    Keralapurath, Madhusudhanan M; Clark, Jason K; Hammond, Sherri; Wagner, John J

    2014-05-01

    Despite the well documented role of the hippocampus in various modes of drug reinstatement behavior, the persisting effects of in vivo cocaine exposure on hippocampal synaptic plasticity are not sufficiently understood. In this report we investigated the effects of cocaine conditioning on long-term potentiation (LTP) in the CA1 region of hippocampus along its septotemporal axis. Male Sprague-Dawley rats experienced a behavioral protocol, in which locomotor activity was monitored in response to various conditioning treatments. LTP was measured in ex vivo slice preparations taken 1-2 weeks after the last behavioral session from the ventral (vH) and dorsal (dH) sectors of hippocampus. Unexpectedly, experiencing the minor intermittent stimuli of the behavioral protocol caused stress-induced metaplastic changes in both vH (increased LTP) and dH (decreased LTP) in the saline conditioned rats relative to behaviorally naïve controls. These stress effects in the vH and dH were blocked by conditioning with either mineralocorticoid (spironolactone) or glucocorticoid (mifepristone) antagonists, respectively. Stress-induced metaplasticity in the vH was also prevented by prior administration of the kappa opioid antagonist nor-binaltorphimine. Cocaine conditioning induced locomotor sensitization and significantly increased LTP in the vH without causing significant change in LTP in the dH. Cocaine-induced metaplasticity in the vH was prevented by co-administration of the dopamine D2-like antagonist eticlopride during cocaine conditioning, but not by co-administration of the D1/5 antagonist SCH 23390. Our results suggest that the functional connectivity of hippocampus is altered by metaplastic triggers such as exposure to drugs of abuse and/or stressors, thereby shifting the efferent output of hippocampus from dH (cortical) toward vH (limbic) influenced circuits.

  4. Systemic Injection of Kainic Acid Differently Affects LTP Magnitude Depending on its Epileptogenic Efficiency

    PubMed Central

    Suárez, Luz M.; Cid, Elena; Gal, Beatriz; Inostroza, Marion; Brotons-Mas, Jorge R.; Gómez-Domínguez, Daniel

    2012-01-01

    Seizures have profound impact on synaptic function and plasticity. While kainic acid is a popular method to induce seizures and to potentially affect synaptic plasticity, it can also produce physiological-like oscillations and trigger some forms of long-term potentiation (LTP). Here, we examine whether induction of LTP is altered in hippocampal slices prepared from rats with different sensitivity to develop status epilepticus (SE) by systemic injection of kainic acid. Rats were treated with multiple low doses of kainic acid (5 mg/kg; i.p.) to develop SE in a majority of animals (72–85% rats). A group of rats were resistant to develop SE (15–28%) after several accumulated doses. Animals were subsequently tested using chronic recordings and object recognition tasks before brain slices were prepared for histological studies and to examine basic features of hippocampal synaptic function and plasticity, including input/output curves, paired-pulse facilitation and theta-burst induced LTP. Consistent with previous reports in kindling and pilocapine models, LTP was reduced in rats that developed SE after kainic acid injection. These animals exhibited signs of hippocampal sclerosis and developed spontaneous seizures. In contrast, resistant rats did not become epileptic and had no signs of cell loss and mossy fiber sprouting. In slices from resistant rats, theta-burst stimulation induced LTP of higher magnitude when compared with control and epileptic rats. Variations on LTP magnitude correlate with animals’ performance in a hippocampal-dependent spatial memory task. Our results suggest dissociable long-term effects of treatment with kainic acid on synaptic function and plasticity depending on its epileptogenic efficiency. PMID:23118939

  5. Screening of agrochemicals in foodstuffs using low-temperature plasma (LTP) ambient ionization mass spectrometry.

    PubMed

    Wiley, Joshua S; García-Reyes, Juan F; Harper, Jason D; Charipar, Nicholas A; Ouyang, Zheng; Cooks, R Graham

    2010-05-01

    Low-temperature plasma (LTP) permits direct ambient ionization and mass analysis of samples in their native environment with minimal or no prior preparation. LTP utilizes dielectric barrier discharges (DBDs) to create a low power plasma which is guided by gas flow onto the sample from which analytes are desorbed and ionized. In this study, the potential of LTP-MS for the detection of pesticide residues in food is demonstrated. Thirteen multi-class agricultural chemicals were studied (ametryn, amitraz, atrazine, buprofezin, DEET, diphenylamine, ethoxyquin, imazalil, isofenphos-methyl, isoproturon, malathion, parathion-ethyl and terbuthylazine). To evaluate the potential of the proposed approach, LTP-MS experiments were performed directly on fruit peels as well as on fruit/vegetable extracts. Most of the agrochemicals examined displayed remarkable sensitivity in the positive ion mode, giving limits of detection (LOD) for the direct measurement in the low picogram range. Tandem mass spectrometry (MS/MS) was used to confirm identification of selected pesticides by using for these experiments spiked fruit/vegetable extracts (QuEChERS, a standard sample treatment protocol) at levels as low as 1 pg, absolute, for some of the analytes. Comparisons of the data obtained by direct LTP-MS were made with the slower but more accurate conventional LC-MS/MS procedure. Herbicides spiked in aqueous solutions were detectable at LODs as low as 0.5 microg L(-1) without the need for any sample preparation. The results demonstrate that ambient LTP-MS can be applied for the detection and confirmation of traces of agrochemicals in actual market-purchased produce and in natural water samples. Quantitative analysis was also performed in a few selected cases and displayed a relatively high degree of linearity over four orders of magnitude.

  6. Syndapin Promotes Formation of a Postsynaptic Membrane System in Drosophila

    PubMed Central

    Fricke, Robert; Bhar, Debjani; Reddy-Alla, Suneel; Krishnan, K. S.; Bogdan, Sven

    2009-01-01

    Syndapins belong to the F-BAR domain protein family whose predicted functions in membrane tubulation remain poorly studied in vivo. At Drosophila neuromuscular junctions, syndapin is associated predominantly with a tubulolamellar postsynaptic membrane system known as the subsynaptic reticulum (SSR). We show that syndapin overexpression greatly expands this postsynaptic membrane system. Syndapin can expand the SSR in the absence of dPAK and Dlg, two known regulators of SSR development. Syndapin's N-terminal F-BAR domain, required for membrane tubulation in cultured cells, is required for SSR expansion. Consistent with a model in which syndapin acts directly on postsynaptic membrane, SSR expansion requires conserved residues essential for membrane binding in vitro. However, syndapin's Src homology (SH) 3 domain, which negatively regulates membrane tubulation in cultured cells, is required for synaptic targeting and strong SSR induction. Our observations advance knowledge of syndapin protein function by 1) demonstrating the in vivo relevance of membrane remodeling mechanisms suggested by previous in vitro and structural analyses, 2) showing that SH3 domains are necessary for membrane expansion observed in vivo, and 3) confirming that F-BAR proteins control complex membrane structures. PMID:19244343

  7. Shank Modulates Postsynaptic Wnt Signaling to Regulate Synaptic Development

    PubMed Central

    Akbergenova, Yulia; Cho, Richard W.; Baas-Thomas, Maximilien S.; Littleton, J. Troy

    2016-01-01

    Prosap/Shank scaffolding proteins regulate the formation, organization, and plasticity of excitatory synapses. Mutations in SHANK family genes are implicated in autism spectrum disorder and other neuropsychiatric conditions. However, the molecular mechanisms underlying Shank function are not fully understood, and no study to date has examined the consequences of complete loss of all Shank proteins in vivo. Here we characterize the single Drosophila Prosap/Shank family homolog. Shank is enriched at the postsynaptic membrane of glutamatergic neuromuscular junctions and controls multiple parameters of synapse biology in a dose-dependent manner. Both loss and overexpression of Shank result in defects in synaptic bouton number and maturation. We find that Shank regulates a noncanonical Wnt signaling pathway in the postsynaptic cell by modulating the internalization of the Wnt receptor Fz2. This study identifies Shank as a key component of synaptic Wnt signaling, defining a novel mechanism for how Shank contributes to synapse maturation during neuronal development. SIGNIFICANCE STATEMENT Haploinsufficiency for SHANK3 is one of the most prevalent monogenic causes of autism spectrum disorder, making it imperative to understand how the Shank family regulates neurodevelopment and synapse function. We created the first animal model lacking all Shank proteins and used the Drosophila neuromuscular junction, a model glutamatergic synapse, to characterize the role of Shank at synapses. We identified a novel function of Shank in synapse maturation via regulation of Wnt signaling in the postsynaptic cell. PMID:27225771

  8. Posttranslational Modifications Regulate the Postsynaptic Localization of PSD-95.

    PubMed

    Vallejo, Daniela; Codocedo, Juan F; Inestrosa, Nibaldo C

    2017-04-01

    The postsynaptic density (PSD) consists of a lattice-like array of interacting proteins that organizes and stabilizes synaptic receptors, ion channels, structural proteins, and signaling molecules required for normal synaptic transmission and synaptic function. The scaffolding and hub protein postsynaptic density protein-95 (PSD-95) is a major element of central chemical synapses and interacts with glutamate receptors, cell adhesion molecules, and cytoskeletal elements. In fact, PSD-95 can regulate basal synaptic stability as well as the activity-dependent structural plasticity of the PSD and, therefore, of the excitatory chemical synapse. Several studies have shown that PSD-95 is highly enriched at excitatory synapses and have identified multiple protein structural domains and protein-protein interactions that mediate PSD-95 function and trafficking to the postsynaptic region. PSD-95 is also a target of several signaling pathways that induce posttranslational modifications, including palmitoylation, phosphorylation, ubiquitination, nitrosylation, and neddylation; these modifications determine the synaptic stability and function of PSD-95 and thus regulate the fates of individual dendritic spines in the nervous system. In the present work, we review the posttranslational modifications that regulate the synaptic localization of PSD-95 and describe their functional consequences. We also explore the signaling pathways that induce such changes.

  9. The brain-specific RasGEF very-KIND is required for normal dendritic growth in cerebellar granule cells and proper motor coordination

    PubMed Central

    Hayashi, Kanehiro; Furuya, Asako; Sakamaki, Yuriko; Akagi, Takumi; Shinoda, Yo; Sadakata, Tetsushi; Hashikawa, Tsutomu; Shimizu, Kazuki; Minami, Haruka; Sano, Yoshitake; Nakayama, Manabu

    2017-01-01

    Very-KIND/Kndc1/KIAA1768 (v-KIND) is a brain-specific Ras guanine nucleotide exchange factor carrying two sets of the kinase non-catalytic C-lobe domain (KIND), and is predominantly expressed in cerebellar granule cells. Here, we report the impact of v-KIND deficiency on dendritic and synaptic growth in cerebellar granule cells in v-KIND knockout (KO) mice. Furthermore, we evaluate motor function in these animals. The gross anatomy of the cerebellum, including the cerebellar lobules, layered cerebellar cortex and densely-packed granule cell layer, in KO mice appeared normal, and was similar to wild-type (WT) mice. However, KO mice displayed an overgrowth of cerebellar granule cell dendrites, compared with WT mice, resulting in an increased number of dendrites, dendritic branches and terminals. Immunoreactivity for vGluT2 (a marker for excitatory presynapses of mossy fiber terminals) was increased in the cerebellar glomeruli of KO mice, compared with WT mice. The postsynaptic density around the terminals of mossy fibers was also increased in KO mice. Although there were no significant differences in locomotor ability between KO and WT animals in their home cages or in the open field, young adult KO mice had an increased grip strength and a tendency to exhibit better motor performance in balance-related tests compared with WT animals. Taken together, our results suggest that v-KIND is required for compact dendritic growth and proper excitatory synaptic connections in cerebellar granule cells, which are necessary for normal motor coordination and balance. PMID:28264072

  10. Overexpression of lipid transfer protein (LTP) genes enhances resistance to plant pathogens and LTP functions in long-distance systemic signaling in tobacco.

    PubMed

    Sarowar, Sujon; Kim, Young Jin; Kim, Ki Deok; Hwang, Byung Kook; Ok, Sung Han; Shin, Jeong Sheop

    2009-03-01

    The lipid signal is essential for the activation of plant defense responses, but downstream components of the signaling pathway are still poorly defined. To investigate the biological functions of pepper lipid transfer protein (LTP), we carried out virus-induced gene silencing (VIGS) in pepper, constitutive expression of CALTPs and grafting experiments in the tobacco plant. Suppression of endogenous CALTPI and CALTPII by VIGS, respectively, resulted in enhanced susceptibility to Xanthomonas campestris pv. vescatoria and pepper mosaic mottle virus in pepper. On the other hand, the constitutive expression of CALTPI and CALTPII genes in tobacco plants showed enhanced resistance to oomycete pathogen, Phytophthora nicotianae and bacterial pathogen, Pseudomonas syringae pv. tabaci. Enhanced resistance is found to be associated with the enhanced CALTP transcript levels in the independent transgenic CALTPI or II tobacco lines. Induced resistance responses in grafted scion leaves revealed that LTP plays a role in long-distance systemic signaling in plants.

  11. Optogenetic mapping of cerebellar inhibitory circuitry reveals spatially biased coordination of interneurons via electrical synapses.

    PubMed

    Kim, Jinsook; Lee, Soojung; Tsuda, Sachiko; Zhang, Xuying; Asrican, Brent; Gloss, Bernd; Feng, Guoping; Augustine, George J

    2014-06-12

    We used high-speed optogenetic mapping technology to examine the spatial organization of local inhibitory circuits formed by cerebellar interneurons. Transgenic mice expressing channelrhodopsin-2 exclusively in molecular layer interneurons allowed us to focally photostimulate these neurons, while measuring resulting responses in postsynaptic Purkinje cells. This approach revealed that interneurons converge upon Purkinje cells over a broad area and that at least seven interneurons form functional synapses with a single Purkinje cell. The number of converging interneurons was reduced by treatment with gap junction blockers, revealing that electrical synapses between interneurons contribute substantially to the spatial convergence. Remarkably, gap junction blockers affected convergence in sagittal slices, but not in coronal slices, indicating a sagittal bias in electrical coupling between interneurons. We conclude that electrical synapse networks spatially coordinate interneurons in the cerebellum and may also serve this function in other brain regions.

  12. A wheat lipid transfer protein (TdLTP4) promotes tolerance to abiotic and biotic stress in Arabidopsis thaliana.

    PubMed

    Safi, Hela; Saibi, Walid; Alaoui, Meryem Mrani; Hmyene, Abdelaziz; Masmoudi, Khaled; Hanin, Moez; Brini, Faïçal

    2015-04-01

    Lipid transfer proteins (LTPs) are members of the family of pathogenesis-related proteins (PR-14) that are believed to be involved in plant defense responses. In this study, we report the isolation and characterization of a novel gene TdLTP4 encoding an LTP protein from durum wheat [Triticum turgidum L. subsp. Durum Desf.]. Molecular Phylogeny analyses of wheat TdLTP4 gene showed a high identity to other plant LTPs. Predicted three-dimensional structural model revealed the presence of six helices and nine loop turns. Expression analysis in two local durum wheat varieties with marked differences in salt and drought tolerance, revealed a higher transcript accumulation of TdLTP4 under different stress conditions in the tolerant variety, compared to the sensitive one. The overexpression of TdLTP4 in Arabidopsis resulted in a promoted plant growth under various stress conditions including NaCl, ABA, JA and H2O2 treatments. Moreover, the LTP-overexpressing lines exhibit less sensitivity to jasmonate than wild-type plants. Furthermore, detached leaves from transgenic Arabidopsis expressing TdLTP4 gene showed enhanced fungal resistance against Alternaria solani and Botrytis cinerea. Together, these data provide the evidence for the involvement of TdLTP4 gene in the tolerance to both abiotic and biotic stresses in crop plants.

  13. Involvement of IP3 Receptors in LTP and LTD Induction in Guinea Pig Hippocampal CA1 Neurons

    ERIC Educational Resources Information Center

    Taufiq, Ahmed Mostafa; Fujii, Satoshi; Yamazaki, Yoshihiko; Sasaki, Hiroshi; Kaneko, Kenya; Li, Jianmin; Kato, Hiroshi; Mikoshiba, Katsuhiko

    2005-01-01

    The role of inositol 1, 4, 5-trisphosphate receptors (IP3Rs) in long-term potentiation (LTP) and long-term depression (LTD) was studied in CA1 neurons in guinea pig hippocampal slices. In standard solution, short tetanic stimulation consisting of 15 pulses at 100 Hz induced LTP, while three short trains of low-frequency stimulation (LFS; 200…

  14. 5-HT1a Receptor Antagonists Block Perforant Path-Dentate LTP Induced in Novel, but Not Familiar, Environments

    ERIC Educational Resources Information Center

    Sanberg, Cyndy Davis; Jones, Floretta L.; Do, Viet H.; Dieguez, Dario, Jr.; Derrick, Brian E.

    2006-01-01

    Numerous studies suggest roles for monoamines in modulating long-term potentiation (LTP). Previously, we reported that both induction and maintenance of perforant path-dentate gyrus LTP is enhanced when induced while animals explore novel environments. Here we investigate the contribution of serotonin and 5-HT1a receptors to the novelty-mediated…

  15. Mutation at the TrkB PLC[gamma]-Docking Site Affects Hippocampal LTP and Associative Learning in Conscious Mice

    ERIC Educational Resources Information Center

    Valenzuela-Harrington, Mauricio; Delgado-Garcia, Jose M.; Minichiello, Liliana; Gruart, Agnes; Sciarretta, Carla

    2007-01-01

    Previous in vitro studies have characterized the electrophysiological properties and molecular events associated with long-term potentiation (LTP), but as yet there are no in vivo data from molecular-level dissection that directly identify LTP as the biological substrate for learning and memory. Understanding whether the molecular pathways…

  16. Consensus Paper: Radiological Biomarkers of Cerebellar Diseases

    PubMed Central

    Baldarçara, Leonardo; Currie, Stuart; Hadjivassiliou, M.; Hoggard, Nigel; Jack, Allison; Jackowski, Andrea P.; Mascalchi, Mario; Parazzini, Cecilia; Reetz, Kathrin; Righini, Andrea; Schulz, Jörg B.; Vella, Alessandra; Webb, Sara Jane; Habas, Christophe

    2016-01-01

    Hereditary and sporadic cerebellar ataxias represent a vast and still growing group of diseases whose diagnosis and differentiation cannot only rely on clinical evaluation. Brain imaging including magnetic resonance (MR) and nuclear medicine techniques allows for characterization of structural and functional abnormalities underlying symptomatic ataxias. These methods thus constitute a potential source of radiological biomarkers, which could be used to identify these diseases and differentiate subgroups of them, and to assess their severity and their evolution. Such biomarkers mainly comprise qualitative and quantitative data obtained from MR including proton spectroscopy, diffusion imaging, tractography, voxel-based morphometry, functional imaging during task execution or in a resting state, and from SPETC and PET with several radiotracers. In the current article, we aim to illustrate briefly some applications of these neuroimaging tools to evaluation of cerebellar disorders such as inherited cerebellar ataxia, fetal developmental malformations, and immune-mediated cerebellar diseases and of neurodegenerative or early-developing diseases, such as dementia and autism in which cerebellar involvement is an emerging feature. Although these radiological biomarkers appear promising and helpful to better understand ataxia-related anatomical and physiological impairments, to date, very few of them have turned out to be specific for a given ataxia with atrophy of the cerebellar system being the main and the most usual alteration being observed. Consequently, much remains to be done to establish sensitivity, specificity, and reproducibility of available MR and nuclear medicine features as diagnostic, progression and surrogate biomarkers in clinical routine. PMID:25382714

  17. Age-Related Enhancement of a Protein Synthesis-Dependent Late Phase of LTP Induced by Low Frequency Paired-Pulse Stimulation in Hippocampus

    ERIC Educational Resources Information Center

    Huang, Yan-You; Kandel, Eric R.

    2006-01-01

    Protein synthesis-dependent late phase of LTP (L-LTP) is typically induced by repeated high-frequency stimulation (HFS). This form of L-LTP is reduced in the aged animal and is positively correlated with age-related memory loss. Here we report a novel form of protein synthesis-dependent late phase of LTP in the CA1 region of hippocampus induced by…

  18. Changes in the cerebellar and cerebro-cerebellar circuit in type 2 diabetes.

    PubMed

    Fang, Peng; An, Jie; Tan, Xin; Zeng, Ling-Li; Shen, Hui; Qiu, Shijun; Hu, Dewen

    2017-01-11

    Currently, 422 million adults suffer from diabetes worldwide, leading to tremendous disabilities and a great burden to families and society. Functional and structural MRIs have demonstrated that patients with type 2 diabetes mellitus (T2DM) exhibit abnormalities in brain regions in the cerebral cortex. However, the changes of cerebellar anatomical connections in diabetic patients remains unclear. In the current study, diffusion tensor imaging deterministic tractography and statistical analysis were employed to investigate abnormal cerebellar anatomical connections in diabetic patients. This is the first study to investigate the altered cerebellar anatomical connectivity in T2DM patients. Decreased anatomical connections were found in the cerebellar and cerebro-cerebellar circuits of T2DM patients, providing valuable new insights into the potential neuro-pathophysiology of diabetes-related motor and cognitive deficits.

  19. A Computational Model for the AMPA Receptor Phosphorylation Master Switch Regulating Cerebellar Long-Term Depression.

    PubMed

    Gallimore, Andrew R; Aricescu, A Radu; Yuzaki, Michisuke; Calinescu, Radu

    2016-01-01

    The expression of long-term depression (LTD) in cerebellar Purkinje cells results from the internalisation of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs) from the postsynaptic membrane. This process is regulated by a complex signalling pathway involving sustained protein kinase C (PKC) activation, inhibition of serine/threonine phosphatase, and an active protein tyrosine phosphatase, PTPMEG. In addition, two AMPAR-interacting proteins-glutamate receptor-interacting protein (GRIP) and protein interacting with C kinase 1 (PICK1)-regulate the availability of AMPARs for trafficking between the postsynaptic membrane and the endosome. Here we present a new computational model of these overlapping signalling pathways. The model reveals how PTPMEG cooperates with PKC to drive LTD expression by facilitating the effect of PKC on the dissociation of AMPARs from GRIP and thus their availability for trafficking. Model simulations show that LTD expression is increased by serine/threonine phosphatase inhibition, and negatively regulated by Src-family tyrosine kinase activity, which restricts the dissociation of AMPARs from GRIP under basal conditions. We use the model to expose the dynamic balance between AMPAR internalisation and reinsertion, and the phosphorylation switch responsible for the perturbation of this balance and for the rapid plasticity initiation and regulation. Our model advances the understanding of PF-PC LTD regulation and induction, and provides a validated extensible platform for more detailed studies of this fundamental synaptic process.

  20. A Computational Model for the AMPA Receptor Phosphorylation Master Switch Regulating Cerebellar Long-Term Depression

    PubMed Central

    Gallimore, Andrew R.; Aricescu, A. Radu; Yuzaki, Michisuke; Calinescu, Radu

    2016-01-01

    The expression of long-term depression (LTD) in cerebellar Purkinje cells results from the internalisation of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs) from the postsynaptic membrane. This process is regulated by a complex signalling pathway involving sustained protein kinase C (PKC) activation, inhibition of serine/threonine phosphatase, and an active protein tyrosine phosphatase, PTPMEG. In addition, two AMPAR-interacting proteins–glutamate receptor-interacting protein (GRIP) and protein interacting with C kinase 1 (PICK1)–regulate the availability of AMPARs for trafficking between the postsynaptic membrane and the endosome. Here we present a new computational model of these overlapping signalling pathways. The model reveals how PTPMEG cooperates with PKC to drive LTD expression by facilitating the effect of PKC on the dissociation of AMPARs from GRIP and thus their availability for trafficking. Model simulations show that LTD expression is increased by serine/threonine phosphatase inhibition, and negatively regulated by Src-family tyrosine kinase activity, which restricts the dissociation of AMPARs from GRIP under basal conditions. We use the model to expose the dynamic balance between AMPAR internalisation and reinsertion, and the phosphorylation switch responsible for the perturbation of this balance and for the rapid plasticity initiation and regulation. Our model advances the understanding of PF-PC LTD regulation and induction, and provides a validated extensible platform for more detailed studies of this fundamental synaptic process. PMID:26807999

  1. REM Sleep-Dependent Bidirectional Regulation of Hippocampal-Based Emotional Memory and LTP.

    PubMed

    Ravassard, Pascal; Hamieh, Al Mahdy; Joseph, Mickaël Antoine; Fraize, Nicolas; Libourel, Paul-Antoine; Lebarillier, Léa; Arthaud, Sébastien; Meissirel, Claire; Touret, Monique; Malleret, Gaël; Salin, Paul-Antoine

    2016-04-01

    Prolonged rapid-eye-movement (REM) sleep deprivation has long been used to study the role of REM sleep in learning and memory processes. However, this method potentially induces stress and fatigue that may directly affect cognitive functions. Here, by using a short-term and nonstressful REM sleep deprivation (RSD) method we assessed in rats the bidirectional influence of reduced and increased REM sleep amount on hippocampal-dependent emotional memory and plasticity. Our results indicate that 4 h RSD impaired consolidation of contextual fear conditioning (CFC) and induction of long-term potentiation (LTP), while decreasing density of Egr1/Zif268-expressing neurons in the CA1 region of the dorsal hippocampus. LTP and Egr1 expression were not affected in ventral CA1. Conversely, an increase in REM sleep restores and further facilitates CFC consolidation and LTP induction, and also increases Egr1 expression in dorsal CA1. Moreover, CFC consolidation, Egr1 neuron density, and LTP amplitude in dorsal CA1 show a positive correlation with REM sleep amount. Altogether, these results indicate that mild changes in REM sleep amount bidirectionally affect memory and synaptic plasticity mechanisms occurring in the CA1 area of the dorsal hippocampus.

  2. Dendritic signals from rat hippocampal CA1 pyramidal neurons during coincident pre- and post-synaptic activity: a combined voltage- and calcium-imaging study

    PubMed Central

    Canepari, Marco; Djurisic, Maja; Zecevic, Dejan

    2007-01-01

    The non-linear and spatially inhomogeneous interactions of dendritic membrane potential signals that represent the first step in the induction of activity-dependent long-term synaptic plasticity are not fully understood, particularly in dendritic regions which are beyond the reach of electrode measurements. We combined voltage-sensitive-dye recordings and Ca2+ imaging of hippocampal CA1 pyramidal neurons to study large regions of the dendritic arbor, including branches of small diameter (distal apical and oblique dendrites). Dendritic membrane potential transients were monitored at high spatial resolution and correlated with supra-linear [Ca2+]i changes during one cycle of a repetitive patterned stimulation protocol that typically results in the induction of long-term potentiation (LTP). While the increase in the peak membrane depolarization during coincident pre- and post-synaptic activity was required for the induction of supra-linear [Ca2+]i signals shown to be necessary for LTP, the change in the baseline-to-peak amplitude of the backpropagating dendritic action potential (bAP) was not critical in this process. At different dendritic locations, the baseline-to-peak amplitude of the bAP could be either increased, decreased or unaltered at sites where EPSP–AP pairing evoked supra-linear summation of [Ca2+]i transients. We suggest that modulations in the bAP baseline-to-peak amplitude by local EPSPs act as a mechanism that brings the membrane potential into the optimal range for Ca2+ influx through NMDA receptors (0 to −15 mV); this may require either boosting or the reduction of the bAP, depending on the initial size of both signals. PMID:17272348

  3. Impact of single-site axonal GABAergic synaptic events on cerebellar interneuron activity

    PubMed Central

    Zorrilla de San Martin, Javier; Jalil, Abdelali

    2015-01-01

    Axonal ionotropic receptors are present in a variety of neuronal types, and their function has largely been associated with the modulation of axonal activity and synaptic release. It is usually assumed that activation of axonal GABAARs comes from spillover, but in cerebellar molecular layer interneurons (MLIs) the GABA source is different: in these cells, GABA release activates presynaptic GABAA autoreceptors (autoRs) together with postsynaptic targets, producing an autoR-mediated synaptic event. The frequency of presynaptic, autoR-mediated miniature currents is twice that of their somatodendritic counterparts, suggesting that autoR-mediated responses have an important effect on interneuron activity. Here, we used local Ca2+ photolysis in MLI axons of juvenile rats to evoke GABA release from individual varicosities to study the activation of axonal autoRs in single release sites. Our data show that single-site autoR conductances are similar to postsynaptic dendritic conductances. In conditions of high [Cl−]i, autoR-mediated conductances range from 1 to 5 nS; this corresponds to ∼30–150 GABAA channels per presynaptic varicosity, a value close to the number of channels in postsynaptic densities. Voltage responses produced by the activation of autoRs in single varicosities are amplified by a Nav-dependent mechanism and propagate along the axon with a length constant of 91 µm. Immunolabeling determination of synapse location shows that on average, one third of the synapses produce autoR-mediated signals that are large enough to reach the axon initial segment. Finally, we show that single-site activation of presynaptic GABAA autoRs leads to an increase in MLI excitability and thus conveys a strong feedback signal that contributes to spiking activity. PMID:26621773

  4. Impact of single-site axonal GABAergic synaptic events on cerebellar interneuron activity.

    PubMed

    de San Martin, Javier Zorrilla; Jalil, Abdelali; Trigo, Federico F

    2015-12-01

    Axonal ionotropic receptors are present in a variety of neuronal types, and their function has largely been associated with the modulation of axonal activity and synaptic release. It is usually assumed that activation of axonal GABA(A)Rs comes from spillover, but in cerebellar molecular layer interneurons (MLIs) the GABA source is different: in these cells, GABA release activates presynaptic GABA(A) autoreceptors (autoRs) together with postsynaptic targets, producing an autoR-mediated synaptic event. The frequency of presynaptic, autoR-mediated miniature currents is twice that of their somatodendritic counterparts, suggesting that autoR-mediated responses have an important effect on interneuron activity. Here, we used local Ca(2+) photolysis in MLI axons of juvenile rats to evoke GABA release from individual varicosities to study the activation of axonal autoRs in single release sites. Our data show that single-site autoR conductances are similar to postsynaptic dendritic conductances. In conditions of high [Cl(-)](i), autoR-mediated conductances range from 1 to 5 nS; this corresponds to ∼30-150 GABA(A) channels per presynaptic varicosity, a value close to the number of channels in postsynaptic densities. Voltage responses produced by the activation of autoRs in single varicosities are amplified by a Na(v)-dependent mechanism and propagate along the axon with a length constant of 91 µm. Immunolabeling determination of synapse location shows that on average, one third of the synapses produce autoR-mediated signals that are large enough to reach the axon initial segment. Finally, we show that single-site activation of presynaptic GABA(A) autoRs leads to an increase in MLI excitability and thus conveys a strong feedback signal that contributes to spiking activity.

  5. Mechanisms and functional roles of glutamatergic synapse diversity in a cerebellar circuit

    PubMed Central

    Zampini, Valeria; Liu, Jian K; Diana, Marco A; Maldonado, Paloma P; Brunel, Nicolas; Dieudonné, Stéphane

    2016-01-01

    Synaptic currents display a large degree of heterogeneity of their temporal characteristics, but the functional role of such heterogeneities remains unknown. We investigated in rat cerebellar slices synaptic currents in Unipolar Brush Cells (UBCs), which generate intrinsic mossy fibers relaying vestibular inputs to the cerebellar cortex. We show that UBCs respond to sinusoidal modulations of their sensory input with heterogeneous amplitudes and phase shifts. Experiments and modeling indicate that this variability results both from the kinetics of synaptic glutamate transients and from the diversity of postsynaptic receptors. While phase inversion is produced by an mGluR2-activated outward conductance in OFF-UBCs, the phase delay of ON UBCs is caused by a late rebound current resulting from AMPAR recovery from desensitization. Granular layer network modeling indicates that phase dispersion of UBC responses generates diverse phase coding in the granule cell population, allowing climbing-fiber-driven Purkinje cell learning at arbitrary phases of the vestibular input. DOI: http://dx.doi.org/10.7554/eLife.15872.001 PMID:27642013

  6. The LTP Experiment on LISA Pathfinder: Operational Definition of TT Gauge in Space

    NASA Astrophysics Data System (ADS)

    Armano, Michele

    2011-10-01

    The European Space Agency (ESA) and the National Aeronautics and Space Administration (NASA) are planning the Laser Interferometer Space Antenna (LISA) mission in order to detect GW. The need of accurate testing of free-fall and knowledge of noise in a space environment similar to LISA's is considered mandatory a pre-phase for the project. Therefore the LISA Pathfinder mission has been designed by ESA to fly the LISA Technology Package (LTP), aiming at testing free-fall by measuring the residual acceleration between two test-bodies in the dynamical scheme we address as "drag-free". The spectral map of the residual acceleration as function of frequency will convey information on the local noise level, thus producing a picture of the environmental working conditions for LISA itself. The thesis contains abundant material on the problem of compensating static gravity, the development of a theory of orthogonalization of reference and cross-talk for the LTP experiment. The construction of the laser detection procedure starting from GR and differential geometry arguments is carried on. Effort was put in pointing out the physical motivations for the choices made in several other papers by the author and colleagues. In this perspective the thesis is meant as a summary tool for the LTP collaboration. In the second part of the thesis we summarize our contributions for a measurement of G onboard LTP and review on possible tests of fundamental physics the mission might embody. A wide part of the thesis is now part of the LTP Operation Master Plan, describing the real science and operations onboard LISA Pathfinder. This thesis was defended on September 26th, 2006 at the University of Como, Italy.

  7. Effects of chronic cocaine abuse on postsynaptic dopamine receptors

    SciTech Connect

    Volkow, N.D.; Fowler, J.S.; Wolf, A.P.; Schlyer, D.; Shiue, C.Y.; Alpert, R.; Dewey, S.L.; Logan, J.; Bendriem, B.; Christman, D. )

    1990-06-01

    To assess the effects of chronic cocaine intoxication on dopamine receptors in human subjects, the authors evaluated ({sup 18}F)N-methylspiroperidol binding using positron emission tomography in 10 cocaine abusers and 10 normal control subjects. Cocaine abusers who had been detoxified for 1 week or less showed significantly lower values for uptake of ({sup 18}F)N-methylspiroperidol in striatum than the normal subjects, whereas the cocaine abusers who had been detoxified for 1 month showed values comparable to those obtained from normal subjects. The authors conclude that postsynaptic dopamine receptor availability decreases with chronic cocaine abuse but may recover after a drug-free interval.

  8. The long-term structural plasticity of cerebellar parallel fiber axons and its modulation by motor learning.

    PubMed

    Carrillo, Jennifer; Cheng, Shao-Ying; Ko, Kwang Woo; Jones, Theresa A; Nishiyama, Hiroshi

    2013-05-08

    Presynaptic axonal varicosities, like postsynaptic spines, are dynamically added and eliminated even in mature neuronal circuitry. To study the role of this axonal structural plasticity in behavioral learning, we performed two-photon in vivo imaging of cerebellar parallel fibers (PFs) in adult mice. PFs make excitatory synapses on Purkinje cells (PCs) in the cerebellar cortex, and long-term potentiation and depression at PF-PC synapses are thought to play crucial roles in cerebellar-dependent learning. Time-lapse vital imaging of PFs revealed that, under a control condition (no behavioral training), ∼10% of PF varicosities appeared and disappeared over a period of 2 weeks without changing the total number of varicosities. The fraction of dynamic PF varicosities significantly diminished during training on an acrobatic motor skill learning task, largely because of reduced addition of new varicosities. Thus, this form of motor learning was associated with greater structural stability of PFs and a slight decrease in the total number of varicosities. Together with prior findings that the number of PF-PC synapses increases during similar training, our results suggest that acrobatic motor skill learning involves a reduction of some PF inputs and a strengthening of others, probably via the conversion of some preexisting PF varicosities into multisynaptic terminals.

  9. Ischemic insult to cerebellar Purkinje cells causes diminished GABAA receptor function and Allopregnanolone neuroprotection is associated with GABAA receptor stabilization

    PubMed Central

    Kelley, MH; Taguchi, N; Ardeshiri, A; Kuroiwa, M; Hurn, PD; Traystman, RJ; Herson, PS

    2009-01-01

    Cerebellar Purkinje cells are particularly vulnerable to ischemic injury and excitotoxicity, although the molecular basis of this sensitivity remains unclear. We tested the hypothesis that ischemia causes rapid down-regulation of GABAA receptors in cerebellar Purkinje cells, thereby increasing susceptibility to excitotoxicity. Oxygen-glucose deprivation caused a decline in functional GABAA receptors, within the first hour of re-oxygenation. Decreased amplitude of miniature inhibitory post-synaptic potentials confirmed that oxygen-glucose deprivation caused a significant decrease in functional synaptic GABAA receptors and quantitative Western blot analysis demonstrated the loss of GABAA receptor current was associated with a decline in total receptor protein. Interestingly, the potent neuroprotectant allopregnanolone prevented the decline in GABAA receptor current and protein. Consistent with our in vitro data, global ischemia in mice caused a significant decline in total cerebellar GABAA receptor protein and Purkinje cell specific immunoreactivity. Moreover, allopregnanolone provided strong protection of Purkinje cells and prevented ischemia-induced decline in GABAA receptor protein. Our findings indicate that ischemia causes a rapid and sustained loss of GABAA receptors in Purkinje cells, whereas allopregnanolone prevents the decline in GABAA receptors and protects against ischemia-induced damage. Thus, interventions which prevent ischemia-induced decline in GABAA receptors may represent a novel neuroprotective strategy. PMID:18699862

  10. Acute intracerebral treatment with amyloid-beta (1–42) alters the profile of neuronal oscillations that accompany LTP induction and results in impaired LTP in freely behaving rats

    PubMed Central

    Kalweit, Alexander Nikolai; Yang, Honghong; Colitti-Klausnitzer, Jens; Fülöp, Livia; Bozsó, Zsolt; Penke, Botond; Manahan-Vaughan, Denise

    2015-01-01

    Accumulation of amyloid plaques comprises one of the major hallmarks of Alzheimer’s disease (AD). In rodents, acute treatment with amyloid-beta (Aβ; 1–42) elicits immediate debilitating effects on hippocampal long-term potentiation (LTP). Whereas LTP contributes to synaptic information storage, information is transferred across neurons by means of neuronal oscillations. Furthermore, changes in theta-gamma oscillations, that appear during high-frequency stimulation (HFS) to induce LTP, predict whether successful LTP will occur. Here, we explored if intra-cerebral treatment with Aβ(1–42), that prevents LTP, also results in alterations of hippocampal oscillations that occur during HFS of the perforant path-dentate gyrus synapse in 6-month-old behaving rats. HFS resulted in LTP that lasted for over 24 h. In Aβ-treated animals, LTP was significantly prevented. During HFS, spectral power for oscillations below 100 Hz (δ, θ, α, β and γ) was significantly higher in Aβ-treated animals compared to controls. In addition, the trough-to-peak amplitudes of theta and gamma cycles were higher during HFS in Aβ-treated animals. We also observed a lower amount of envelope-to-signal correlations during HFS in Aβ-treated animals. Overall, the characteristic profile of theta-gamma oscillations that accompany successful LTP induction was disrupted. These data indicate that alterations in network oscillations accompany Aβ-effects on hippocampal LTP. This may comprise an underlying mechanism through which disturbances in synaptic information storage and hippocampus-dependent memory occurs in AD. PMID:25999827

  11. Reevaluation of the Beam and Radial Hypotheses of Parallel Fiber Action in the Cerebellar Cortex

    PubMed Central

    Cramer, Samuel W.; Gao, Wangcai; Chen, Gang

    2013-01-01

    The role of parallel fibers (PFs) in cerebellar physiology remains controversial. Early studies inspired the “beam” hypothesis whereby granule cell (GC) activation results in PF-driven, postsynaptic excitation of beams of Purkinje cells (PCs). However, the “radial” hypothesis postulates that the ascending limb of the GC axon provides the dominant input to PCs and generates patch-like responses. Using optical imaging and single-cell recordings in the mouse cerebellar cortex in vivo, this study reexamines the beam versus radial controversy. Electrical stimulation of mossy fibers (MFs) as well as microinjection of NMDA in the granular layer generates beam-like responses with a centrally located patch-like response. Remarkably, ipsilateral forepaw stimulation evokes a beam-like response in Crus I. Discrete molecular layer lesions demonstrate that PFs contribute to the peripherally generated responses in Crus I. In contrast, vibrissal stimulation induces patch-like activation of Crus II and GABAA antagonists fail to convert this patch-like activity into a beam-like response, implying that molecular layer inhibition does not prevent beam-like responses. However, blocking excitatory amino acid transporters (EAATs) generates beam-like responses in Crus II. These beam-like responses are suppressed by focal inhibition of MF-GC synaptic transmission. Using EAAT4 reporter transgenic mice, we show that peripherally evoked patch-like responses in Crus II are aligned between parasagittal bands of EAAT4. This is the first study to demonstrate beam-like responses in the cerebellar cortex to peripheral, MF, and GC stimulation in vivo. Furthermore, the spatial pattern of the responses depends on extracellular glutamate and its local regulation by EAATs. PMID:23843513

  12. Cerebellar modules operate at different frequencies

    PubMed Central

    Zhou, Haibo; Lin, Zhanmin; Voges, Kai; Ju, Chiheng; Gao, Zhenyu; Bosman, Laurens WJ; Ruigrok, Tom JH; Hoebeek, Freek E

    2014-01-01

    Due to the uniform cyto-architecture of the cerebellar cortex, its overall physiological characteristics have traditionally been considered to be homogeneous. In this study, we show in awake mice at rest that spiking activity of Purkinje cells, the sole output cells of the cerebellar cortex, differs between cerebellar modules and correlates with their expression of the glycolytic enzyme aldolase C or zebrin. Simple spike and complex spike frequencies were significantly higher in Purkinje cells located in zebrin-negative than zebrin-positive modules. The difference in simple spike frequency persisted when the synaptic input to, but not intrinsic activity of, Purkinje cells was manipulated. Blocking TRPC3, the effector channel of a cascade of proteins that have zebrin-like distribution patterns, attenuated the simple spike frequency difference. Our results indicate that zebrin-discriminated cerebellar modules operate at different frequencies, which depend on activation of TRPC3, and that this property is relevant for all cerebellar functions. DOI: http://dx.doi.org/10.7554/eLife.02536.001 PMID:24843004

  13. Metabolic anatomy of paraneoplastic cerebellar degeneration

    SciTech Connect

    Anderson, N.E.; Posner, J.B.; Sidtis, J.J.; Moeller, J.R.; Strother, S.C.; Dhawan, V.; Rottenberg, D.A.

    1988-06-01

    Eleven patients with acquired cerebellar degeneration (10 of whom had paraneoplastic cerebellar degeneration (PCD)) were evaluated using neuropsychological tests and /sup 18/F-fluorodeoxyglucose/positron emission tomography to (1) quantify motor, cognitive, and metabolic abnormalities; (2) determine if characteristic alterations in the regional cerebral metabolic rate for glucose (rCMRGlc) are associated with PCD; and (3) correlate behavioral and metabolic measures of disease severity. Eighteen volunteer subjects served as normal controls. Although some PCD neuropsychological test scores were abnormal, these results could not, in general, be dissociated from the effects of dysarthria and ataxia. rCMRGlc was reduced in patients with PCD (versus normal control subjects) in all regions except the brainstem. Analysis of patient and control rCMRGlc data using a mathematical model of regional metabolic interactions revealed two metabolic pattern descriptors, SSF1 and SSF2, which distinguished patients with PCD from normal control subjects; SSF2, which described a metabolic coupling between cerebellum, cuneus, and posterior temporal, lateral frontal, and paracentral cortex, correlated with quantitative indices of cerebellar dysfunction. Our inability to document substantial intellectual impairment in 7 of 10 patients with PCD contrasts with the 50% incidence of dementia in PCD reported by previous investigators. Widespread reductions in PCD rCMRGlc may result from the loss of cerebellar efferents to thalamus and forebrain structures, a reverse cerebellar diaschisis.

  14. Regionalization of the isthmic and cerebellar primordia.

    PubMed

    Narboux-Nême, Nicolas; Louvi, Angeliki; Alexandre, Paula; Wassef, Marion

    2005-01-01

    The complex migrations of neurons born in the dorsal neural tube of the isthmic and rhombomere l (rl) domains complicate the delineation of the cerebellar primordium. We show that Purkinje cells (P) are likely generated over a wide territory before gathering in the future cerebellar primordium under the developing external granular layer. Later expansion of the cerebellum over a restricted ependymal domain could rely on mutual interations between P cells and granule cell progenitors (GCP). P are attracted by GCP and in turn stimulate their proliferation, increasing the surface of the developing cortex. At later stages, regionalization of the developing and adult cerebellar cortex can be detected through regional variations in the distribution of several P cell markers. Whether and how the developmental and adult P subtypes are related is still unknown and it is unclear if they delineate the same sets of cerebellar subdivisions. We provide evidence that the early P regionalization is involved in intrinsic patterning of the cerebellar primordium, in particular it relate to the organization of the corticonuclear connection. We propose that the early P regionalization provides a scaffold to the mature P regionalization but that the development of functional afferent connections induces a period of P plasticity during which the early regional identity of P could be remodeled.

  15. Secondary orthostatic tremor in the setting of cerebellar degeneration.

    PubMed

    Sarva, Harini; Severt, William Lawrence; Jacoby, Nuri; Pullman, Seth L; Saunders-Pullman, Rachel

    2016-05-01

    Orthostatic tremor (OT) and cerebellar ataxia are uncommon and difficult to treat. We present two patients with OT and cerebellar degeneration, one of whom had spinocerebellar ataxia type 2 and a good treatment response.

  16. Neurodevelopmental malformations of the cerebellar vermis in genetically engineered rats

    EPA Science Inventory

    The cerebellar vermis is particularly vulnerable to neurodevelopmental malformations in humans and rodents. Sprague-Dawley, and Long-Evans rats exhibit spontaneous cerebellar malformations consisting of heterotopic neurons and glia in the molecular layer of the vermis. Malformati...

  17. Landmark based shape analysis for cerebellar ataxia classification and cerebellar atrophy pattern visualization

    NASA Astrophysics Data System (ADS)

    Yang, Zhen; Abulnaga, S. Mazdak; Carass, Aaron; Kansal, Kalyani; Jedynak, Bruno M.; Onyike, Chiadi; Ying, Sarah H.; Prince, Jerry L.

    2016-03-01

    Cerebellar dysfunction can lead to a wide range of movement disorders. Studying the cerebellar atrophy pattern associated with different cerebellar disease types can potentially help in diagnosis, prognosis, and treatment planning. In this paper, we present a landmark based shape analysis pipeline to classify healthy control and different ataxia types and to visualize the characteristic cerebellar atrophy patterns associated with different types. A highly informative feature representation of the cerebellar structure is constructed by extracting dense homologous landmarks on the boundary surfaces of cerebellar sub-structures. A diagnosis group classifier based on this representation is built using partial least square dimension reduction and regularized linear discriminant analysis. The characteristic atrophy pattern for an ataxia type is visualized by sampling along the discriminant direction between healthy controls and the ataxia type. Experimental results show that the proposed method can successfully classify healthy controls and different ataxia types. The visualized cerebellar atrophy patterns were consistent with the regional volume decreases observed in previous studies, but the proposed method provides intuitive and detailed understanding about changes of overall size and shape of the cerebellum, as well as that of individual lobules.

  18. Landmark Based Shape Analysis for Cerebellar Ataxia Classification and Cerebellar Atrophy Pattern Visualization

    PubMed Central

    Yang, Zhen; Abulnaga, S. Mazdak; Carass, Aaron; Kansal, Kalyani; Jedynak, Bruno M.; Onyike, Chiadi; Ying, Sarah H.; Prince, Jerry L.

    2016-01-01

    Cerebellar dysfunction can lead to a wide range of movement disorders. Studying the cerebellar atrophy pattern associated with different cerebellar disease types can potentially help in diagnosis, prognosis, and treatment planning. In this paper, we present a landmark based shape analysis pipeline to classify healthy control and different ataxia types and to visualize the characteristic cerebellar atrophy patterns associated with different types. A highly informative feature representation of the cerebellar structure is constructed by extracting dense homologous landmarks on the boundary surfaces of cerebellar sub-structures. A diagnosis group classifier based on this representation is built using partial least square dimension reduction and regularized linear discriminant analysis. The characteristic atrophy pattern for an ataxia type is visualized by sampling along the discriminant direction between healthy controls and the ataxia type. Experimental results show that the proposed method can successfully classify healthy controls and different ataxia types. The visualized cerebellar atrophy patterns were consistent with the regional volume decreases observed in previous studies, but the proposed method provides intuitive and detailed understanding about changes of overall size and shape of the cerebellum, as well as that of individual lobules. PMID:27303111

  19. Summation of excitatory postsynaptic potentials in electrically-coupled neurones.

    PubMed

    Vazquez, Y; Mendez, B; Trueta, C; De-Miguel, F F

    2009-09-29

    Dendritic electrical coupling increases the number of effective synaptic inputs onto neurones by allowing the direct spread of synaptic potentials from one neurone to another. Here we studied the summation of excitatory postsynaptic potentials (EPSPs) produced locally and arriving from the coupled neurone (transjunctional) in pairs of electrically-coupled Retzius neurones of the leech. We combined paired recordings of EPSPs, the production of artificial excitatory postsynaptic potentials (APSPs) in neurone pairs with different coupling coefficients and simulations of EPSPs produced in the coupled dendrites. Summation of the EPSPs produced in the dendrites was always linear, suggesting that synchronous EPSPs are produced at two or more different pairs of coupled dendrites and not in both sides of any one gap junction. The different spatio-temporal relationships explored between pairs of EPSPs or APSPs produced three main effects. (1) Synchronous pairs of EPSPs or APSPs exhibited an elongation of their decay phase compared to single EPSPs. (2) Asymmetries in the amplitudes between the pair of EPSPs added a "hump" to the smallest EPSP. (3) Modelling the inputs near the electrical synapse or anticipating the production of the transjunctional APSP increased the amplitude of the compound EPSP. The magnitude of all these changes depended on the coupling coefficient of the neurones. We also show that the hump improves the passive conduction of EPSPs by adding low frequency components. The diverse effects of summation of local and alien EPSPs shown here endow electrically-coupled neurones with a wider repertoire of adjustable integrative possibilities.

  20. Cold-induced exodus of postsynaptic proteins from dendritic spines.

    PubMed

    Cheng, Hui-Hsuan; Huang, Zu-Han; Lin, Wei-Hsiang; Chow, Wei-Yuan; Chang, Yen-Chung

    2009-02-01

    Dendritic spines are small protrusions on neuronal dendrites and the major target of the excitatory inputs in mammalian brains. Cultured neurons and brain slices are important tools in studying the biochemical and cellular properties of dendritic spines. During the processes of immunocytochemical studies of neurons and the preparation of brain slices, neurons were often kept at temperatures lower than 37 degrees C for varied lengths of time. This study sought to investigate whether and how cold treatment would affect the protein composition of dendritic spines. The results indicated that upon cold treatment four postsynaptic proteins, namely, alpha,beta-tubulins, calcium, calmodulin-dependent protein kinase IIalpha, and cytoplasmic dynein heavy chain and microtubule-associated protein 2, but not PSD-95 or AMPA receptors, exited from the majority of dendritic spines of cultured rat hippocampal neurons in a Gd(3+)-sensitive manner. The cold-induced exit of tubulins from dendritic spines was further found to be an energy-dependent process involving the activation of Gd(3+)-sensitive calcium channels and ryanodine receptors. The results thus indicate that changes in temperature, calcium concentration, and energy supply of the medium surrounding neurons would affect the protein composition of the dendritic spines and conceivably the protein composition of the subcellular organizations, such as the postsynaptic density, in the cytoplasm of dendritic spines.

  1. SNAP-25, a Known Presynaptic Protein with Emerging Postsynaptic Functions

    PubMed Central

    Antonucci, Flavia; Corradini, Irene; Fossati, Giuliana; Tomasoni, Romana; Menna, Elisabetta; Matteoli, Michela

    2016-01-01

    A hallmark of synaptic specializations is their dependence on highly organized complexes of proteins that interact with each other. The loss or modification of key synaptic proteins directly affects the properties of such networks, ultimately impacting synaptic function. SNAP-25 is a component of the SNARE complex, which is central to synaptic vesicle exocytosis, and, by directly interacting with different calcium channels subunits, it negatively modulates neuronal voltage-gated calcium channels, thus regulating intracellular calcium dynamics. The SNAP-25 gene has been associated with distinct brain diseases, including Attention Deficit Hyperactivity Disorder (ADHD), schizophrenia and bipolar disorder, indicating that the protein may act as a shared biological substrate among different “synaptopathies”. The mechanisms by which alterations in SNAP-25 may concur to these psychiatric diseases are still undefined, although alterations in neurotransmitter release have been indicated as potential causative processes. This review summarizes recent work showing that SNAP-25 not only controls exo/endocytic processes at the presynaptic terminal, but also regulates postsynaptic receptor trafficking, spine morphogenesis, and plasticity, thus opening the possibility that SNAP-25 defects may contribute to psychiatric diseases by impacting not only presynaptic but also postsynaptic functions. PMID:27047369

  2. [Study of cerebellar infarction with isolated vertigo].

    PubMed

    Utsumi, Ai; Enomoto, Hiroyuki; Yamamoto, Kaoru; Kimura, Yu; Koizuka, Izumi; Tsukuda, Mamoru

    2010-07-01

    Isolated vertigo is generally attributed to labyrinthine disease, but may also signal otherwise asymptomatic cerebellar infarction. Of 309 subjects admitted between April 2004 and March 2009 for the single symptom of acute vertigo initially thought to be labyrinthine, four were found to have cerebellar infarction of the posterior inferior cerebellar artery area (PICA). All were over 60 years old and had risk factors including hypertension, diabetes mellitus, arrhythmia, and/or hyperlipidemia. Two had trunk ataxia, with magnetic resonance imaging (MRI) showing infarction within a few days. The other two could walk without apparent trunk ataxia, however, it took 4 to 7 days to find the infarction, mainly through neurological, neurootological, and MRI findings. Neurologically, astasia, dysbasia or trunk ataxia were important signs. Neurootologically, nystagmus and electronystagmographic testing involving eye tracking, saccade, and optokinetic patttens were useful.

  3. 21 CFR 882.5820 - Implanted cerebellar stimulator.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Implanted cerebellar stimulator. 882.5820 Section... (CONTINUED) MEDICAL DEVICES NEUROLOGICAL DEVICES Neurological Therapeutic Devices § 882.5820 Implanted cerebellar stimulator. (a) Identification. An implanted cerebellar stimulator is a device used to...

  4. The Cerebellar Mutism Syndrome and Its Relation to Cerebellar Cognitive Function and the Cerebellar Cognitive Affective Disorder

    ERIC Educational Resources Information Center

    Wells, Elizabeth M.; Walsh, Karin S.; Khademian, Zarir P.; Keating, Robert F.; Packer, Roger J.

    2008-01-01

    The postoperative cerebellar mutism syndrome (CMS), consisting of diminished speech output, hypotonia, ataxia, and emotional lability, occurs after surgery in up to 25% of patients with medulloblastoma and occasionally after removal of other posterior fossa tumors. Although the mutism is transient, speech rarely normalizes and the syndrome is…

  5. A subtype-specific function for the extracellular domain of neuroligin 1 in hippocampal LTP.

    PubMed

    Shipman, Seth L; Nicoll, Roger A

    2012-10-18

    At neuronal excitatory synapses, two major subtypes of the synaptic adhesion molecule neuroligin are present. These subtypes, neuroligin 1 and neuroligin 3, have roles in synaptogenesis and synaptic maintenance that appear largely overlapping. In this study, we combine electrophysiology with molecular deletion and replacement of these proteins to identify similarities and differences between these subtypes. In doing so, we identify a subtype-specific role in LTP for neuroligin 1 in young CA1, which persists into adulthood in the dentate gyrus. As neuroligin 3 showed no requirement for LTP, we constructed chimeric proteins of the two excitatory neuroligin subtypes to identify the molecular determinants particular to the unique function of neuroligin 1. Using in vivo molecular replacement experiments, we find that these unique functions depend on a region in its extracellular domain containing the B site splice insertion previously shown to determine specificity of neurexin binding.

  6. Combined LTP and LTD of modulatory inputs controls neuronal processing of primary sensory inputs.

    PubMed

    Doiron, Brent; Zhao, Yanjun; Tzounopoulos, Thanos

    2011-07-20

    A hallmark of brain organization is the integration of primary and modulatory pathways by principal neurons. However, the pathway interactions that shape primary input processing remain unknown. We investigated this problem in mouse dorsal cochlear nucleus (DCN) where principal cells integrate primary, auditory nerve input with modulatory, parallel fiber input. Using a combined experimental and computational approach, we show that combined LTP and LTD of parallel fiber inputs to DCN principal cells and interneurons, respectively, broaden the time window within which synaptic inputs summate. Enhanced summation depolarizes the resting membrane potential and thus lowers the response threshold to auditory nerve inputs. Combined LTP and LTD, by preserving the variance of membrane potential fluctuations and the membrane time constant, fixes response gain and spike latency as threshold is lowered. Our data reveal a novel mechanism mediating adaptive and concomitant homeostatic regulation of distinct features of neuronal processing of sensory inputs.

  7. Distributed cerebellar plasticity implements adaptable gain control in a manipulation task: a closed-loop robotic simulation

    PubMed Central

    Garrido, Jesús A.; Luque, Niceto R.; D'Angelo, Egidio; Ros, Eduardo

    2013-01-01

    Adaptable gain regulation is at the core of the forward controller operation performed by the cerebro-cerebellar loops and it allows the intensity of motor acts to be finely tuned in a predictive manner. In order to learn and store information about body-object dynamics and to generate an internal model of movement, the cerebellum is thought to employ long-term synaptic plasticity. LTD at the PF-PC synapse has classically been assumed to subserve this function (Marr, 1969). However, this plasticity alone cannot account for the broad dynamic ranges and time scales of cerebellar adaptation. We therefore tested the role of plasticity distributed over multiple synaptic sites (Hansel et al., 2001; Gao et al., 2012) by generating an analog cerebellar model embedded into a control loop connected to a robotic simulator. The robot used a three-joint arm and performed repetitive fast manipulations with different masses along an 8-shape trajectory. In accordance with biological evidence, the cerebellum model was endowed with both LTD and LTP at the PF-PC, MF-DCN and PC-DCN synapses. This resulted in a network scheme whose effectiveness was extended considerably compared to one including just PF-PC synaptic plasticity. Indeed, the system including distributed plasticity reliably self-adapted to manipulate different masses and to learn the arm-object dynamics over a time course that included fast learning and consolidation, along the lines of what has been observed in behavioral tests. In particular, PF-PC plasticity operated as a time correlator between the actual input state and the system error, while MF-DCN and PC-DCN plasticity played a key role in generating the gain controller. This model suggests that distributed synaptic plasticity allows generation of the complex learning properties of the cerebellum. The incorporation of further plasticity mechanisms and of spiking signal processing will allow this concept to be extended in a more realistic computational scenario

  8. Interaction between Purkinje Cells and Inhibitory Interneurons May Create Adjustable Output Waveforms to Generate Timed Cerebellar Output

    PubMed Central

    Hong, Simon; Optican, Lance M.

    2008-01-01

    We develop a new model that explains how the cerebellum may generate the timing in classical delay eyeblink conditioning. Recent studies show that both Purkinje cells (PCs) and inhibitory interneurons (INs) have parallel signal processing streams with two time scales: an AMPA receptor-mediated fast process and a metabotropic glutamate receptor (mGluR)-mediated slow process. Moreover, one consistent finding is an increased excitability of PC dendrites (in Larsell's lobule HVI) in animals when they acquire the classical delay eyeblink conditioning naturally, in contrast to in vitro studies, where learning involves long-term depression (LTD). Our model proposes that the delayed response comes from the slow dynamics of mGluR-mediated IP3 activation, and the ensuing calcium concentration change, and not from LTP/LTD. The conditioned stimulus (tone), arriving on the parallel fibers, triggers this slow activation in INs and PC spines. These excitatory (from PC spines) and inhibitory (from INs) signals then interact at the PC dendrites to generate variable waveforms of PC activation. When the unconditioned stimulus (puff), arriving on the climbing fibers, is coupled frequently with this slow activation the waveform is amplified (due to an increased excitability) and leads to a timed pause in the PC population. The disinhibition of deep cerebellar nuclei by this timed pause causes the delayed conditioned response. This suggested PC-IN interaction emphasizes a richer role of the INs in learning and also conforms to the recent evidence that mGluR in the cerebellar cortex may participate in slow motor execution. We show that the suggested mechanism can endow the cerebellar cortex with the versatility to learn almost any temporal pattern, in addition to those that arise in classical conditioning. PMID:18648667

  9. Rapid formation and remodeling of postsynaptic densities in developing dendrites.

    PubMed

    Marrs, G S; Green, S H; Dailey, M E

    2001-10-01

    The dynamics of postsynaptic density (PSD) formation and remodeling were investigated in live developing hippocampal tissue slices. Time lapse imaging of transfected neurons expressing GFP-tagged PSD95, a prominent PSD protein, revealed that up to 40% of PSDs in developing dendrites are structurally dynamic; they rapidly (<15 min) appear or disappear, but also grow, shrink and move within shafts and spines. New spines containing PSDs were formed by conversion of dynamic filopodia-like spine precursors in which PSDs appeared de novo, or by direct extension of spines or spine precursors carrying preformed PSDs from the shaft. PSDs are therefore highly dynamic structures that can undergo rapid structural alteration within dendrite shafts, spines and spine precursors, permitting rapid formation and remodeling of synaptic connections in developing CNS tissues.

  10. Metaplastic Effect of Apamin on LTP and Paired-Pulse Facilitation

    ERIC Educational Resources Information Center

    Ris, Laurence; Capron, Brigitte; Sclavons, Coralie; Liegeois, Jean-Francois; Seutin, Vincent; Godaux, Emile

    2007-01-01

    In area CA1 of hippocampal slices, a single 1-sec train of 100-Hz stimulation generally triggers a short-lasting long-term potentiation (S-LTP) of 1-2 h. Here, we found that when such a train was applied 45 min after application of the small conductance Ca[superscript 2+]-activated K[superscript +] (SK) channel blocker apamin, it induced a…

  11. Entorhinal theta-frequency input to the dentate gyrus trisynaptically evokes hippocampal CA1 LTP

    PubMed Central

    Stepan, Jens; Dine, Julien; Fenzl, Thomas; Polta, Stephanie A.; von Wolff, Gregor; Wotjak, Carsten T.; Eder, Matthias

    2012-01-01

    There exists substantial evidence that some forms of explicit learning in mammals require long-term potentiation (LTP) at hippocampal CA3-CA1 synapses. While CA1 LTP has been well characterized at the monosynaptic level, it still remains unclear how the afferent systems to the hippocampus can initiate formation of this neuroplastic phenomenon. Using voltage-sensitive dye imaging (VSDI) in a mouse brain slice preparation, we show that evoked entorhinal cortical (EC) theta-frequency input to the dentate gyrus highly effectively generates waves of neuronal activity which propagate through the entire trisynaptic circuit of the hippocampus (“HTC-Waves”). This flow of activity, which we also demonstrate in vivo, critically depends on frequency facilitation of mossy fiber to CA3 synaptic transmission. The HTC-Waves are rapidly boosted by the cognitive enhancer caffeine (5 μM) and the stress hormone corticosterone (100 nM). They precisely follow the rhythm of the EC input, involve high-frequency firing (>100 Hz) of CA3 pyramidal neurons, and induce NMDA receptor-dependent CA1 LTP within a few seconds. Our study provides the first experimental evidence that synchronous theta-rhythmical spiking of EC stellate cells, as occurring during EC theta oscillations, has the capacity to drive induction of CA1 LTP via the hippocampal trisynaptic pathway. Moreover, we present data pointing to a basic filter mechanism of the hippocampus regarding EC inputs and describe a methodology to reveal alterations in the “input–output relationship” of the hippocampal trisynaptic circuit. PMID:22988432

  12. Nicotine primes the effect of cocaine on the induction of LTP in the amygdala.

    PubMed

    Huang, Yan-You; Kandel, Denise B; Kandel, Eric R; Levine, Amir

    2013-11-01

    In human populations, there is a well-defined sequence of involvement in drugs of abuse, in which the use of nicotine or alcohol precedes the use of marijuana, which in turn, precedes the use of cocaine. The term "Gateway Hypothesis" describes this developmental sequence of drug involvement. In prior work, we have developed a mouse model to study the underlying metaplastic behavioral, cellular and molecular mechanisms by which exposure to one drug, namely nicotine, affects the response to another drug, namely cocaine. We found that nicotine enhances significantly the changes in synaptic plasticity in the striatum induced by cocaine (Levine et al., 2011). Here we ask: does the metaplastic effect of nicotine on cocaine also apply in the amygdala, a brain region that is involved in the orchestration of emotions and in drug addiction? We find that pretreatment with nicotine enhances long-term synaptic potentiation (LTP) in response to cocaine in the amygdala. Both short-term (1 day) and long-term (7 days) pre-exposure to nicotine facilitate the induction of LTP by cocaine. The effect of nicotine on LTP is unidirectional; exposure to nicotine following treatment with cocaine is ineffective. This metaplastic effect of nicotine on cocaine is long lasting but reversible. The facilitation of LTP can be obtained for 24 but not 40 days after cessation of nicotine. As is the case in the striatum, pretreatment with Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, simulates the priming effect of nicotine. These results provide further evidence that the priming effect of nicotine may be achieved, at least partially, by the inhibition of histone acetylation and indicate that the amygdala appears to be an important brain structure for the processing of the metaplastic effect of nicotine on cocaine. This article is part of the Special Issue entitled 'Glutamate Receptor-Dependent Synaptic Plasticity'.

  13. Modulation of LTP at rat hippocampal CA3-CA1 synapses by direct current stimulation.

    PubMed

    Ranieri, F; Podda, M V; Riccardi, E; Frisullo, G; Dileone, M; Profice, P; Pilato, F; Di Lazzaro, V; Grassi, C

    2012-04-01

    Transcranial direct current stimulation (tDCS) can produce a lasting polarity-specific modulation of cortical excitability in the brain, and it is increasingly used in experimental and clinical settings. Recent studies suggest that the after-effects of tDCS are related to molecular mechanisms of activity-dependent synaptic plasticity. Here we investigated the effect of DCS on the induction of one of the most studied N-methyl-d-aspartate receptor-dependent forms of long-term potentiation (LTP) of synaptic activity at CA3-CA1 synapses in the hippocampus. We show that DCS applied to rat brain slices determines a modulation of LTP that is increased by anodal and reduced by cathodal DCS. Immediate early genes, such as c-fos and zif268 (egr1/NGFI-A/krox24), are rapidly induced following neuronal activation, and a specific role of zif268 in the induction and maintenance of LTP has been demonstrated. We found that both anodal and cathodal DCS produce a marked subregion-specific increase in the expression of zif268 protein in the cornus ammonis (CA) region, whereas the same protocols of stimulation produce a less pronounced increase in c-fos protein expression in the CA and in dentate gyrus regions of the hippocampus. Brain-derived neurotrophic factor expression was also investigated, and it was found to be reduced in cathodal-stimulated slices. The present data demonstrate that it is possible to modulate LTP by using DCS and provide the rationale for the use of DCS in neurological diseases to promote the adaptive and suppress the maladaptive forms of brain plasticity.

  14. mGluR5 positive allosteric modulators facilitate both hippocampal LTP and LTD and enhance spatial learning.

    PubMed

    Ayala, Jennifer E; Chen, Yelin; Banko, Jessica L; Sheffler, Douglas J; Williams, Richard; Telk, Alexandra N; Watson, Noreen L; Xiang, Zixiu; Zhang, Yongqin; Jones, Paulianda J; Lindsley, Craig W; Olive, M Foster; Conn, P Jeffrey

    2009-08-01

    Highly selective positive allosteric modulators (PAMs) of metabotropic glutamate receptor subtype 5 (mGluR5) have emerged as a potential approach to treat positive symptoms associated with schizophrenia. mGluR5 plays an important role in both long-term potentiation (LTP) and long-term depression (LTD), suggesting that mGluR5 PAMs may also have utility in improving impaired cognitive function. However, if mGluR5 PAMs shift the balance of LTP and LTD or induce a state in which afferent activity induces lasting changes in synaptic function that are not appropriate for a given pattern of activity, this could disrupt rather than enhance cognitive function. We determined the effect of selective mGluR5 PAMs on the induction of LTP and LTD at the Schaffer collateral-CA1 synapse in the hippocampus. mGluR5-selective PAMs significantly enhanced threshold theta-burst stimulation (TBS)-induced LTP. In addition, mGluR5 PAMs enhanced both DHPG-induced LTD and LTD induced by the delivery of paired-pulse low-frequency stimulation. Selective potentiation of mGluR5 had no effect on LTP induced by suprathreshold TBS or saturated LTP. The finding that potentiation of mGluR5-mediated responses to stimulation of glutamatergic afferents enhances both LTP and LTD and supports the hypothesis that the activation of mGluR5 by endogenous glutamate contributes to both forms of plasticity. Furthermore, two systemically active mGluR5 PAMs enhanced performance in the Morris water maze, a measure of hippocampus-dependent spatial learning. Discovery of small molecules that enhance both LTP and LTD in an activity-appropriate manner shows a unique action on synaptic plasticity that may provide a novel approach for the treatment of impaired cognitive function.

  15. Cerebellar Hypoplasia and Dysmorphia in Neurofibromatosis Type 1.

    PubMed

    Toelle, Sandra P; Poretti, Andrea; Weber, Peter; Seute, Tatjana; Bromberg, Jacoline E C; Scheer, Ianina; Boltshauser, Eugen

    2015-12-01

    Unidentified bright objects (UBO) and tumors are well-known cerebellar abnormalities in neurofibromatosis type 1 (NF1). Literature reports on malformative cerebellar anomalies in neurofibromatosis type 1 (NF1), however, are scant. We retrospectively studied the clinical and neuroimaging findings of 5 patients with NF1 (4 females, age 6 to 29 years at last follow-up) and cerebellar anomalies. Cerebellar symptoms on neurological examination were mild or even not evident whereas learning disabilities were more or less pronounced in four patients. Two patients had cerebellar hypoplasia (diffusely enlarged cerebellar interfoliar spaces) and three cerebellar dysmorphias involving mainly one cerebellar hemisphere. In NF1, malformative cerebellar anomalies are rare (estimated prevalence of about 1%), but most likely underestimated and easily overlooked, because physicians tend to focus on more prevalent, obvious, and well-known findings such as optic pathway gliomas, other tumors, and UBO. This kind of cerebellar anomaly in NF1 has most likely a malformative origin, but the exact pathogenesis is unknown. The individual clinical significance is difficult to determine. We suggest that cerebellar anomalies should be systematically evaluated in neuroimaging studies of NF1 patients.

  16. Inverse Stochastic Resonance in Cerebellar Purkinje Cells

    PubMed Central

    Häusser, Michael; Gutkin, Boris S.; Roth, Arnd

    2016-01-01

    Purkinje neurons play an important role in cerebellar computation since their axons are the only projection from the cerebellar cortex to deeper cerebellar structures. They have complex internal dynamics, which allow them to fire spontaneously, display bistability, and also to be involved in network phenomena such as high frequency oscillations and travelling waves. Purkinje cells exhibit type II excitability, which can be revealed by a discontinuity in their f-I curves. We show that this excitability mechanism allows Purkinje cells to be efficiently inhibited by noise of a particular variance, a phenomenon known as inverse stochastic resonance (ISR). While ISR has been described in theoretical models of single neurons, here we provide the first experimental evidence for this effect. We find that an adaptive exponential integrate-and-fire model fitted to the basic Purkinje cell characteristics using a modified dynamic IV method displays ISR and bistability between the resting state and a repetitive activity limit cycle. ISR allows the Purkinje cell to operate in different functional regimes: the all-or-none toggle or the linear filter mode, depending on the variance of the synaptic input. We propose that synaptic noise allows Purkinje cells to quickly switch between these functional regimes. Using mutual information analysis, we demonstrate that ISR can lead to a locally optimal information transfer between the input and output spike train of the Purkinje cell. These results provide the first experimental evidence for ISR and suggest a functional role for ISR in cerebellar information processing. PMID:27541958

  17. Vergence Deficits in Patients with Cerebellar Lesions

    ERIC Educational Resources Information Center

    Sander, T.; Sprenger, A.; Neumann, G.; Machner, B.; Gottschalk, S.; Rambold, H.; Helmchen, C.

    2009-01-01

    The cerebellum is part of the cortico-ponto-cerebellar circuit for conjugate eye movements. Recent animal data suggest an additional role of the cerebellum for the control of binocular alignment and disconjugate, i.e. vergence eye movements. The latter is separated into two different components: fast vergence (to step targets) and slow vergence…

  18. Improving cerebellar segmentation with statistical fusion

    NASA Astrophysics Data System (ADS)

    Plassard, Andrew J.; Yang, Zhen; Prince, Jerry L.; Claassen, Daniel O.; Landman, Bennett A.

    2016-03-01

    The cerebellum is a somatotopically organized central component of the central nervous system well known to be involved with motor coordination and increasingly recognized roles in cognition and planning. Recent work in multiatlas labeling has created methods that offer the potential for fully automated 3-D parcellation of the cerebellar lobules and vermis (which are organizationally equivalent to cortical gray matter areas). This work explores the trade offs of using different statistical fusion techniques and post hoc optimizations in two datasets with distinct imaging protocols. We offer a novel fusion technique by extending the ideas of the Selective and Iterative Method for Performance Level Estimation (SIMPLE) to a patch-based performance model. We demonstrate the effectiveness of our algorithm, Non- Local SIMPLE, for segmentation of a mixed population of healthy subjects and patients with severe cerebellar anatomy. Under the first imaging protocol, we show that Non-Local SIMPLE outperforms previous gold-standard segmentation techniques. In the second imaging protocol, we show that Non-Local SIMPLE outperforms previous gold standard techniques but is outperformed by a non-locally weighted vote with the deeper population of atlases available. This work advances the state of the art in open source cerebellar segmentation algorithms and offers the opportunity for routinely including cerebellar segmentation in magnetic resonance imaging studies that acquire whole brain T1-weighted volumes with approximately 1 mm isotropic resolution.

  19. Improving Cerebellar Segmentation with Statistical Fusion

    PubMed Central

    Plassard, Andrew J.; Yang, Zhen; Prince, Jerry L.; Claassen, Daniel O.; Landman, Bennett A.

    2016-01-01

    The cerebellum is a somatotopically organized central component of the central nervous system well known to be involved with motor coordination and increasingly recognized roles in cognition and planning. Recent work in multi-atlas labeling has created methods that offer the potential for fully automated 3-D parcellation of the cerebellar lobules and vermis (which are organizationally equivalent to cortical gray matter areas). This work explores the trade offs of using different statistical fusion techniques and post hoc optimizations in two datasets with distinct imaging protocols. We offer a novel fusion technique by extending the ideas of the Selective and Iterative Method for Performance Level Estimation (SIMPLE) to a patch-based performance model. We demonstrate the effectiveness of our algorithm, Non-Local SIMPLE, for segmentation of a mixed population of healthy subjects and patients with severe cerebellar anatomy. Under the first imaging protocol, we show that Non-Local SIMPLE outperforms previous gold-standard segmentation techniques. In the second imaging protocol, we show that Non-Local SIMPLE outperforms previous gold standard techniques but is outperformed by a non-locally weighted vote with the deeper population of atlases available. This work advances the state of the art in open source cerebellar segmentation algorithms and offers the opportunity for routinely including cerebellar segmentation in magnetic resonance imaging studies that acquire whole brain T1-weighted volumes with approximately 1 mm isotropic resolution. PMID:27127334

  20. Improving Cerebellar Segmentation with Statistical Fusion.

    PubMed

    Plassard, Andrew J; Yang, Zhen; Prince, Jerry L; Claassen, Daniel O; Landman, Bennett A

    2016-02-27

    The cerebellum is a somatotopically organized central component of the central nervous system well known to be involved with motor coordination and increasingly recognized roles in cognition and planning. Recent work in multi-atlas labeling has created methods that offer the potential for fully automated 3-D parcellation of the cerebellar lobules and vermis (which are organizationally equivalent to cortical gray matter areas). This work explores the trade offs of using different statistical fusion techniques and post hoc optimizations in two datasets with distinct imaging protocols. We offer a novel fusion technique by extending the ideas of the Selective and Iterative Method for Performance Level Estimation (SIMPLE) to a patch-based performance model. We demonstrate the effectiveness of our algorithm, Non-Local SIMPLE, for segmentation of a mixed population of healthy subjects and patients with severe cerebellar anatomy. Under the first imaging protocol, we show that Non-Local SIMPLE outperforms previous gold-standard segmentation techniques. In the second imaging protocol, we show that Non-Local SIMPLE outperforms previous gold standard techniques but is outperformed by a non-locally weighted vote with the deeper population of atlases available. This work advances the state of the art in open source cerebellar segmentation algorithms and offers the opportunity for routinely including cerebellar segmentation in magnetic resonance imaging studies that acquire whole brain T1-weighted volumes with approximately 1 mm isotropic resolution.

  1. Acute cerebellar ataxia, acute cerebellitis, and opsoclonus-myoclonus syndrome.

    PubMed

    Desai, Jay; Mitchell, Wendy G

    2012-11-01

    Acute cerebellar ataxia and acute cerebellitis represent a process characterized by parainfectious, postinfectious, or postvaccination cerebellar inflammation. There is considerable overlap between these entities. The mildest cases of acute cerebellar ataxia represent a benign condition that is characterized by acute truncal and gait ataxia, variably with appendicular ataxia, nystagmus, dysarthria, and hypotonia. It occurs mostly in young children, presents abruptly, and recovers over weeks. Neuroimaging is normal. Severe cases of cerebellitis represent the other end of the spectrum, presenting with acute cerebellar signs often overshadowed by alteration of consciousness, focal neurological deficits, raised intracranial pressure, hydrocephalus, and even herniation. Neuroimaging is abnormal and the prognosis is less favorable than in acute cerebellar ataxia. Acute disseminated encephalomyelitis may be confused with acute cerebellitis when the clinical findings are predominantly cerebellar, but lesions on neuroimaging are usually widespread. Paraneoplastic opsoclonus-myoclonus syndrome is often initially misdiagnosed as acute cerebellar ataxia, but has very specific features, course, and etiopathogensis.

  2. Isolation and full characterisation of a potentially allergenic lipid transfer protein (LTP) in almond.

    PubMed

    Buhler, Sofie; Tedeschi, Tullia; Faccini, Andrea; Garino, Cristiano; Arlorio, Marco; Dossena, Arnaldo; Sforza, Stefano

    2015-01-01

    Non-specific lipid transfer proteins (nsLTP) were shown to be among the most significant allergens, in particular in several fruits belonging to the Rosaceae family. The molecular features of LTPs, such as the presence of eight cysteine residues forming four disulfide bridges, confer a compact structure, decreasing the probability of degradation due to cooking or digestion, thereby increasing the chance of systemic absorption and severe allergic reactions. Few studies on LTP-induced allergies regarding almond (Prunus dulcis L) are available in the literature. In the present work, we describe for the first time the extraction and purification of an almond LTP, achieving its full characterisation by using liquid chromatography and exact mass spectrometry; the full sequence was identified by means of LC-ESI-Orbitrap-MS applying a bottom-up approach. The characterised protein consists of 92 amino acids and has a calculated exact MW of 9579.0. The presence of four disulfide bridges was confirmed after reduction, as shown by a mass increment of 8 Da. Finally, its potential allergenicity was confirmed via an in silico approach. The results presented here demonstrate the enormous potential of advanced MS techniques for obtaining high-quality structural and functional data of allergenic proteins in a short time.

  3. Subchronic phencyclidine treatment in adult mice increases GABAergic transmission and LTP threshold in the hippocampus.

    PubMed

    Nomura, Toshihiro; Oyamada, Yoshihiro; Fernandes, Herman B; Remmers, Christine L; Xu, Jian; Meltzer, Herbert Y; Contractor, Anis

    2016-01-01

    Repeated administration of non-competitive N-methyl-d-aspartate (NMDA) receptor antagonists such as phencyclidine (PCP) to rodents causes long-lasting deficits in cognition and memory, and has effects on behaviors that have been suggested to be models of the cognitive impairment associated with schizophrenia (CIAS). Despite this being a widely studied animal model, little is known about the long lasting changes in synapses and circuits that underlie the altered behaviors. Here we examined synaptic transmission ex-vivo in the hippocampus of mice after a subchronic PCP (scPCP) administration regime. We found that after at least one week of drug free washout period when mice have impaired cognitive function, the threshold for long-term potentiation (LTP) of CA1 excitatory synapses was elevated. This elevated LTP threshold was directly related to increased inhibitory input to CA1 pyramidal cells through increased activity of GABAergic neurons. These results suggest repeated PCP administration causes a long-lasting metaplastic change in the inhibitory circuits in the hippocampus that results in impaired LTP, and could contribute to the deficits in hippocampal-dependent memory in PCP-treated mice. Changes in GABA signaling have been described in patients with schizophrenia, therefore our results support using scPCP as a model of CIAS. This article is part of the Special Issue entitled 'Synaptopathy--from Biology to Therapy'.

  4. A PARP1-ERK2 synergism is required for the induction of LTP

    PubMed Central

    Visochek, L.; Grigoryan, G.; Kalal, A.; Milshtein-Parush, H.; Gazit, N.; Slutsky, I.; Yeheskel, A.; Shainberg, A.; Castiel, A.; Seger, R.; Langelier, M. F.; Dantzer, F.; Pascal, J. M.; Segal, M.; Cohen-Armon, M.

    2016-01-01

    Unexpectedly, a post-translational modification of DNA-binding proteins, initiating the cell response to single-strand DNA damage, was also required for long-term memory acquisition in a variety of learning paradigms. Our findings disclose a molecular mechanism based on PARP1-Erk synergism, which may underlie this phenomenon. A stimulation induced PARP1 binding to phosphorylated Erk2 in the chromatin of cerebral neurons caused Erk-induced PARP1 activation, rendering transcription factors and promoters of immediate early genes (IEG) accessible to PARP1-bound phosphorylated Erk2. Thus, Erk-induced PARP1 activation mediated IEG expression implicated in long-term memory. PARP1 inhibition, silencing, or genetic deletion abrogated stimulation-induced Erk-recruitment to IEG promoters, gene expression and LTP generation in hippocampal CA3-CA1-connections. Moreover, a predominant binding of PARP1 to single-strand DNA breaks, occluding its Erk binding sites, suppressed IEG expression and prevented the generation of LTP. These findings outline a PARP1-dependent mechanism required for LTP generation, which may be implicated in long-term memory acquisition and in its deterioration in senescence. PMID:27121568

  5. A PARP1-ERK2 synergism is required for the induction of LTP.

    PubMed

    Visochek, L; Grigoryan, G; Kalal, A; Milshtein-Parush, H; Gazit, N; Slutsky, I; Yeheskel, A; Shainberg, A; Castiel, A; Seger, R; Langelier, M F; Dantzer, F; Pascal, J M; Segal, M; Cohen-Armon, M

    2016-04-28

    Unexpectedly, a post-translational modification of DNA-binding proteins, initiating the cell response to single-strand DNA damage, was also required for long-term memory acquisition in a variety of learning paradigms. Our findings disclose a molecular mechanism based on PARP1-Erk synergism, which may underlie this phenomenon. A stimulation induced PARP1 binding to phosphorylated Erk2 in the chromatin of cerebral neurons caused Erk-induced PARP1 activation, rendering transcription factors and promoters of immediate early genes (IEG) accessible to PARP1-bound phosphorylated Erk2. Thus, Erk-induced PARP1 activation mediated IEG expression implicated in long-term memory. PARP1 inhibition, silencing, or genetic deletion abrogated stimulation-induced Erk-recruitment to IEG promoters, gene expression and LTP generation in hippocampal CA3-CA1-connections. Moreover, a predominant binding of PARP1 to single-strand DNA breaks, occluding its Erk binding sites, suppressed IEG expression and prevented the generation of LTP. These findings outline a PARP1-dependent mechanism required for LTP generation, which may be implicated in long-term memory acquisition and in its deterioration in senescence.

  6. Subchronic phencyclidine treatment in adult mice increases GABAergic transmission and LTP threshold in the hippocampus

    PubMed Central

    Nomura, Toshihiro; Oyamada, Yoshihiro; Fernandes, Herman B.; Remmers, Christine; Xu, Jian; Meltzer, Herbert; Contractor, Anis

    2015-01-01

    Repeated administration of non-competitive N-methyl-d-aspartate (NMDA) receptor antagonists such as phencyclidine (PCP) to rodents causes long-lasting deficits in cognition and memory, and has effects on behaviors that have been suggested to be models of the cognitive impairment associated with schizophrenia (CIAS). Despite this being a widely studied animal model, little is known about the long lasting changes in synapses and circuits that underlie the altered behaviors. Here we examined synaptic transmission ex-vivo in the hippocampus of mice after a subchronic PCP (scPCP) administration regime. We found that after at least one week of drug free washout period when mice have impaired cognitive function, the threshold for long term potentiation (LTP) of CA1 excitatory synapses was elevated. This elevated LTP threshold was directly related to increased inhibitory input to CA1 pyramidal cells through increased activity of GABAergic neurons. These results suggest repeated PCP administration causes a long-lasting metaplastic change in the inhibitory circuits in the hippocampus that results in impaired LTP, and could contribute to the deficits in hippocampal-dependent memory in PCP-treated mice. Changes in GABA signaling have been described in patients with schizophrenia, therefore our results support using scPCP as a model of CIAS. PMID:25937215

  7. Postsynaptic SDC2 induces transsynaptic signaling via FGF22 for bidirectional synaptic formation

    PubMed Central

    Hu, Hsiao-Tang; Umemori, Hisashi; Hsueh, Yi-Ping

    2016-01-01

    Functional synapse formation requires tight coordination between pre- and post-synaptic termini. Previous studies have shown that postsynaptic expression of heparan sulfate proteoglycan syndecan-2 (SDC2) induces dendritic spinogenesis. Those SDC2-induced dendritic spines are frequently associated with presynaptic termini. However, how postsynaptic SDC2 accelerates maturation of corresponding presynaptic termini is unknown. Because fibroblast growth factor 22 (FGF22), a heparan sulfate binding growth factor, has been shown to act as a presynaptic organizer released from the postsynaptic site, it seems possible that postsynaptic SDC2 presents FGF22 to the presynaptic FGF receptor to promote presynaptic differentiation. Here, we show that postsynaptic SDC2 uses its ectodomain to interact with and facilitate dendritic filopodial targeting of FGF22, triggering presynaptic maturation. Since SDC2 also enhances filopodial targeting of NMDAR via interaction with the CASK-mLIN7-MINT1 adaptor complex, presynaptic maturation promoted by FGF22 further feeds back to activate NMDAR at corresponding postsynaptic sites through increased neurotransmitter release and, consequently, promotes the dendritic filopodia-spines (F-S) transition. Meanwhile, via regulation of the KIF17 motor, CaMKII (activated by the NMDAR pathway) may further facilitate FGF22 targeting to dendritic filopodia that receive presynaptic stimulation. Our study suggests a positive feedback that promotes the coordination of postsynaptic and presynaptic differentiation. PMID:27627962

  8. Improved segmentation of cerebellar structures in children

    PubMed Central

    Narayanan, Priya Lakshmi; Boonazier, Natalie; Warton, Christopher; Molteno, Christopher D; Joseph, Jesuchristopher; Jacobson, Joseph L; Jacobson, Sandra W; Zöllei, Lilla; Meintjes, Ernesta M

    2016-01-01

    Background Consistent localization of cerebellar cortex in a standard coordinate system is important for functional studies and detection of anatomical alterations in studies of morphometry. To date, no pediatric cerebellar atlas is available. New method The probabilistic Cape Town Pediatric Cerebellar Atlas (CAPCA18) was constructed in the age-appropriate National Institute of Health Pediatric Database asymmetric template space using manual tracings of 16 cerebellar compartments in 18 healthy children (9–13 years) from Cape Town, South Africa. The individual atlases of the training subjects were also used to implement multi atlas label fusion using multi atlas majority voting (MAMV) and multi atlas generative model (MAGM) approaches. Segmentation accuracy in 14 test subjects was compared for each method to ‘gold standard’ manual tracings. Results Spatial overlap between manual tracings and CAPCA18 automated segmentation was 73% or higher for all lobules in both hemispheres, except VIIb and X. Automated segmentation using MAGM yielded the best segmentation accuracy over all lobules (mean Dice Similarity Coefficient 0.76; range 0.55–0.91). Comparison with existing methods In all lobules, spatial overlap of CAPCA18 segmentations with manual tracings was similar or higher than those obtained with SUIT (spatially unbiased infra-tentorial template), providing additional evidence of the benefits of an age appropriate atlas. MAGM segmentation accuracy was comparable to values reported recently by Park et al. (2014) in adults (across all lobules mean DSC = 0.73, range 0.40–0.89). Conclusions CAPCA18 and the associated multi atlases of the training subjects yield improved segmentation of cerebellar structures in children. PMID:26743973

  9. A probabilistic atlas of the cerebellar white matter.

    PubMed

    van Baarsen, K M; Kleinnijenhuis, M; Jbabdi, S; Sotiropoulos, S N; Grotenhuis, J A; van Cappellen van Walsum, A M

    2016-01-01

    Imaging of the cerebellar cortex, deep cerebellar nuclei and their connectivity are gaining attraction, due to the important role the cerebellum plays in cognition and motor control. Atlases of the cerebellar cortex and nuclei are used to locate regions of interest in clinical and neuroscience studies. However, the white matter that connects these relay stations is of at least similar functional importance. Damage to these cerebellar white matter tracts may lead to serious language, cognitive and emotional disturbances, although the pathophysiological mechanism behind it is still debated. Differences in white matter integrity between patients and controls might shed light on structure-function correlations. A probabilistic parcellation atlas of the cerebellar white matter would help these studies by facilitating automatic segmentation of the cerebellar peduncles, the localization of lesions and the comparison of white matter integrity between patients and controls. In this work a digital three-dimensional probabilistic atlas of the cerebellar white matter is presented, based on high quality 3T, 1.25mm resolution diffusion MRI data from 90 subjects participating in the Human Connectome Project. The white matter tracts were estimated using probabilistic tractography. Results over 90 subjects were symmetrical and trajectories of superior, middle and inferior cerebellar peduncles resembled the anatomy as known from anatomical studies. This atlas will contribute to a better understanding of cerebellar white matter architecture. It may eventually aid in defining structure-function correlations in patients with cerebellar disorders.

  10. Cerebellar modulation of human associative plasticity

    PubMed Central

    Hamada, Masashi; Strigaro, Gionata; Murase, Nagako; Sadnicka, Anna; Galea, Joseph M; Edwards, Mark J; Rothwell, John C

    2012-01-01

    Paired associative stimulation (PAS) is a method commonly used in human studies of motor cortex synaptic plasticity. It involves repeated pairs of electrical stimuli to the median nerve and transcranial magnetic stimulation (TMS) of the motor cortex. If the interval between peripheral and TMS stimulation is around 21–25 ms, corticospinal excitability is increased for the following 30–60 min via a long term potentiation (LTP)-like effect within the primary motor cortex. Previous work has shown that PAS depends on the present and previous levels of activity in cortex, and that it can be modified by motor learning or attention. Here we show that simultaneous transcranial direct current stimulation (TDCS; 2 mA) over the cerebellum can abolish the PAS effect entirely. Surprisingly, the effect is seen when the PAS interval is 25 ms but not when it is 21.5 ms. There are two implications from this work. First, the cerebellum influences PAS effects in motor cortex; second, LTP-like effects of PAS have at least two different mechanisms. The results are relevant for interpretation of pathological changes that have been reported in response to PAS in people with movement disorders and to changes in healthy individuals following exercise or other interventions. PMID:22473780

  11. Automated suppression of errors in LTP-II slope measurements with x-ray optics. Part1: Review of LTP errors and methods for the error reduction

    SciTech Connect

    Ali, Zulfiqar; Yashchuk, Valeriy V.

    2011-05-11

    Systematic error and instrumental drift are the major limiting factors of sub-microradian slope metrology with state-of-the-art x-ray optics. Significant suppression of the errors can be achieved by using an optimal measurement strategy suggested in [Rev. Sci. Instrum. 80, 115101 (2009)]. With this series of LSBL Notes, we report on development of an automated, kinematic, rotational system that provides fully controlled flipping, tilting, and shifting of a surface under test. The system is integrated into the Advanced Light Source long trace profiler, LTP-II, allowing for complete realization of the advantages of the optimal measurement strategy method. We provide details of the system’s design, operational control and data acquisition. The high performance of the system is demonstrated via the results of high precision measurements with a spherical test mirror.

  12. Structural cerebellar correlates of cognitive and motor dysfunctions in cerebellar degeneration.

    PubMed

    Kansal, Kalyani; Yang, Zhen; Fishman, Ann M; Sair, Haris I; Ying, Sarah H; Jedynak, Bruno M; Prince, Jerry L; Onyike, Chiadi U

    2017-03-01

    See King et al. (doi:10.1093/aww348) for a scientific commentary on this article.Detailed mapping of clinical dysfunctions to the cerebellar lobules in disease populations is necessary to establish the functional significance of lobules implicated in cognitive and motor functions in normal subjects. This study constitutes the first quantitative examination of the lobular correlates of a broad range of cognitive and motor phenomena in cerebellar disease. We analysed cross-sectional data from 72 cases with cerebellar disease and 36 controls without cerebellar disease. Cerebellar lobule volumes were derived from a graph-cut based segmentation algorithm. Sparse partial least squares, a variable selection approach, was used to identify lobules associated with motor function, language, executive function, memory, verbal learning, perceptual organization and visuomotor coordination. Motor dysfunctions were chiefly associated with the anterior lobe and posterior lobule HVI. Confrontation naming, noun fluency, recognition, and perceptual organization did not have cerebellar associations. Verb and phonemic fluency, working memory, cognitive flexibility, immediate and delayed recall, verbal learning, and visuomotor coordination were variably associated with HVI, Crus I, Crus II, HVII B and/or HIX. Immediate and delayed recall also showed associations with the anterior lobe. These findings provide preliminary anatomical evidence for a functional topography of the cerebellum first defined in task-based functional magnetic resonance imaging studies of normal subjects and support the hypotheses that (i) cerebellar efferents target frontal lobe neurons involved in forming action representations and new search strategies; (ii) there is greater involvement of the cerebellum when immediate recall tasks involve more complex verbal stimuli (e.g. longer words versus digits); and (iii) it is involved in spontaneous retrieval of long-term memory. More generally, they provide an anatomical

  13. Effects of subchronic aluminum exposure on spatial memory, ultrastructure and L-LTP of hippocampus in rats.

    PubMed

    Zhang, Lifeng; Jin, Cuihong; Liu, Qiufang; Lu, Xiaobo; Wu, Shengwen; Yang, Jinghua; Du, Yanqiu; Zheng, Linlin; Cai, Yuan

    2013-01-01

    Epidemiological investigations have indicated that aluminum (Al), as an important environmental neurotoxicant, could cause damage to the cognitive function which was closely related with neurodegenerative diseases. Long-term potentiation (LTP) is one form of synaptic plasticity in association with cognitive function. Previous studies have demonstrated that Al impaired early phase long-term potentiation (E-LTP) in vivo and in vitro. However, Al-induced damage to late phase long-term potentiation (L-LTP) has poorly been studied. The present study was designed to observe the effects of subchronic Al exposure on the spatial memory, hippocampus ultrastructure and L-LTP in rats. Pregnant Wistar rats were assigned to four groups. Neonatal rats were exposed to Al by parental lactation from parturition to weaning for 3 weeks and then fed with the distilled water containing 0, 0.2%, 0.4% and 0.6% aluminum chloride (AlCl3) respectively from weaning to postnatal 3 months. The levels of Al in blood and hippocampus were quantitated by atomic absorption spectrophotometer. Morris water maze test was performed to study spatial memory. The induction and maintenance of L-LTP in area of Schaffer collateral- CA1 synapse was recorded by extracellular microelectrode recording technology in hippocampus of experimental rats. Hippocampus was collected for transmission electron microscopy observation. The results showed that the Al concentrations in blood and hippocampus of Al-exposed rats were higher than those of the control rats. Al could impair spatial memory ability of rats. Neuronal and synaptic ultrastructure from Al-exposed rats presented pathological changes; the incidence of L-LTP has a decrease trend while population spike (PS) amplitude was much smaller significantly stimulated by high-frequency stimulation (HFS) in Al-exposed rats. Our findings showed that Al exposure caused spatial memory damage, under which the neuronal and synaptic ultrastructure changes maybe were their

  14. A toolbox to visually explore cerebellar shape changes in cerebellar disease and dysfunction

    NASA Astrophysics Data System (ADS)

    Abulnaga, S. Mazdak; Yang, Zhen; Carass, Aaron; Kansal, Kalyani; Jedynak, Bruno M.; Onyike, Chiadi U.; Ying, Sarah H.; Prince, Jerry L.

    2016-03-01

    The cerebellum plays an important role in motor control and is also involved in cognitive processes. Cerebellar function is specialized by location, although the exact topographic functional relationship is not fully understood. The spinocerebellar ataxias are a group of neurodegenerative diseases that cause regional atrophy in the cerebellum, yielding distinct motor and cognitive problems. The ability to study the region-specific atrophy patterns can provide insight into the problem of relating cerebellar function to location. In an effort to study these structural change patterns, we developed a toolbox in MATLAB to provide researchers a unique way to visually explore the correlation between cerebellar lobule shape changes and function loss, with a rich set of visualization and analysis modules. In this paper, we outline the functions and highlight the utility of the toolbox. The toolbox takes as input landmark shape representations of subjects' cerebellar substructures. A principal component analysis is used for dimension reduction. Following this, a linear discriminant analysis and a regression analysis can be performed to find the discriminant direction associated with a specific disease type, or the regression line of a specific functional measure can be generated. The characteristic structural change pattern of a disease type or of a functional score is visualized by sampling points on the discriminant or regression line. The sampled points are used to reconstruct synthetic cerebellar lobule shapes. We showed a few case studies highlighting the utility of the toolbox and we compare the analysis results with the literature.

  15. Crossed Cerebellar Atrophy of the Lateral Cerebellar Nucleus in an Endothelin-1-Induced, Rodent Model of Ischemic Stroke

    PubMed Central

    Chan, Hugh H.; Cooperrider, Jessica L.; Park, Hyun-Joo; Wathen, Connor A.; Gale, John T.; Baker, Kenneth B.; Machado, Andre G.

    2017-01-01

    Crossed cerebellar diaschisis (CCD) is a functional deficit of the cerebellar hemisphere resulting from loss of afferent input consequent to a lesion of the contralateral cerebral hemisphere. It is manifested as a reduction of metabolism and blood flow and, depending on severity and duration, it can result in atrophy, a phenomenon known as crossed cerebellar atrophy (CCA). While CCA has been well-demonstrated in humans, it remains poorly characterized in animal models of stroke. In this study we evaluated the effects of cerebral cortical ischemia on contralateral cerebellar anatomy using an established rodent model of chronic stroke. The effects of cortical ischemia on the cerebellar hemispheres, vermis and deep nuclei were characterized. Intracortical microinjections of endothelin-1 (ET-1) were delivered to the motor cortex of Long Evans rats to induce ischemic stroke, with animals sacrificed 6 weeks later. Naive animals served as controls. Cerebral sections and cerebellar sections including the deep nuclei were prepared for analysis with Nissl staining. Cortical ischemia was associated with significant thickness reduction of the molecular layer at the Crus 1 and parafloccular lobule (PFL), but not in fourth cerebellar lobule (4Cb), as compared to the ipsilesional cerebellar hemisphere. A significant reduction in volume and cell density of the lateral cerebellar nucleus (LCN), the rodent correlate of the dentate nucleus, was also noted. The results highlight the relevance of corticopontocerebellar (CPC) projections for cerebellar metabolism and function, including its direct projections to the LCN. PMID:28261086

  16. Cerebellar Dysfunction in a Patient with HIV.

    PubMed

    Gonzalez-Ibarra, Fernando; Abdul, Waheed; Eivaz-Mohammadi, Sahar; Foscue, Christopher; Gongireddy, Srinivas; Syed, Amer

    2014-01-01

    A 50-year-old AIDS patient with a CD4 T-cell count of 114/mm(3) was admitted with cerebellar symptoms of left CN XI weakness, wide-based gait with left-sided dysmetria, abnormal heel-knee-shin test, and dysdiadochokinesia. MRI showed region of hyperintensity in the left inferior cerebellar hemisphere involving the cortex and underlying white matter. Serological tests for HSV1, HSV2, and syphilis were negative. Her CSF contained high protein content and a WBC of 71/mm(3), predominantly lymphocytes. The CSF was also negative for cryptococcal antigen and VDRL. CSF culture did not grow microbes. CSF PCR assay was negative for HSV1 and HSV2 but was positive for JC virus (1,276 copies). The most likely diagnosis is granule cell neuronopathy (GCN), which can only be definitively confirmed with biopsy and immunohistochemistry.

  17. Marijuana alters the human cerebellar clock.

    PubMed

    O'Leary, Daniel S; Block, Robert I; Turner, Beth M; Koeppel, Julie; Magnotta, Vincent A; Ponto, Laura Boles; Watkins, G Leonard; Hichwa, Richard D; Andreasen, Nancy C

    2003-06-11

    The effects of marijuana on brain perfusion and internal timing were assessed using [15O] water PET in occasional and chronic users. Twelve volunteers who smoked marijuana recreationally about once weekly, and 12 volunteers who smoked daily for a number of years performed a self-paced counting task during PET imaging, before and after smoking marijuana and placebo cigarettes. Smoking marijuana increased rCBF in the ventral forebrain and cerebellar cortex in both groups, but resulted in significantly less frontal lobe activation in chronic users. Counting rate increased after smoking marijuana in both groups, as did a behavioral measure of self-paced tapping, and both increases correlated with rCBF in the cerebellum. Smoking marijuana appears to accelerate a cerebellar clock altering self-paced behaviors.

  18. Capping of the N-terminus of PSD-95 by calmodulin triggers its postsynaptic release.

    PubMed

    Zhang, Yonghong; Matt, Lucas; Patriarchi, Tommaso; Malik, Zulfiqar A; Chowdhury, Dhrubajyoti; Park, Deborah K; Renieri, Alessandra; Ames, James B; Hell, Johannes W

    2014-06-17

    Postsynaptic density protein-95 (PSD-95) is a central element of the postsynaptic architecture of glutamatergic synapses. PSD-95 mediates postsynaptic localization of AMPA receptors and NMDA receptors and plays an important role in synaptic plasticity. PSD-95 is released from postsynaptic membranes in response to Ca(2+) influx via NMDA receptors. Here, we show that Ca(2+)/calmodulin (CaM) binds at the N-terminus of PSD-95. Our NMR structure reveals that both lobes of CaM collapse onto a helical structure of PSD-95 formed at its N-terminus (residues 1-16). This N-terminal capping of PSD-95 by CaM blocks palmitoylation of C3 and C5, which is required for postsynaptic PSD-95 targeting and the binding of CDKL5, a kinase important for synapse stability. CaM forms extensive hydrophobic contacts with Y12 of PSD-95. The PSD-95 mutant Y12E strongly impairs binding to CaM and Ca(2+)-induced release of PSD-95 from the postsynaptic membrane in dendritic spines. Our data indicate that CaM binding to PSD-95 serves to block palmitoylation of PSD-95, which in turn promotes Ca(2+)-induced dissociation of PSD-95 from the postsynaptic membrane.

  19. Synaptic activation modifies microtubules underlying transport of postsynaptic cargo.

    PubMed

    Maas, Christoph; Belgardt, Dorthe; Lee, Han Kyu; Heisler, Frank F; Lappe-Siefke, Corinna; Magiera, Maria M; van Dijk, Juliette; Hausrat, Torben J; Janke, Carsten; Kneussel, Matthias

    2009-05-26

    Synaptic plasticity, the ability of synapses to change in strength, requires alterations in synaptic molecule compositions over time, and synapses undergo selective modifications on stimulation. Molecular motors operate in sorting/transport of neuronal proteins; however, the targeting mechanisms that guide and direct cargo delivery remain elusive. We addressed the impact of synaptic transmission on the regulation of intracellular microtubule (MT)-based transport. We show that increased neuronal activity, as induced through GlyR activity blockade, facilitates tubulin polyglutamylation, a posttranslational modification thought to represent a molecular traffic sign for transport. Also, GlyR activity blockade alters the binding of the MT-associated protein MAP2 to MTs. By using the kinesin (KIF5) and the postsynaptic protein gephyrin as models, we show that such changes of MT tracks are accompanied by reduced motor protein mobility and cargo delivery into neurites. Notably, the observed neurite targeting deficits are prevented on functional depletion or gene expression knockdown of neuronal polyglutamylase. Our data suggest a previously undescribed concept of synaptic transmission regulating MT-dependent cargo delivery.

  20. MPP2 is a postsynaptic MAGUK scaffold protein that links SynCAM1 cell adhesion molecules to core components of the postsynaptic density

    PubMed Central

    Rademacher, Nils; Schmerl, Bettina; Lardong, Jennifer A.; Wahl, Markus C.; Shoichet, Sarah A.

    2016-01-01

    At neuronal synapses, multiprotein complexes of trans-synaptic adhesion molecules, scaffold proteins and neurotransmitter receptors assemble to essential building blocks required for synapse formation and maintenance. Here we describe a novel role for the membrane-associated guanylate kinase (MAGUK) protein MPP2 (MAGUK p55 subfamily member 2) at synapses of rat central neurons. Through interactions mediated by its C-terminal SH3-GK domain module, MPP2 binds to the abundant postsynaptic scaffold proteins PSD-95 and GKAP and localises to postsynaptic sites in hippocampal neurons. MPP2 also colocalises with the synaptic adhesion molecule SynCAM1. We demonstrate that the SynCAM1 C-terminus interacts directly with the MPP2 PDZ domain and that MPP2 does not interact in this manner with other highly abundant postsynaptic transmembrane proteins. Our results highlight a previously unexplored role for MPP2 at postsynaptic sites as a scaffold that links SynCAM1 cell adhesion molecules to core proteins of the postsynaptic density. PMID:27756895

  1. Cerebellar secretin modulates eyeblink classical conditioning

    PubMed Central

    Fuchs, Jason R.; Robinson, Gain M.; Dean, Aaron M.; Schoenberg, Heidi E.; Williams, Michael R.; Morielli, Anthony D.

    2014-01-01

    We have previously shown that intracerebellar infusion of the neuropeptide secretin enhances the acquisition phase of eyeblink conditioning (EBC). Here, we sought to test whether endogenous secretin also regulates EBC and to test whether the effect of exogenous and endogenous secretin is specific to acquisition. In Experiment 1, rats received intracerebellar infusions of the secretin receptor antagonist 5-27 secretin or vehicle into the lobulus simplex of cerebellar cortex immediately prior to sessions 1–3 of acquisition. Antagonist-infused rats showed a reduction in the percentage of eyeblink CRs compared with vehicle-infused rats. In Experiment 2, rats received intracerebellar infusions of secretin or vehicle immediately prior to sessions 1–2 of extinction. Secretin did not significantly affect extinction performance. In Experiment 3, rats received intracerebellar infusions of 5-27 secretin or vehicle immediately prior to sessions 1–2 of extinction. The secretin antagonist did not significantly affect extinction performance. Together, our current and previous results indicate that both exogenous and endogenous cerebellar secretin modulate acquisition, but not extinction, of EBC. We have previously shown that (1) secretin reduces surface expression of the voltage-gated potassium channel α-subunit Kv1.2 in cerebellar cortex and (2) intracerebellar infusions of a Kv1.2 blocker enhance EBC acquisition, much like secretin. Kv1.2 is almost exclusively expressed in cerebellar cortex at basket cell–Purkinje cell pinceaus and Purkinje cell dendrites; we propose that EBC-induced secretin release from PCs modulates EBC acquisition by reducing surface expression of Kv1.2 at one or both of these sites. PMID:25403455

  2. Autism and cerebellar dysfunction: Evidence from animal models.

    PubMed

    Tsai, Peter T

    2016-10-01

    Autism is a prevalent neurodevelopmental disorder whose origins are not well understood. Cerebellar involvement has been implicated in the pathogenesis of autism spectrum disorders with increasing evidence from both clinical studies and animal models supporting an important role for cerebellar dysfunction in autism spectrum disorders. This article discusses the various cerebellar contributions to autism spectrum disorders. Both clinical and preclinical studies are discussed and future research directions highlighted.

  3. Cerebro-cerebellar circuits in autism spectrum disorder.

    PubMed

    D'Mello, Anila M; Stoodley, Catherine J

    2015-01-01

    The cerebellum is one of the most consistent sites of abnormality in autism spectrum disorder (ASD) and cerebellar damage is associated with an increased risk of ASD symptoms, suggesting that cerebellar dysfunction may play a crucial role in the etiology of ASD. The cerebellum forms multiple closed-loop circuits with cerebral cortical regions that underpin movement, language, and social processing. Through these circuits, cerebellar dysfunction could impact the core ASD symptoms of social and communication deficits and repetitive and stereotyped behaviors. The emerging topography of sensorimotor, cognitive, and affective subregions in the cerebellum provides a new framework for interpreting the significance of regional cerebellar findings in ASD and their relationship to broader cerebro-cerebellar circuits. Further, recent research supports the idea that the integrity of cerebro-cerebellar loops might be important for early cortical development; disruptions in specific cerebro-cerebellar loops in ASD might impede the specialization of cortical regions involved in motor control, language, and social interaction, leading to impairments in these domains. Consistent with this concept, structural, and functional differences in sensorimotor regions of the cerebellum and sensorimotor cerebro-cerebellar circuits are associated with deficits in motor control and increased repetitive and stereotyped behaviors in ASD. Further, communication and social impairments are associated with atypical activation and structure in cerebro-cerebellar loops underpinning language and social cognition. Finally, there is converging evidence from structural, functional, and connectivity neuroimaging studies that cerebellar right Crus I/II abnormalities are related to more severe ASD impairments in all domains. We propose that cerebellar abnormalities may disrupt optimization of both structure and function in specific cerebro-cerebellar circuits in ASD.

  4. Cerebro-cerebellar circuits in autism spectrum disorder

    PubMed Central

    D'Mello, Anila M.; Stoodley, Catherine J.

    2015-01-01

    The cerebellum is one of the most consistent sites of abnormality in autism spectrum disorder (ASD) and cerebellar damage is associated with an increased risk of ASD symptoms, suggesting that cerebellar dysfunction may play a crucial role in the etiology of ASD. The cerebellum forms multiple closed-loop circuits with cerebral cortical regions that underpin movement, language, and social processing. Through these circuits, cerebellar dysfunction could impact the core ASD symptoms of social and communication deficits and repetitive and stereotyped behaviors. The emerging topography of sensorimotor, cognitive, and affective subregions in the cerebellum provides a new framework for interpreting the significance of regional cerebellar findings in ASD and their relationship to broader cerebro-cerebellar circuits. Further, recent research supports the idea that the integrity of cerebro-cerebellar loops might be important for early cortical development; disruptions in specific cerebro-cerebellar loops in ASD might impede the specialization of cortical regions involved in motor control, language, and social interaction, leading to impairments in these domains. Consistent with this concept, structural, and functional differences in sensorimotor regions of the cerebellum and sensorimotor cerebro-cerebellar circuits are associated with deficits in motor control and increased repetitive and stereotyped behaviors in ASD. Further, communication and social impairments are associated with atypical activation and structure in cerebro-cerebellar loops underpinning language and social cognition. Finally, there is converging evidence from structural, functional, and connectivity neuroimaging studies that cerebellar right Crus I/II abnormalities are related to more severe ASD impairments in all domains. We propose that cerebellar abnormalities may disrupt optimization of both structure and function in specific cerebro-cerebellar circuits in ASD. PMID:26594140

  5. Acute bilateral cerebellar infarction in the territory of the medial branches of posterior inferior cerebellar arteries.

    PubMed

    Gurer, G; Sahin, G; Cekirge, S; Tan, E; Saribas, O

    2001-10-01

    The most frequent type of cerebellar infarcts involved the posterior inferior cerebellar artery (PICA) and superior cerebellar artery territories but bilateral involvement of lateral or medial branches of PICA is extremely rare. In this report, we present a 55-year-old male who admitted to hospital with vomiting, nausea and dizziness. On examination left-sided hemiparesia and ataxic gait were detected. Infarct on bilateral medial branch of PICA artery territories was found out with cranial magnetic resonance imaging (MRI) technique and 99% stenosis of the left vertebral artery was found out with digital subtraction arteriography. The patient was put on heparin treatment. After 3 weeks, his complaints and symptoms had disappeared except for mild gait ataxia.

  6. Early chronic blockade of NR2B subunits and transient activation of NMDA receptors modulate LTP in mouse auditory cortex.

    PubMed

    Mao, Yuting; Zang, Shaoyun; Zhang, Jiping; Sun, Xinde

    2006-02-16

    In the auditory cortex, the properties of NMDA receptors depend primarily on the ratio of NR2A and NR2B subunits. NR2B subunit expression is high at the beginning of critical period and lower in adulthood. Because NMDA receptors are crucial in triggering long-term potentiation (LTP) and long-term depression, developmental or experience-dependent modification of NMDAR subunit composition is likely to influence synaptic plasticity. To examine how NMDA subunit change during postnatal development affect the adult synaptic plasticity, we employed chronic ifenprodil blockade of NR2B subunits and analyzed evoked field potentials in adult C57BL/6 mice auditory cortex (AC). We found that chronic loss of NR2B activity led to a decline in LTP magnitude in the AC of adult mice. Adding NMDA to the artificial cerebrospinal fluid (ACSF) in blocked mice had the opposite effect, producing LTP magnitudes at or exceeding those found in treated or untreated animals. These results suggest that, even in adulthood when NR2B expression is downregulated, these receptor subunits play an important role in experience-dependent plasticity of mouse auditory cortex. Blockade from P60 did not result in any decrease of LTP amplitude, suggesting that chronic block in postnatal period may permanently affect cortical circuits so that they cannot produce significant LTP in adulthood.

  7. Pitch discrimination in cerebellar patients: evidence for a sensory deficit.

    PubMed

    Parsons, Lawrence M; Petacchi, Augusto; Schmahmann, Jeremy D; Bower, James M

    2009-12-15

    In the last two decades, a growing body of research showing cerebellar involvement in an increasing number of nonmotor tasks and systems has prompted an expansion of speculations concerning the function of the cerebellum. Here, we tested the predictions of a hypothesis positing cerebellar involvement in sensory data acquisition. Specifically, we examined the effect of global cerebellar degeneration on primary auditory sensory function by means of a pitch discrimination task. The just noticeable difference in pitch between two tones was measured in 15 healthy controls and in 15 high functioning patients afflicted with varying degrees of global cerebellar degeneration caused by hereditary, idiopathic, paraneoplastic, or postinfectious pancerebellitis. Participants also performed an auditory detection task assessing sustained attention, a test of verbal auditory working memory, and an audiometric test. Patient pitch discrimination thresholds were on average five and a half times those of controls and were proportional to the degree of cerebellar ataxia assessed independently. Patients and controls showed normal hearing thresholds and similar performance in control tasks in sustained attention and verbal auditory working memory. These results suggest there is an effect of cerebellar degeneration on primary auditory function. The findings are consistent with other recent demonstrations of cerebellar-related sensory impairments, and with robust cerebellar auditorily evoked activity, confirmed by quantitative meta-analysis, across a range of functional neuroimaging studies dissociated from attention, motor, affective, and cognitive variables. The data are interpreted in the context of a sensory hypothesis of cerebellar function.

  8. Effects of Transforming Growth Factor Beta 1 in Cerebellar Development: Role in Synapse Formation

    PubMed Central

    Araujo, Ana P. B.; Diniz, Luan P.; Eller, Cristiane M.; de Matos, Beatriz G.; Martinez, Rodrigo; Gomes, Flávia C. A.

    2016-01-01

    Granule cells (GC) are the most numerous glutamatergic neurons in the cerebellar cortex and represent almost half of the neurons of the central nervous system. Despite recent advances, the mechanisms of how the glutamatergic synapses are formed in the cerebellum remain unclear. Among the TGF-β family, TGF-beta 1 (TGF-β1) has been described as a synaptogenic molecule in invertebrates and in the vertebrate peripheral nervous system. A recent paper from our group demonstrated that TGF-β1 increases the excitatory synapse formation in cortical neurons. Here, we investigated the role of TGF-β1 in glutamatergic cerebellar neurons. We showed that the expression profile of TGF-β1 and its receptor, TβRII, in the cerebellum is consistent with a role in synapse formation in vitro and in vivo. It is low in the early postnatal days (P1–P9), increases after postnatal day 12 (P12), and remains high until adulthood (P30). We also found that granule neurons express the TGF-β receptor mRNA and protein, suggesting that they may be responsive to the synaptogenic effect of TGF-β1. Treatment of granular cell cultures with TGF-β1 increased the number of glutamatergic excitatory synapses by 100%, as shown by immunocytochemistry assays for presynaptic (synaptophysin) and post-synaptic (PSD-95) proteins. This effect was dependent on TβRI activation because addition of a pharmacological inhibitor of TGF-β, SB-431542, impaired the formation of synapses between granular neurons. Together, these findings suggest that TGF-β1 has a specific key function in the cerebellum through regulation of excitatory synapse formation between granule neurons. PMID:27199658

  9. Developmental regulation of the late phase of long-term potentiation (L-LTP) and metaplasticity in hippocampal area CA1 of the rat

    PubMed Central

    Cao, Guan

    2012-01-01

    Long-term potentiation (LTP) is a form of synaptic plasticity thought to underlie memory; thus knowing its developmental profile is fundamental to understanding function. Like memory, LTP has multiple phases with distinct timing and mechanisms. The late phase of LTP (L-LTP), lasting longer than 3 h, is protein synthesis dependent and involves changes in the structure and content of dendritic spines, the major sites of excitatory synapses. In previous work, tetanic stimulation first produced L-LTP at postnatal day 15 (P15) in area CA1 of rat hippocampus. Here we used a more robust induction paradigm involving theta-burst stimulation (TBS) in acute slices and found the developmental onset of L-LTP to be 3 days earlier at P12. In contrast, at P8–11, TBS only reversed the synaptic depression that occurs from test-pulse stimulation in developing (P8–15) hippocampus. A second bout of TBS delivered 30–180 min later produced L-LTP at P10–11 but not at P8–9 and enhanced L-LTP at P12–15. Both the developmental onset and the enhanced L-LTP produced by repeated bouts of TBS were blocked by the N-methyl-d-aspartate receptor antagonist dl-2-amino-5-phosphonovaleric acid. Thus the developmental onset age is P12 for L-LTP induced by the more robust and perhaps more naturalistic TBS induction paradigm. Metaplasticity produced by repeated bouts of TBS is developmentally regulated, advancing the capacity for L-LTP from P12 to P10, but not to younger ages. Together these findings provide a new basis from which to investigate mechanisms that regulate the developmental onset of this important form of synaptic plasticity. PMID:22114158

  10. Sensitivity of N-methyl-D-aspartate receptor-mediated excitatory postsynaptic potentials and synaptic plasticity to TCN 201 and TCN 213 in rat hippocampal slices.

    PubMed

    Izumi, Yukitoshi; Zorumski, Charles F

    2015-02-01

    Whereas ifenprodil has been used as a selective GluN1/GluN2B (NR1/NR2B, B-type) receptor antagonist to distinguish between GluN2B (NR2B) and GluN2A (NR2A)-containing N-methyl-d-aspartate receptors (NMDARs), TCN 201 (3-chloro-4-fluoro-N-[4-[[2-(phenylcarbonyl)hydrazino]carbonyl]benzyl]benzenesulphonamide) and TCN 213 [N-(cyclohexylmethyl)-2-[{5-[(phenylmethyl)amino]-1,3,4-thiadiazol-2-yl}thio]acetamide] have been found to be selective GluN1/GluN2A (NR1/NR2A, A-type) antagonists. Based on the premise that A- and B-types are major synaptic NMDARs, we examined whether inhibition of NMDAR excitatory postsynaptic potentials (EPSPs) by the TCN compounds and ifenprodil are complementary. Contrary to this prediction, inhibition of NMDAR EPSPs by the TCN compounds and ifenprodil were largely overlapping in the CA1 region of hippocampal slices from 30-day-old rats. After partial inhibition by ifenprodil, TCN compounds produced little further suppression of NMDAR EPSPs. Similarly, after partial inhibition by TCN compounds ifenprodil failed to further suppress NMDAR EPSPs. However, low micromolar d-2-amino-5-phosphonovalerate, a competitive NMDAR antagonist, which alone only partially inhibits NMDAR EPSPs, markedly suppresses residual NMDAR responses in the presence of ifenprodil or the TCNs, suggesting that low 2-amino-5-phosphonovalerate antagonizes both ifenprodil- and TCN-insensitive synaptic NMDARs. These observations can be most readily interpreted if ifenprodil and TCNs act on a similar population of synaptic NMDARs. Recent lines of evidence suggest that the majority of hippocampal synaptic NMDARs are triheteromers. If so, modulation of GluN2A, and not just GluN2B NMDARs, could dampen long-term depression (LTD). Indeed, both TCNs, like ifenprodil, blocked LTD, suggesting the involvement of ifenprodil- and TCN-sensitive NMDARs in LTD induction. However, the TCNs plus ifenprodil failed to inhibit long-term potentiation (LTP), suggesting that neither ifenprodil- nor TCN

  11. Impairment of Memory Consolidation by Galanin Correlates with In-Vivo Inhibition of Both LTP and CREB Phosphorylation

    PubMed Central

    Kinney, Jefferson W.; Sanchez-Alavez, Manuel; Barr, Alasdair M.; Criado, Jose R.; Crawley, Jacqueline N.; Behrens, M. Margarita; Henriksen, Steven J.; Bartfai, Tamas

    2009-01-01

    Changes in the state of CREB phosphorylation and in LTP in the hippocampus have been associated with learning and memory. Here we show that galanin, the neuropeptide released in the hippocampal formation from cholinergic and noradrenergic fibers, that has been shown to produce impairments in memory consolidation in the Morris water maze task inhibits both LTP and CREB phosphorylation in the rat hippocampus in-vivo. While there are many transmitters regulating CREB phosphorylation none has been shown to suppress behaviorally-induced hippocampal CREB phosphorylation as potently as galanin. The in-vivo inhibition of dentate gyrus-LTP and of CREB phosphorylation by the agonist occupancy of GalR1 and GALR2-type galanin receptors provides strong in-vivo cellular and molecular correlates to galanin-induced learning deficits and designates galanin as a major regulator of the memory consolidation process. PMID:19531380

  12. On the role of a Lipid-Transfer Protein. Arabidopsis ltp3 mutant is compromised in germination and seedling growth.

    PubMed Central

    Pagnussat, Luciana A; Oyarburo, Natalia; Cimmino, Carlos; Pinedo, Marcela L; de la Canal, Laura

    2015-01-01

    Plant Lipid-Transfer Proteins (LTPs) exhibit the ability to reversibly bind/transport lipids in vitro. LTPs have been involved in diverse physiological processes but conclusive evidence on their role has only been presented for a few members, none of them related to seed physiology. Arabidopsis seeds rely on storage oil breakdown to supply carbon skeletons and energy for seedling growth. Here, Arabidopsis ltp3 mutant was analyzed for its ability to germinate and for seedling establishment. Ltp3 showed delayed germination and reduced germination frequency. Seedling growth appeared reduced in the mutant but this growth restriction was rescued by the addition of an exogenous carbon supply, suggesting a defective oil mobilization. Lipid breakdown analysis during seedling growth revealed a differential profile in the mutant compared to the wild type. The involvement of LTP3 in germination and seedling growth and its relationship with the lipid transfer ability of this protein is discussed. PMID:26479260

  13. On the role of a Lipid-Transfer Protein. Arabidopsis ltp3 mutant is compromised in germination and seedling growth.

    PubMed

    Pagnussat, Luciana A; Oyarburo, Natalia; Cimmino, Carlos; Pinedo, Marcela L; de la Canal, Laura

    2015-01-01

    Plant Lipid-Transfer Proteins (LTPs) exhibit the ability to reversibly bind/transport lipids in vitro. LTPs have been involved in diverse physiological processes but conclusive evidence on their role has only been presented for a few members, none of them related to seed physiology. Arabidopsis seeds rely on storage oil breakdown to supply carbon skeletons and energy for seedling growth. Here, Arabidopsis ltp3 mutant was analyzed for its ability to germinate and for seedling establishment. Ltp3 showed delayed germination and reduced germination frequency. Seedling growth appeared reduced in the mutant but this growth restriction was rescued by the addition of an exogenous carbon supply, suggesting a defective oil mobilization. Lipid breakdown analysis during seedling growth revealed a differential profile in the mutant compared to the wild type. The involvement of LTP3 in germination and seedling growth and its relationship with the lipid transfer ability of this protein is discussed.

  14. Synaptic excitation is regulated by the postsynaptic dSK channel at the Drosophila larval NMJ.

    PubMed

    Gertner, Daniel M; Desai, Sunil; Lnenicka, Gregory A

    2014-06-15

    In the mammalian central nervous system, the postsynaptic small-conductance Ca(2+)-dependent K(+) (SK) channel has been shown to reduce postsynaptic depolarization and limit Ca(2+) influx through N-methyl-d-aspartate receptors. To examine further the role of the postsynaptic SK channel in synaptic transmission, we studied its action at the Drosophila larval neuromuscular junction (NMJ). Repetitive synaptic stimulation produced an increase in postsynaptic membrane conductance leading to depression of excitatory postsynaptic potential amplitude and hyperpolarization of the resting membrane potential (RMP). This reduction in synaptic excitation was due to the postsynaptic Drosophila SK (dSK) channel; synaptic depression, increased membrane conductance and RMP hyperpolarization were reduced in dSK mutants or after expressing a Ca(2+) buffer in the muscle. Ca(2+) entering at the postsynaptic membrane was sufficient to activate dSK channels based upon studies in which the muscle membrane was voltage clamped to prevent opening voltage-dependent Ca(2+) channels. Increasing external Ca(2+) produced an increase in resting membrane conductance and RMP that was not seen in dSK mutants or after adding the glutamate-receptor blocker philanthotoxin. Thus it appeared that dSK channels were also activated by spontaneous transmitter release and played a role in setting membrane conductance and RMP. In mammals, dephosphorylation by protein phosphatase 2A (PP2A) increased the Ca(2+) sensitivity of the SK channel; PP2A appeared to increase the sensitivity of the dSK channel since PP2A inhibitors reduced activation of the dSK channel by evoked synaptic activity or increased external Ca(2+). It is proposed that spontaneous and evoked transmitter release activate the postsynaptic dSK channel to limit synaptic excitation and stabilize synapses.

  15. Synaptic excitation is regulated by the postsynaptic dSK channel at the Drosophila larval NMJ

    PubMed Central

    Gertner, Daniel M.; Desai, Sunil

    2014-01-01

    In the mammalian central nervous system, the postsynaptic small-conductance Ca2+-dependent K+ (SK) channel has been shown to reduce postsynaptic depolarization and limit Ca2+ influx through N-methyl-d-aspartate receptors. To examine further the role of the postsynaptic SK channel in synaptic transmission, we studied its action at the Drosophila larval neuromuscular junction (NMJ). Repetitive synaptic stimulation produced an increase in postsynaptic membrane conductance leading to depression of excitatory postsynaptic potential amplitude and hyperpolarization of the resting membrane potential (RMP). This reduction in synaptic excitation was due to the postsynaptic Drosophila SK (dSK) channel; synaptic depression, increased membrane conductance and RMP hyperpolarization were reduced in dSK mutants or after expressing a Ca2+ buffer in the muscle. Ca2+ entering at the postsynaptic membrane was sufficient to activate dSK channels based upon studies in which the muscle membrane was voltage clamped to prevent opening voltage-dependent Ca2+ channels. Increasing external Ca2+ produced an increase in resting membrane conductance and RMP that was not seen in dSK mutants or after adding the glutamate-receptor blocker philanthotoxin. Thus it appeared that dSK channels were also activated by spontaneous transmitter release and played a role in setting membrane conductance and RMP. In mammals, dephosphorylation by protein phosphatase 2A (PP2A) increased the Ca2+ sensitivity of the SK channel; PP2A appeared to increase the sensitivity of the dSK channel since PP2A inhibitors reduced activation of the dSK channel by evoked synaptic activity or increased external Ca2+. It is proposed that spontaneous and evoked transmitter release activate the postsynaptic dSK channel to limit synaptic excitation and stabilize synapses. PMID:24671529

  16. Postsynaptic actin regulates active zone spacing and glutamate receptor apposition at the Drosophila neuromuscular junction.

    PubMed

    Blunk, Aline D; Akbergenova, Yulia; Cho, Richard W; Lee, Jihye; Walldorf, Uwe; Xu, Ke; Zhong, Guisheng; Zhuang, Xiaowei; Littleton, J Troy

    2014-07-01

    Synaptic communication requires precise alignment of presynaptic active zones with postsynaptic receptors to enable rapid and efficient neurotransmitter release. How transsynaptic signaling between connected partners organizes this synaptic apparatus is poorly understood. To further define the mechanisms that mediate synapse assembly, we carried out a chemical mutagenesis screen in Drosophila to identify mutants defective in the alignment of active zones with postsynaptic glutamate receptor fields at the larval neuromuscular junction. From this screen we identified a mutation in Actin 57B that disrupted synaptic morphology and presynaptic active zone organization. Actin 57B, one of six actin genes in Drosophila, is expressed within the postsynaptic bodywall musculature. The isolated allele, act(E84K), harbors a point mutation in a highly conserved glutamate residue in subdomain 1 that binds members of the Calponin Homology protein family, including spectrin. Homozygous act(E84K) mutants show impaired alignment and spacing of presynaptic active zones, as well as defects in apposition of active zones to postsynaptic glutamate receptor fields. act(E84K) mutants have disrupted postsynaptic actin networks surrounding presynaptic boutons, with the formation of aberrant actin swirls previously observed following disruption of postsynaptic spectrin. Consistent with a disruption of the postsynaptic actin cytoskeleton, spectrin, adducin and the PSD-95 homolog Discs-Large are all mislocalized in act(E84K) mutants. Genetic interactions between act(E84K) and neurexin mutants suggest that the postsynaptic actin cytoskeleton may function together with the Neurexin-Neuroligin transsynaptic signaling complex to mediate normal synapse development and presynaptic active zone organization.

  17. Postsynaptic actin regulates active zone spacing and glutamate receptor apposition at the Drosophila neuromuscular junction

    PubMed Central

    Blunk, Aline D.; Akbergenova, Yulia; Cho, Richard W.; Lee, Jihye; Walldorf, Uwe; Xu, Ke; Zhong, Guisheng; Zhuang, Xiaowei; Littleton, J. Troy

    2014-01-01

    Synaptic communication requires precise alignment of presynaptic active zones with postsynaptic receptors to enable rapid and efficient neurotransmitter release. How transsynaptic signaling between connected partners organizes this synaptic apparatus is poorly understood. To further define the mechanisms that mediate synapse assembly, we carried out a chemical mutagenesis screen in Drosophila to identify mutants defective in the alignment of active zones with postsynaptic glutamate receptor fields at the larval neuromuscular junction. From this screen we identified a mutation in actin 57B that disrupted synaptic morphology and presynaptic active zone organization. Actin 57B, one of six actin genes in Drosophila, is expressed within the postsynaptic bodywall musculature. The isolated allele, actE84K, harbors a point mutation in a highly conserved glutamate residue in subdomain 1 that binds members of the Calponin Homology protein family, including spectrin. Homozygous actE84K mutants show impaired alignment and spacing of presynaptic active zones, as well as defects in apposition of active zones to postsynaptic glutamate receptor fields. actE84K mutants have disrupted postsynaptic actin networks surrounding presynaptic boutons, with the formation of aberrant actin swirls previously observed following disruption of postsynaptic spectrin. Consistent with a disruption of the postsynaptic actin cytoskeleton, spectrin, adducin and the PSD-95 homolog Disc-Large are all mislocalized in actE84K mutants. Genetic interactions between actE84K and neurexin mutants suggest that the postsynaptic actin cytoskeleton may function together with the Neurexin-Neuroligin transsynaptic signaling complex to mediate normal synapse development and presynaptic active zone organization. PMID:25066865

  18. Identification of common interneurons mediating pre- and postsynaptic inhibition in the cat spinal cord.

    PubMed

    Solodkin, M; Jiménez, I; Rudomin, P

    1984-06-29

    The spike-triggered averaging of dorsal and ventral root potentials permits the identification of two populations of interneurons in the intermediate nucleus of the cat spinal cord. One produced negative dorsal root potentials and inhibitory ventral root potentials, in some cases with monosynaptic latencies, suggesting that they mediate presynaptic inhibition of group I afferent fibers from muscles and postsynaptic inhibition of motoneurons. The other population mediated only nonreciprocal postsynaptic inhibition of motoneurons.

  19. Characterization of postsynaptic Ca2+ signals at the Drosophila larval NMJ.

    PubMed

    Desai, Sunil A; Lnenicka, Gregory A

    2011-08-01

    Postsynaptic intracellular Ca(2+) concentration ([Ca(2+)](i)) has been proposed to play an important role in both synaptic plasticity and synaptic homeostasis. In particular, postsynaptic Ca(2+) signals can alter synaptic efficacy by influencing transmitter release, receptor sensitivity, and protein synthesis. We examined the postsynaptic Ca(2+) transients at the Drosophila larval neuromuscular junction (NMJ) by injecting the muscle fibers with Ca(2+) indicators rhod-2 and Oregon Green BAPTA-1 (OGB-1) and then monitoring their increased fluorescence during synaptic activity. We observed discrete postsynaptic Ca(2+) transients along the NMJ during single action potentials (APs) and quantal Ca(2+) transients produced by spontaneous transmitter release. Most of the evoked Ca(2+) transients resulted from the release of one or two quanta of transmitter and occurred largely at synaptic boutons. The magnitude of the Ca(2+) signals was correlated with synaptic efficacy; the Is terminals, which produce larger excitatory postsynaptic potentials (EPSPs) and have a greater quantal size than Ib terminals, produced a larger Ca(2+) signal per terminal length and larger quantal Ca(2+) signals than the Ib terminals. During a train of APs, the postsynaptic Ca(2+) signal increased but remained localized to the postsynaptic membrane. In addition, we showed that the plasma membrane Ca(2+)-ATPase (PMCA) played a role in extruding Ca(2+) from the postsynaptic region of the muscle. Drosophila melanogaster has a single PMCA gene, predicted to give rise to various isoforms by alternative splicing. Using RT-PCR, we detected the expression of multiple transcripts in muscle and nervous tissues; the physiological significance of the same is yet to be determined.

  20. Importance of nitric oxide for local increases of blood flow in rat cerebellar cortex during electrical stimulation.

    PubMed Central

    Akgören, N; Fabricius, M; Lauritzen, M

    1994-01-01

    The endothelium-derived relaxing factor, probably nitric oxide (NO), is a potent vasodilator that regulates the vascular tone in several vascular beds, including the brain. We explored the possibility that NO might be of importance for the increase of cerebral blood flow (CBF) associated with activity of the well-defined neuronal circuits of the rat cerebellar cortex. Laser-Doppler flowmetry was used to measure increases of cerebellar blood flow evoked by trains of electrical stimulations of the dorsal surface. The evoked increases of CBF were frequency-dependent, being larger on than off the parallel fiber tracts, suggesting that conduction along parallel fibers and synaptic activation of target cells were important for the increase of CBF. This was verified experimentally since the evoked CBF increases were abolished by tetrodotoxin and reduced by 10 mM Mg2+ and selective antagonists for non-N-methyl-D-aspartate receptors. The cerebellar cortex contains high levels of NO synthase. This raised the possibility that NO was involved in the increase of CBF associated with neuronal activation. NO synthase inhibition by topical application of NG-nitro-L-arginine attenuated the evoked CBF increase by about 50%. This effect was partially reversed by pretreatment with L-arginine, the natural substrate for the enzyme, while NG-nitro-D-arginine, the inactive enantiomer, had no effect on the evoked CBF increases. Simultaneous blockade of non-N-methyl-D-aspartate receptors and NO synthase had no further suppressing effect on the blood flow increase than either substance alone, suggesting that the NO-dependent flow rise was dependent on postsynaptic mechanisms. These findings are consistent with the idea that local synthesis of NO is involved in the transduction mechanism between neuronal activity and increased CBF. Images PMID:7517038

  1. Activation of NPY type 5 receptors induces a long-lasting increase in spontaneous GABA release from cerebellar inhibitory interneurons

    PubMed Central

    Dubois, C. J.; Ramamoorthy, P.; Whim, M. D.

    2012-01-01

    Neuropeptide Y (NPY), a widely distributed neuropeptide in the central nervous system, can transiently suppress inhibitory synaptic transmission and alter membrane excitability via Y2 and Y1 receptors (Y2rs and Y1rs), respectively. Although many GABAergic neurons express Y5rs, the functional role of these receptors in inhibitory neurons is not known. Here, we investigated whether activation of Y5rs can modulate inhibitory transmission in cerebellar slices. Unexpectedly, application of NPY triggered a long-lasting increase in the frequency of miniature inhibitory postsynaptic currents in stellate cells. NPY also induced a sustained increase in spontaneous GABA release in cultured cerebellar neurons. When cerebellar cultures were examined for Y5r immunoreactivity, the staining colocalized with that of VGAT, a presynaptic marker for GABAergic cells, suggesting that Y5rs are located in the presynaptic terminals of inhibitory neurons. RT-PCR experiments confirmed the presence of Y5r mRNA in the cerebellum. The NPY-induced potentiation of GABA release was blocked by Y5r antagonists and mimicked by application of a selective peptide agonist for Y5r. Thus Y5r activation is necessary and sufficient to trigger an increase in GABA release. Finally, the potentiation of inhibitory transmission could not be reversed by a Y5r antagonist once it was initiated, consistent with the development of a long-term potentiation. These results indicate that activation of presynaptic Y5rs induces a sustained increase in spontaneous GABA release from inhibitory neurons in contrast to the transient suppression of inhibitory transmission that is characteristic of Y1r and Y2r activation. Our findings thus reveal a novel role of presynaptic Y5rs in inhibitory interneurons in regulating GABA release and suggest that these receptors could play a role in shaping neuronal network activity in the cerebellum. PMID:22190627

  2. Acid-sensing ion channel 1a contributes to hippocampal LTP inducibility through multiple mechanisms

    PubMed Central

    Liu, Ming-Gang; Li, Hu-Song; Li, Wei-Guang; Wu, Yan-Jiao; Deng, Shi-Ning; Huang, Chen; Maximyuk, Oleksandr; Sukach, Volodymyr; Krishtal, Oleg; Zhu, Michael X.; Xu, Tian-Le

    2016-01-01

    The exact roles of acid-sensing ion channels (ASICs) in synaptic plasticity remain elusive. Here, we address the contribution of ASIC1a to five forms of synaptic plasticity in the mouse hippocampus using an in vitro multi-electrode array recording system. We found that genetic deletion or pharmacological blockade of ASIC1a greatly reduced, but did not fully abolish, the probability of long-term potentiation (LTP) induction by either single or repeated high frequency stimulation or theta burst stimulation in the CA1 region. However, these treatments did not affect hippocampal long-term depression induced by low frequency electrical stimulation or (RS)-3,5-dihydroxyphenylglycine. We also show that ASIC1a exerts its action in hippocampal LTP through multiple mechanisms that include but are not limited to augmentation of NMDA receptor function. Taken together, these results reveal new insights into the role of ASIC1a in hippocampal synaptic plasticity and the underlying mechanisms. This unbiased study also demonstrates a novel and objective way to assay synaptic plasticity mechanisms in the brain. PMID:26996240

  3. Sos2 is dispensable for NMDA-induced Erk activation and LTP induction

    PubMed Central

    Arai, Junko A.; Li, Shaomin; Feig, Larry A.

    2009-01-01

    N-methyl-D-aspartate (NMDA) receptor-induced activation of extracellular signal-related protein kinase (Erk) plays important roles in various neuronal functions including long-term potentiation (LTP). Son of sevenless (Sos) proteins have been implicated in NMDA-induced Erk activation in neurons of young mice. However, contribution of each of the two Sos isoforms, Sos1 and Sos2, has not been clarified. In this study, Sos2 involvement in NMDA-induced Erk activation was examined. We observed no defect in Erk phosphorylation induced by NMDA treatment of cortical neuronal cultures from Sos2-/- newborn mice. Moreover, theta-burst induced LTP induction in the hippocampus of Sos2-/- mice was also normal. Finally, Erk activation by either depolarization or BDNF treatment was also normal in cultured neurons from Sos2 knockout mice. These results imply that Sos1 is the major regulator of these well-known neuronal Sos functions and suggest that a novel function for Sos2 in neurons remains to be determined. PMID:19429099

  4. LTP is accompanied by an enhanced local excitability of pyramidal neuron dendrites.

    PubMed

    Frick, Andreas; Magee, Jeffrey; Johnston, Daniel

    2004-02-01

    The propagation and integration of signals in the dendrites of pyramidal neurons is regulated, in part, by the distribution and biophysical properties of voltage-gated ion channels. It is thus possible that any modification of these channels in a specific part of the dendritic tree might locally alter these signaling processes. Using dendritic and somatic whole-cell recordings, combined with calcium imaging in rat hippocampal slices, we found that the induction of long-term potentiation (LTP) was accompanied by a local increase in dendritic excitability that was dependent on the activation of NMDA receptors. These changes favored the back-propagation of action potentials into this dendritic region with a subsequent boost in the Ca(2+) influx. Dendritic cell-attached patch recordings revealed a hyperpolarized shift in the inactivation curve of transient, A-type K(+) currents that can account for the enhanced excitability. These results suggest an important mechanism associated with LTP for shaping signal processing and controlling dendritic function.

  5. Mitochondrial support of persistent presynaptic vesicle mobilization with age-dependent synaptic growth after LTP

    PubMed Central

    Smith, Heather L; Bourne, Jennifer N; Cao, Guan; Chirillo, Michael A; Ostroff, Linnaea E; Watson, Deborah J; Harris, Kristen M

    2016-01-01

    Mitochondria support synaptic transmission through production of ATP, sequestration of calcium, synthesis of glutamate, and other vital functions. Surprisingly, less than 50% of hippocampal CA1 presynaptic boutons contain mitochondria, raising the question of whether synapses without mitochondria can sustain changes in efficacy. To address this question, we analyzed synapses from postnatal day 15 (P15) and adult rat hippocampus that had undergone theta-burst stimulation to produce long-term potentiation (TBS-LTP) and compared them to control or no stimulation. At 30 and 120 min after TBS-LTP, vesicles were decreased only in presynaptic boutons that contained mitochondria at P15, and vesicle decrement was greatest in adult boutons containing mitochondria. Presynaptic mitochondrial cristae were widened, suggesting a sustained energy demand. Thus, mitochondrial proximity reflected enhanced vesicle mobilization well after potentiation reached asymptote, in parallel with the apparently silent addition of new dendritic spines at P15 or the silent enlargement of synapses in adults. DOI: http://dx.doi.org/10.7554/eLife.15275.001 PMID:27991850

  6. Performance of the upgraded LTP-II at the ALS Optical Metrology Laboratory

    SciTech Connect

    Advanced Light Source; Yashchuk, Valeriy V; Kirschman, Jonathan L.; Domning, Edward E.; McKinney, Wayne R.; Morrison, Gregory Y.; Smith, Brian V.; Yashchuk, Valeriy V.

    2008-07-14

    The next generation of synchrotrons and free electron laser facilities requires x-ray optical systems with extremely high performance, generally of diffraction limited quality. Fabrication and use of such optics requires adequate, highly accurate metrology and dedicated instrumentation. Previously, we suggested ways to improve the performance of the Long Trace Profiler (LTP), a slope measuring instrument widely used to characterize x-ray optics at long spatial wavelengths. The main way is use of a CCD detector and corresponding technique for calibration of photo-response non-uniformity [J. L. Kirschman, et al., Proceedings of SPIE 6704, 67040J (2007)]. The present work focuses on the performance and characteristics of the upgraded LTP-II at the ALS Optical Metrology Laboratory. This includes a review of the overall aspects of the design, control system, the movement and measurement regimes for the stage, and analysis of the performance by a slope measurement of a highly curved super-quality substrate with less than 0.3 microradian (rms)slope variation.

  7. Extracellular Tau Oligomers Produce An Immediate Impairment of LTP and Memory.

    PubMed

    Fá, M; Puzzo, D; Piacentini, R; Staniszewski, A; Zhang, H; Baltrons, M A; Li Puma, D D; Chatterjee, I; Li, J; Saeed, F; Berman, H L; Ripoli, C; Gulisano, W; Gonzalez, J; Tian, H; Costa, J A; Lopez, P; Davidowitz, E; Yu, W H; Haroutunian, V; Brown, L M; Palmeri, A; Sigurdsson, E M; Duff, K E; Teich, A F; Honig, L S; Sierks, M; Moe, J G; D'Adamio, L; Grassi, C; Kanaan, N M; Fraser, P E; Arancio, O

    2016-01-20

    Non-fibrillar soluble oligomeric forms of amyloid-β peptide (oAβ) and tau proteins are likely to play a major role in Alzheimer's disease (AD). The prevailing hypothesis on the disease etiopathogenesis is that oAβ initiates tau pathology that slowly spreads throughout the medial temporal cortex and neocortices independently of Aβ, eventually leading to memory loss. Here we show that a brief exposure to extracellular recombinant human tau oligomers (oTau), but not monomers, produces an impairment of long-term potentiation (LTP) and memory, independent of the presence of high oAβ levels. The impairment is immediate as it raises as soon as 20 min after exposure to the oligomers. These effects are reproduced either by oTau extracted from AD human specimens, or naturally produced in mice overexpressing human tau. Finally, we found that oTau could also act in combination with oAβ to produce these effects, as sub-toxic doses of the two peptides combined lead to LTP and memory impairment. These findings provide a novel view of the effects of tau and Aβ on memory loss, offering new therapeutic opportunities in the therapy of AD and other neurodegenerative diseases associated with Aβ and tau pathology.

  8. An integrator circuit in cerebellar cortex.

    PubMed

    Maex, Reinoud; Steuber, Volker

    2013-09-01

    The brain builds dynamic models of the body and the outside world to predict the consequences of actions and stimuli. A well-known example is the oculomotor integrator, which anticipates the position-dependent elasticity forces acting on the eye ball by mathematically integrating over time oculomotor velocity commands. Many models of neural integration have been proposed, based on feedback excitation, lateral inhibition or intrinsic neuronal nonlinearities. We report here that a computational model of the cerebellar cortex, a structure thought to implement dynamic models, reveals a hitherto unrecognized integrator circuit. In this model, comprising Purkinje cells, molecular layer interneurons and parallel fibres, Purkinje cells were able to generate responses lasting more than 10 s, to which both neuronal and network mechanisms contributed. Activation of the somatic fast sodium current by subthreshold voltage fluctuations was able to maintain pulse-evoked graded persistent activity, whereas lateral inhibition among Purkinje cells via recurrent axon collaterals further prolonged the responses to step and sine wave stimulation. The responses of Purkinje cells decayed with a time-constant whose value depended on their baseline spike rate, with integration vanishing at low (< 1 per s) and high rates (> 30 per s). The model predicts that the apparently fast circuit of the cerebellar cortex may control the timing of slow processes without having to rely on sensory feedback. Thus, the cerebellar cortex may contain an adaptive temporal integrator, with the sensitivity of integration to the baseline spike rate offering a potential mechanism of plasticity of the response time-constant.

  9. Dopamine Transporter Blockade Increases LTP in the CA1 Region of the Rat Hippocampus via Activation of the D3 Dopamine Receptor

    ERIC Educational Resources Information Center

    Swant, Jarod; Wagner, John J.

    2006-01-01

    Dopamine has been demonstrated to be involved in the modulation of long-term potentiation (LTP) in the CA1 region of the hippocampus. As monoamine transporter blockade will increase the actions of endogenous monoamine neurotransmitters, the effect of a dopamine transporter (DAT) antagonist on LTP was assessed using field excitatory postsynaptic…

  10. Enriching the Environment of [alpha]CaMKII[superscript T286A] Mutant Mice Reveals that LTD Occurs in Memory Processing but Must be Subsequently Reversed by LTP

    ERIC Educational Resources Information Center

    Soto, Florentina; Giese, K. Peter; Edwards, Frances A.; Parsley, Stephanie L.; Pilgram, Sara M.

    2007-01-01

    [alpha]CaMKII[superscript T286A] mutant mice lack long-term potentiation (LTP) in the hippocampal CA1 region and are impaired in spatial learning. In situ hybridization confirms that the mutant mice show the same developmental expression of [alpha]CaMKII as their wild-type littermates. A simple hypothesis would suggest that if LTP is a substrate…

  11. BraLTP1, a Lipid Transfer Protein Gene Involved in Epicuticular Wax Deposition, Cell Proliferation and Flower Development in Brassica napus

    PubMed Central

    Liu, Fang; Xiong, Xiaojuan; Wu, Lei; Fu, Donghui; Hayward, Alice; Zeng, Xinhua; Cao, Yinglong; Wu, Yuhua; Li, Yunjing; Wu, Gang

    2014-01-01

    Plant non-specific lipid transfer proteins (nsLTPs) constitute large multigene families that possess complex physiological functions, many of which remain unclear. This study isolated and characterized the function of a lipid transfer protein gene, BraLTP1 from Brassica rapa, in the important oilseed crops Brassica napus. BraLTP1 encodes a predicted secretory protein, in the little known VI Class of nsLTP families. Overexpression of BnaLTP1 in B. napus caused abnormal green coloration and reduced wax deposition on leaves and detailed wax analysis revealed 17–80% reduction in various major wax components, which resulted in significant water-loss relative to wild type. BnaLTP1 overexpressing leaves exhibited morphological disfiguration and abaxially curled leaf edges, and leaf cross-sections revealed cell overproliferation that was correlated to increased cytokinin levels (tZ, tZR, iP, and iPR) in leaves and high expression of the cytokinin biosynthsis gene IPT3. BnaLTP1-overexpressing plants also displayed morphological disfiguration of flowers, with early-onset and elongated carpel development and outwardly curled stamen. This was consistent with altered expression of a a number of ABC model genes related to flower development. Together, these results suggest that BraLTP1 is a new nsLTP gene involved in wax production or deposition, with additional direct or indirect effects on cell division and flower development. PMID:25314222

  12. Neocortical networks entrain neuronal circuits in cerebellar cortex

    PubMed Central

    Roš, Hana; Sachdev, Robert N. S.; Yu, Yuguo; Šestan, Nenad; McCormick, David A.

    2011-01-01

    Activity in neocortex is often characterized by synchronized oscillations of neurons and networks, resulting in the generation of a local field potential and electroencephalogram. Do the neuronal networks of the cerebellum also generate synchronized oscillations and are they under the influence of those in the neocortex? Here we show that in the absence of any overt external stimulus, the cerebellar cortex generates a slow oscillation that is correlated with that of the neocortex. Disruption of the neocortical slow oscillation abolishes the cerebellar slow oscillation, whereas blocking cerebellar activity has no overt effect on the neocortex. We provide evidence that the cerebellar slow oscillation results in part from the activation of granule, Golgi, and Purkinje neurons. In particular, we show that granule and Golgi cells discharge trains of single spikes, and Purkinje cells generate complex spikes, during the Up state of the slow oscillation. Purkinje cell simple spiking is weakly related to the cerebellar and neocortical slow oscillation in a minority of cells. Our results indicate that the cerebellum generates rhythmic network activity that can be recorded as an LFP in the anesthetized animal, which is driven by synchronized oscillations of the neocortex. Furthermore, we show that correlations between neocortical and cerebellar LFPs persist in the awake animal, indicating that neocortical circuits modulate cerebellar neurons in a similar fashion in natural behavioral states. Thus, the projection neurons of the neocortex collectively exert a driving and modulatory influence on cerebellar network activity. PMID:19692605

  13. Acute cerebellar ataxia with human parvovirus B19 infection

    PubMed Central

    Shimizu, Y.; Ueno, T.; Komatsu, H.; Takada, H.; Nunoue, T.

    1999-01-01

    A 2 year old boy developed acute cerebellar ataxia in association with erythema infectiosum. During the disease, genomic DNA and antibodies against human parvovirus B19 were detected in serum but not in cerebrospinal fluid. Parvovirus B19 associated acute cerebellar ataxia might occur due to transient vascular reaction in the cerebellum during infection.

 PMID:10325764

  14. [Clinical study of two cases of traumatic cerebellar injury].

    PubMed

    Yokota, H; Nakazawa, S; Kobayashi, S; Taniguchi, Y; Yukihide, T

    1990-01-01

    Two cases of traumatic cerebellar injury complicated with a traumatic medial longitudinal fasciculus (MLF) syndrome or cerebellar mutism were reported, and the cause of these mechanisms was discussed: Case 1: A 9-year-old boy who struck his head in the occipital region during an automobile accident was operated on for a delayed traumatic intracerebellar hematoma. The operation improved the level of his consciousness but MLF syndrome was noticed. The mechanism of traumatic MLF syndrome was discussed in relation to vascular injury and to neurovascular friction. The outcome of the syndrome including our case, which recovered spontaneously, seemed to support the theory of neurovascular injury. Case 2: A 6-year-old boy who struck his head in the temporooccipital region during an automobile accident was admitted to our hospital without conciousness. On admission, contusion of the temporal lobe and left cerebellar hemisphere was demonstrated by a computerized tomography (CT) and magnetic resonance imaging (MRI). A mute state (cerebellar mutism) was recognized after his recovery of consciousness. The cause of the cerebellar mutism was thought to be an injury of the cerebellar vermis or left cerebellar hemisphere. The findings of CT scan and MRI in our case suggested that the cause of the cerebellar mutism was the contusion of these areas.

  15. Distinct Critical Cerebellar Subregions for Components of Verbal Working Memory

    ERIC Educational Resources Information Center

    Cooper, Freya E.; Grube, Manon; Von Kriegstein, Katharina; Kumar, Sukhbinder; English, Philip; Kelly, Thomas P.; Chinnery, Patrick F.; Griffiths, Timothy D.

    2012-01-01

    A role for the cerebellum in cognition has been proposed based on studies suggesting a profile of cognitive deficits due to cerebellar stroke. Such studies are limited in the determination of the detailed organisation of cerebellar subregions that are critical for different aspects of cognition. In this study we examined the correlation between…

  16. Humor and laughter in patients with cerebellar degeneration.

    PubMed

    Frank, B; Propson, B; Göricke, S; Jacobi, H; Wild, B; Timmann, D

    2012-06-01

    Humor is a complex behavior which includes cognitive, affective and motor responses. Based on observations of affective changes in patients with cerebellar lesions, the cerebellum may support cerebral and brainstem areas involved in understanding and appreciation of humorous stimuli and expression of laughter. The aim of the present study was to examine if humor appreciation, perception of humorous stimuli, and the succeeding facial reaction differ between patients with cerebellar degeneration and healthy controls. Twenty-three adults with pure cerebellar degeneration were compared with 23 age-, gender-, and education-matched healthy control subjects. No significant difference in humor appreciation and perception of humorous stimuli could be found between groups using the 3 Witz-Dimensionen Test, a validated test asking for funniness and aversiveness of jokes and cartoons. Furthermore, while observing jokes, humorous cartoons, and video sketches, facial expressions of subjects were videotaped and afterwards analysed using the Facial Action Coding System. Using depression as a covariate, the number, and to a lesser degree, the duration of facial expressions during laughter were reduced in cerebellar patients compared to healthy controls. In sum, appreciation of humor appears to be largely preserved in patients with chronic cerebellar degeneration. Cerebellar circuits may contribute to the expression of laughter. Findings add to the literature that non-motor disorders in patients with chronic cerebellar disease are generally mild, but do not exclude that more marked disorders may show up in acute cerebellar disease and/or in more specific tests of humor appreciation.

  17. IKK regulates the deubiquitinase CYLD at the postsynaptic density

    SciTech Connect

    Thein, Soe; Pham, Anna; Bayer, K. Ulrich; Tao-Cheng, Jung-Hwa; Dosemeci, Ayse

    2014-07-18

    Highlights: • CYLD is phosphorylated by IKK in isolated PSDs in the absence of Ca{sup 2+}. • CYLD is phosphorylated by IKK at the PSDs of intact neurons in basal conditions. • Phosphorylation of CYLD by IKK increases its deubiquitinase activity. • The process is likely to influence protein trafficking at the PSD in basal conditions. - Abstract: K63-linked polyubiquitination of proteins regulates their trafficking into specific cellular pathways such as endocytosis and autophagy. CYLD, a deubiquitinase specific for K63-linked polyubiquitins, is present in high quantities at the postsynaptic density (PSD). It was previously shown that, under excitatory conditions, CaMKII activates CYLD in a Ca{sup 2+}-dependent manner. The observation that CYLD can also be phosphorylated in the absence of Ca{sup 2+} in isolated PSDs led us to further explore the regulation of CYLD under basal conditions. A possible involvement of the autonomous form of CaMKII and IKK, both kinases known to be localized at the PSD, was examined. A CaMKII inhibitor CN21 had no effect on CYLD phosphorylation in the absence of Ca{sup 2+}, but two different IKK inhibitors, IKK16 and tatNEMO, inhibited its phosphorylation. Immuno-electron microscopy on hippocampal cultures, using an antibody for CYLD phosphorylated at S-418, revealed that the phosphorylated form of CYLD is present at the PSD under basal conditions. Phosphorylation of CYLD under basal conditions was inhibited by IKK16. NMDA treatment further promoted phosphorylation of CYLD at the PSD, but IKK16 failed to block the NMDA-induced effect. In vitro experiments using purified proteins demonstrated direct phosphorylation and activation of CYLD by the beta catalytic subunit of IKK. Activation of IKK in isolated PSDs also promoted phosphorylation of CYLD and an increase in endogenous deubiquitinase activity for K63-linked polyubiquitins. Altogether, the results suggest that in the absence of excitatory conditions, constitutive IKK activity

  18. Distinct critical cerebellar subregions for components of verbal working memory

    PubMed Central

    Cooper, Freya E.; Grube, Manon; Von Kriegstein, Katharina; Kumar, Sukhbinder; English, Philip; Kelly, Thomas P.; Chinnery, Patrick F.; Griffiths, Timothy D.

    2014-01-01

    A role for the cerebellum in cognition has been proposed based on studies suggesting a profile of cognitive deficits due to cerebellar stroke. Such studies are limited in the determination of the detailed organisation of cerebellar subregions that are critical for different aspects of cognition. In this study we examined the correlation between cognitive performance and cerebellar integrity in a specific degeneration of the cerebellar cortex: Spinocerebellar Ataxia type 6 (SCA6). The results demonstrate a critical relationship between verbal working memory and grey matter density in superior (bilateral lobules VI and crus I of lobule VII) and inferior (bilateral lobules VIIIa and VIIIb, and right lobule IX) parts of the cerebellum. We demonstrate that distinct cerebellar regions subserve different components of the prevalent psychological model for verbal working memory based on a phonological loop. The work confirms the involvement of the cerebellum in verbal working memory and defines specific subsystems for this within the cerebellum. PMID:22133495

  19. Preterm cerebellar growth impairment after postnatal exposure to glucocorticoids

    PubMed Central

    Tam, Emily W. Y.; Chau, Vann; Ferriero, Donna M.; Barkovich, A. James; Poskitt, Kenneth J.; Studholme, Colin; Fok, Eric D.-Y.; Grunau, Ruth E.; Glidden, David V.; Miller, Steven P.

    2012-01-01

    With improving survival rates of preterm newborns, adverse cognitive outcomes are increasingly recognized. Adverse cognitive outcomes are associated with decreased cerebellar volumes, and modifiable risk factors for these adverse outcomes should be identified. Animal models demonstrate reduced preterm cerebellar growth after exposure to glucocorticoids. Preterm neonates were prospectively studied with serial MRI examinations near birth and again near term-equivalent age. Adjusting for associated clinical factors, antenatal bethamethasone was not associated with changes in cerebellar volume. Postnatal exposure to clinically routine doses of hydrocortisone or dexamethasone were associated with impaired cerebellar, but not cerebral, growth. Modifying postnatal risk factors for impaired cerebellar development, and particularly glucocorticoid exposure, may help to decrease risk for adverse neurological outcome after preterm birth. PMID:22013125

  20. The physiological basis of therapies for cerebellar ataxias

    PubMed Central

    Mitoma, Hiroshi; Manto, Mario

    2016-01-01

    Cerebellar ataxias represent a group of heterogeneous disorders impacting on activities of daily living and quality of life. Various therapies have been proposed to improve symptoms in cerebellar ataxias. This review examines the physiological background of the various treatments currently administered worldwide. We analyze the mechanisms of action of drugs with a focus on aminopyridines and other antiataxic medications, of noninvasive cerebellar stimulation, and of motor rehabilitation. Considering the cerebellum as a controller, we propose the novel concept of ‘restorable stage’. Because of its unique anatomical architecture and its diffuse connectivity in particular with the cerebral cortex, keeping in mind the anatomophysiology of the cerebellar circuitry is a necessary step to understand the rationale of therapies of cerebellar ataxias and develop novel therapeutic tools. PMID:27582895

  1. Cerebellar vermis plays a causal role in visual motion discrimination.

    PubMed

    Cattaneo, Zaira; Renzi, Chiara; Casali, Stefano; Silvanto, Juha; Vecchi, Tomaso; Papagno, Costanza; D'Angelo, Egidio

    2014-09-01

    Cerebellar patients have been found to show deficits in visual motion discrimination, suggesting that the cerebellum may play a role in visual sensory processing beyond mediating motor control. Here we show that triple-pulse online transcranial magnetic stimulation (TMS) over cerebellar vermis but not over the cerebellar hemispheres significantly impaired motion discrimination. Critically, the interference caused by vermis TMS on motion discrimination did not depend on an indirect effect of TMS over nearby visual areas, as demonstrated by a control experiment in which TMS over V1 but not over cerebellar vermis significantly impaired orientation discrimination. These findings demonstrate the causal role of the cerebellar vermis in visual motion processing in neurologically normal participants.

  2. Cerebellar mass as a location of acute lymphoblastic leukaemia.

    PubMed

    Desideri, Ilaria; Canovetti, Silvia; Pesaresi, Ilaria; Caniglia, Michele; Ciancia, Eugenio; Bartolozzi, Carlo; Puglioli, Michele; Cosottini, Mirco

    2014-09-01

    A 22-year-old man with acute lymphoblastic leukaemia was referred to our observation for headache, cervical pain and sopor. A computed tomography study revealed triventricular obstructive hydrocephalus due to a left cerebellar hyperdense mass impinging on the fourth ventricle. A magnetic resonance study demonstrated an area of hyperintensity on T2-weighted images, hypointensity on T1, restricted diffusivity and contrast enhancement involving the left hemispherical cerebellar cortex and the vermis and causing cerebellar herniation. After surgical excision of the lesion, histological examination revealed an infiltrate of lymphoblastic leukaemia with B cells. Leukaemic intracranial masses are rare. Our report describes a case presenting a cerebellar mass of leukaemic tissue characterized by high cellularity and low apparent diffusion coefficient value comparable to acute ischaemia. Therefore leukaemic intracranial mass has to be considered in the differential diagnosis of cerebellar masses.

  3. New evidence for the cerebellar involvement in personality traits

    PubMed Central

    Picerni, Eleonora; Petrosini, Laura; Piras, Fabrizio; Laricchiuta, Daniela; Cutuli, Debora; Chiapponi, Chiara; Fagioli, Sabrina; Girardi, Paolo; Caltagirone, Carlo; Spalletta, Gianfranco

    2013-01-01

    Following the recognition of its role in sensory-motor coordination and learning, the cerebellum has been involved in cognitive, emotional, and even personality domains. This study investigated the relationships between cerebellar macro- and micro-structural variations and temperamental traits measured by Temperament and Character Inventory (TCI). High resolution T1-weighted, and Diffusion Tensor Images of 100 healthy subjects aged 18–59 years were acquired by 3 Tesla Magnetic Resonance scanner. In multiple regression analyses, cerebellar Gray Matter (GM) or White Matter (WM) volumes, GM Mean Diffusivity (MD), and WM Fractional Anisotropy (FA) were used as dependent variables, TCI scores as regressors, gender, age, and education years as covariates. Novelty Seeking scores were associated positively with the cerebellar GM volumes and FA, and negatively with MD. No significant association between Harm Avoidance, Reward Dependence or Persistence scores and cerebellar structural measures was found. The present data put toward a cerebellar involvement in the management of novelty. PMID:24106465

  4. New evidence for the cerebellar involvement in personality traits.

    PubMed

    Picerni, Eleonora; Petrosini, Laura; Piras, Fabrizio; Laricchiuta, Daniela; Cutuli, Debora; Chiapponi, Chiara; Fagioli, Sabrina; Girardi, Paolo; Caltagirone, Carlo; Spalletta, Gianfranco

    2013-01-01

    Following the recognition of its role in sensory-motor coordination and learning, the cerebellum has been involved in cognitive, emotional, and even personality domains. This study investigated the relationships between cerebellar macro- and micro-structural variations and temperamental traits measured by Temperament and Character Inventory (TCI). High resolution T1-weighted, and Diffusion Tensor Images of 100 healthy subjects aged 18-59 years were acquired by 3 Tesla Magnetic Resonance scanner. In multiple regression analyses, cerebellar Gray Matter (GM) or White Matter (WM) volumes, GM Mean Diffusivity (MD), and WM Fractional Anisotropy (FA) were used as dependent variables, TCI scores as regressors, gender, age, and education years as covariates. Novelty Seeking scores were associated positively with the cerebellar GM volumes and FA, and negatively with MD. No significant association between Harm Avoidance, Reward Dependence or Persistence scores and cerebellar structural measures was found. The present data put toward a cerebellar involvement in the management of novelty.

  5. Calcium channels responsible for potassium-induced transmitter release at rat cerebellar synapses.

    PubMed Central

    Momiyama, A; Takahashi, T

    1994-01-01

    The effects of calcium channel blockers on potassium-induced transmitter release were studied in thin slices of cerebellum from neonatal rats using whole-cell patch clamp methods. Miniature inhibitory postsynaptic currents (mIPSCs) mediated by gamma-aminobutyric acid (GABA) were recorded from deep cerebellar nuclear neurones in the presence of tetrodotoxin. The frequency of mIPSCs was reproducibly increased by a brief application of high-potassium solution. In the presence of the L-type Ca2+ channel blocker nicardipine (10 microM), the potassium-induced increase in mIPSC frequency was suppressed by 49%. Neither the mean amplitude nor the time course of mIPSCs was affected by the blocker. The N-type Ca2+ channel blocker omega-conotoxin GVIA (omega-CgTX, 3 microM) had no effect on the frequency of potassium-induced mIPSCs. The P-type Ca2+ channel blocker omega-Aga-IVA (200 nM) suppressed the potassium-induced increase in mIPSC frequency by 83% without affecting the mean amplitude or time course of mIPSCs. Comparing these data with previous studies of neurally evoked transmission, it is concluded that the Ca2+ channel subtypes responsible for potassium-induced transmitter release may be different from those mediating fast synaptic transmission. PMID:7913967

  6. Anoctamin Calcium-Activated Chloride Channels May Modulate Inhibitory Transmission in the Cerebellar Cortex.

    PubMed

    Zhang, Weiping; Schmelzeisen, Steffen; Parthier, Daniel; Frings, Stephan; Möhrlen, Frank

    2015-01-01

    Calcium-activated chloride channels of the anoctamin (alias TMEM16) protein family fulfill critical functions in epithelial fluid transport, smooth muscle contraction and sensory signal processing. Little is known, however, about their contribution to information processing in the central nervous system. Here we examined the recent finding that a calcium-dependent chloride conductance impacts on GABAergic synaptic inhibition in Purkinje cells of the cerebellum. We asked whether anoctamin channels may underlie this chloride conductance. We identified two anoctamin channel proteins, ANO1 and ANO2, in the cerebellar cortex. ANO1 was expressed in inhibitory interneurons of the molecular layer and the granule cell layer. Both channels were expressed in Purkinje cells but, while ANO1 appeared to be retained in the cell body, ANO2 was targeted to the dendritic tree. Functional studies confirmed that ANO2 was involved in a calcium-dependent mode of ionic plasticity that reduces the efficacy of GABAergic synapses. ANO2 channels attenuated GABAergic transmission by increasing the postsynaptic chloride concentration, hence reducing the driving force for chloride influx. Our data suggest that ANO2 channels are involved in a Ca2+-dependent regulation of synaptic weight in GABAergic inhibition. Thus, in balance with the chloride extrusion mechanism via the co-transporter KCC2, ANO2 appears to regulate ionic plasticity in the cerebellum.

  7. Neuroligins Sculpt Cerebellar Purkinje-Cell Circuits by Differential Control of Distinct Classes of Synapses.

    PubMed

    Zhang, Bo; Chen, Lulu Y; Liu, Xinran; Maxeiner, Stephan; Lee, Sung-Jin; Gokce, Ozgun; Südhof, Thomas C

    2015-08-19

    Neuroligins are postsynaptic cell-adhesion molecules that bind presynaptic neurexins and are genetically linked to autism. Neuroligins are proposed to organize synaptogenesis and/or synaptic transmission, but no systematic analysis of neuroligins in a defined circuit is available. Here, we show that conditional deletion of all neuroligins in cerebellar Purkinje cells caused loss of distal climbing-fiber synapses and weakened climbing-fiber but not parallel-fiber synapses, consistent with alternative use of neuroligins and cerebellins as neurexin ligands for the excitatory climbing-fiber versus parallel-fiber synapses. Moreover, deletion of neuroligins increased the size of inhibitory basket/stellate-cell synapses but simultaneously severely impaired their function. Multiple neuroligin isoforms differentially contributed to climbing-fiber and basket/stellate-cell synapse functions, such that inhibitory synapse-specific neuroligin-2 was unexpectedly essential for maintaining normal climbing-fiber synapse numbers. Using systematic analyses of all neuroligins in a defined neural circuit, our data thus show that neuroligins differentially contribute to various Purkinje-cell synapses in the cerebellum in vivo.

  8. Neuroligins Sculpt Cerebellar Purkinje-Cell Circuits by Differential Control of Distinct Classes of Synapses

    PubMed Central

    Zhang, Bo; Chen, Lulu Y.; Liu, Xinran; Maxeiner, Stephan; Lee, Sung-Jin; Gokce, Ozgun; Südhof, Thomas C.

    2015-01-01

    Neuroligins are postsynaptic cell-adhesion molecules that bind presynaptic neurexins and are genetically linked to autism. Neuroligins are proposed to organize synaptogenesis and/or synaptic transmission, but no systematic analysis of neuroligins in a defined circuit is available. Here, we show that conditional deletion of all neuroligins in cerebellar Purkinje cells caused loss of distal climbing-fiber synapses and weakened climbing-fiber but not parallel-fiber synapses, consistent with alternative use of neuroligins and cerebellins as neurexin ligands for the excitatory climbing-fiber vs. parallel-fiber synapses. Moreover, deletion of neuroligins increased the size of inhibitory basket/stellate-cell synapses but simultaneously severely impaired their function. Multiple neuroligin isoforms differentially contributed to climbing-fiber and basket/stellate-cell synapse functions, such that inhibitory synapse-specific neuroligin-2 was unexpectedly essential for maintaining normal climbing-fiber synapse numbers. Using systematic analyses of all neuroligins in a defined neural circuit, our data thus show that neuroligins differentially contribute to various Purkinje-cell synapses in the cerebellum in vivo. PMID:26291161

  9. Anoctamin Calcium-Activated Chloride Channels May Modulate Inhibitory Transmission in the Cerebellar Cortex

    PubMed Central

    Parthier, Daniel; Frings, Stephan; Möhrlen, Frank

    2015-01-01

    Calcium-activated chloride channels of the anoctamin (alias TMEM16) protein family fulfill critical functions in epithelial fluid transport, smooth muscle contraction and sensory signal processing. Little is known, however, about their contribution to information processing in the central nervous system. Here we examined the recent finding that a calcium-dependent chloride conductance impacts on GABAergic synaptic inhibition in Purkinje cells of the cerebellum. We asked whether anoctamin channels may underlie this chloride conductance. We identified two anoctamin channel proteins, ANO1 and ANO2, in the cerebellar cortex. ANO1 was expressed in inhibitory interneurons of the molecular layer and the granule cell layer. Both channels were expressed in Purkinje cells but, while ANO1 appeared to be retained in the cell body, ANO2 was targeted to the dendritic tree. Functional studies confirmed that ANO2 was involved in a calcium-dependent mode of ionic plasticity that reduces the efficacy of GABAergic synapses. ANO2 channels attenuated GABAergic transmission by increasing the postsynaptic chloride concentration, hence reducing the driving force for chloride influx. Our data suggest that ANO2 channels are involved in a Ca2+-dependent regulation of synaptic weight in GABAergic inhibition. Thus, in balance with the chloride extrusion mechanism via the co-transporter KCC2, ANO2 appears to regulate ionic plasticity in the cerebellum. PMID:26558388

  10. The ltp gene of temperate Streptococcus thermophilus phage TP-J34 confers superinfection exclusion to Streptococcus thermophilus and Lactococcus lactis

    SciTech Connect

    Sun Xingmin . E-mail: Xingmin_Sun@brown.edu; Goehler, Andre; Heller, Knut J. . E-mail: knut.heller@bfel.de; Neve, Horst

    2006-06-20

    The ltp gene, located within the lysogeny module of temperate Streptococcus thermophilus phage TP-J34, has been shown to be expressed in lysogenic strain S. thermophilus J34. It codes for a lipoprotein, as demonstrated by inhibition of cleavage of the signal sequence by globomycin. Exposure of Ltp on the surface of Lactococcus lactis protoplasts bearing a plasmid-encoded copy of ltp has been demonstrated by immunogold labeling and electron microscopy. Expression of ltp in prophage- and plasmid-cured S. thermophilus J34-6f interfered with TP-J34 infection. While plating efficiency was reduced by a factor of about 40 and lysis of strain J34-6f in liquid medium was delayed considerably, phage adsorption was not affected at all. Intracellular accumulation of phage DNA was shown to be inhibited by Ltp. This indicates interference of Ltp with infection at the stage of triggering DNA release and injection into the cell, indicating a role of Ltp in superinfection exclusion. Expression of ltp in L. lactis Bu2-60 showed that the same superinfection exclusion mechanism was strongly effective against phage P008, a member of the lactococcal 936 phage species: no plaque-formation was detectable with even 10{sup 9} phage per ml applied, and lysis in liquid medium did not occur. In Lactococcus also, Ltp apparently inhibited phage DNA release and/or injection. Ltp appears to be a member of a family of small, secreted proteins with a 42 amino acids repeat structure encoded by genes of Gram-positive bacteria. Some of these homologous genes are part of the genomes of prophages.

  11. Augmenting saturated LTP by broadly spaced episodes of theta-burst stimulation in hippocampal area CA1 of adult rats and mice

    PubMed Central

    Cao, Guan

    2014-01-01

    Hippocampal long-term potentiation (LTP) is a model system for studying cellular mechanisms of learning and memory. Recent interest in mechanisms underlying the advantage of spaced over massed learning has prompted investigation into the effects of distributed episodes of LTP induction. The amount of LTP induced in hippocampal area CA1 by one train (1T) of theta-burst stimulation (TBS) in young Sprague-Dawley rats was further enhanced by additional bouts of 1T given at 1-h intervals. However, in young Long-Evans (LE) rats, 1T did not initially saturate LTP. Instead, a stronger LTP induction paradigm using eight trains of TBS (8T) induced saturated LTP in hippocampal slices from both young and adult LE rats as well as adult mice. The saturated LTP induced by 8T could be augmented by another episode of 8T following an interval of at least 90 min. The success rate across animals and slices in augmenting LTP by an additional episode of 8T increased significantly with longer intervals between the first and last episodes, ranging from 0% at 30- and 60-min intervals to 13–66% at 90- to 180-min intervals to 90–100% at 240-min intervals. Augmentation above initially saturated LTP was blocked by the N-methyl-d-aspartate (NMDA) glutamate receptor antagonist d-2-amino-5-phosphonovaleric acid (d-APV). These findings suggest that the strength of induction and interval between episodes of TBS, as well as the strain and age of the animal, are important components in the augmentation of LTP. PMID:25057146

  12. Acute and chronic interference with BDNF/TrkB-signaling impair LTP selectively at mossy fiber synapses in the CA3 region of mouse hippocampus.

    PubMed

    Schildt, Sandra; Endres, Thomas; Lessmann, Volkmar; Edelmann, Elke

    2013-08-01

    Brain-derived neurotrophic factor (BDNF) signaling via TrkB crucially regulates synaptic plasticity in the brain. Although BDNF is abundant at hippocampal mossy fiber (MF) synapses, which critically contribute to hippocampus dependent memory, its role in MF synaptic plasticity (long-term potentiation, LTP) remained largely unclear. Using field potential recordings in CA3 of adult heterozygous BDNF knockout (ko, BDNF+/-) mice we observed impaired (∼50%) NMDAR-independent MF-LTP. In contrast to MF synapses, LTP at neighboring associative/commissural (A/C) fiber synapses remained unaffected. To exclude that impaired MF-LTP in BDNF+/- mice was due to developmental changes in response to chronically reduced BDNF levels, and to prove the importance of acute availability of BDNF in MF-LTP, we also tested effects of acute interference with BDNF/TrkB signaling. Inhibition of TrkB tyrosine kinase signaling with k252a, or with the selective BDNF scavenger TrkB-Fc, both inhibited MF-LTP to the same extent as observed in BDNF+/- mice. Basal synaptic transmission, short-term plasticity, and synaptic fatigue during LTP induction were not significantly altered by treatment with k252a or TrkB-Fc, or by chronic BDNF reduction in BDNF+/- mice. Since the acute interference with BDNF-signaling did not completely block MF-LTP, our results provide evidence that an additional mechanism besides BDNF induced TrkB signaling contributes to this type of LTP. Our results prove for the first time a mechanistic action of acute BDNF/TrkB signaling in presynaptic expression of MF-LTP in adult hippocampus.

  13. Spinocerebellar ataxia type 6 protein aggregates cause deficits in motor learning and cerebellar plasticity.

    PubMed

    Mark, Melanie D; Krause, Martin; Boele, Henk-Jan; Kruse, Wolfgang; Pollok, Stefan; Kuner, Thomas; Dalkara, Deniz; Koekkoek, Sebastiaan; De Zeeuw, Chris I; Herlitze, Stefan

    2015-06-10

    Spinocerebellar ataxia type 6 (SCA6) is linked to poly-glutamine (polyQ) within the C terminus (CT) of the pore-forming subunits of P/Q-type Ca(2+) channels (Cav2.1) and is characterized by CT protein aggregates found in cerebellar Purkinje cells (PCs). One hypothesis regarding SCA6 disease is that a CT fragment of the Cav2.1 channel, which is detected specifically in cytosolic and nuclear fractions in SCA6 patients, is associated with the SCA6 pathogenesis. To test this hypothesis, we expressed P/Q-type channel protein fragments from two different human CT splice variants, as predicted from SCA6 patients, in PCs of mice using viral and transgenic approaches. These splice variants represent a short (CT-short without polyQs) and a long (CT-long with 27 polyQs) CT fragment. Our results show that the different splice variants of the CTs differentially distribute within PCs, i.e., the short CTs reveal predominantly nuclear inclusions, whereas the long CTs prominently reveal both nuclear and cytoplasmic aggregates. Postnatal expression of CTs in PCs in mice reveals that only CT-long causes SCA6-like symptoms, i.e., deficits in eyeblink conditioning (EBC), ataxia, and PC degeneration. The physiological phenotypes associated specifically with the long CT fragment can be explained by an impairment of LTD and LTP at the parallel fiber-to-PC synapse and alteration in spontaneous PC activity. Thus, our results suggest that the polyQ carrying the CT fragment of the P/Q-type channel is sufficient to cause SCA6 pathogenesis in mice and identifies EBC as a new diagnostic strategy to evaluate Ca(2+) channel-mediated human diseases.

  14. D1/D5 Receptors and Histone Deacetylation Mediate the Gateway Effect of LTP in Hippocampal Dentate Gyrus

    ERIC Educational Resources Information Center

    Huang, Yan-You; Lavine, Amir; Kandel, Denise B.; Yin, Deqi; Colnaghi, Luca; Drisaldi, Bettina; Kandel, Eric R.

    2014-01-01

    The dentate gyrus (DG) of the hippocampus is critical for spatial memory and is also thought to be involved in the formation of drug-related associative memory. Here, we attempt to test an aspect of the Gateway Hypothesis, by studying the effect of consecutive exposure to nicotine and cocaine on long-term synaptic potentiation (LTP) in the DG. We…

  15. A Form of Perforant Path LTP Can Occur without ERK1/2 Phosphorylation or Immediate Early Gene Induction

    ERIC Educational Resources Information Center

    Steward, Oswald; Huang, Fen; Guzowski, John F.

    2007-01-01

    Stimulation paradigms that induce perforant path long-term potentiation (LTP) initiate phosphorylation of ERK1/2 and induce expression of a variety of immediate early genes (IEGs). These events are thought to be critical components of the mechanism for establishing the changes in synaptic efficacy that endure for hours or longer. Here we show that…

  16. Metaplastic LTP inhibition after LTD induction in CA1 hippocampal slices involves NMDA Receptor-mediated Neurosteroidogenesis

    PubMed Central

    Izumi, Yukitoshi; O'Dell, Kazuko A; Zorumski, Charles F

    2013-01-01

    Long-term depression (LTD) induced by low-frequency electrical stimulation (LFS) in the CA1 region of the hippocampus is a form of synaptic plasticity thought to contribute to learning and memory and to the pathophysiology of neuropsychiatric disorders. In naïve hippocampal slices from juvenile rats, we previously found that LTD induction can impair subsequent induction of long-term potentiation (LTP) via a form of N-methyl-d-aspartate receptor (NMDAR)-dependent metaplasticity, and have recently observed that pharmacologically induced NMDAR-dependent LTP inhibition involves 5α-reduced neurosteroids that augment the actions of γ-aminobutyric acid (GABA). In this study, we found that both LFS-induced LTD and subsequent inhibition of LTP induction involve neurosteroid synthesis via NMDAR activation. Furthermore, the timing of 5α-reductase inhibition relative to LFS can dissociate effects on LTD and metaplastic LTP inhibition. These findings indicate that 5α-reduced neurosteroids play an important role in synaptic plasticity and synaptic modulation in the hippocampus. PMID:24303196

  17. D1/D5 receptors and histone deacetylation mediate the Gateway Effect of LTP in hippocampal dentate gyrus.

    PubMed

    Huang, Yan-You; Levine, Amir; Kandel, Denise B; Yin, Deqi; Colnaghi, Luca; Drisaldi, Bettina; Kandel, Eric R

    2014-02-18

    The dentate gyrus (DG) of the hippocampus is critical for spatial memory and is also thought to be involved in the formation of drug-related associative memory. Here, we attempt to test an aspect of the Gateway Hypothesis, by studying the effect of consecutive exposure to nicotine and cocaine on long-term synaptic potentiation (LTP) in the DG. We find that a single injection of cocaine does not alter LTP. However, pretreatment with nicotine followed by a single injection of cocaine causes a substantial enhancement of LTP. This priming effect of nicotine is unidirectional: There is no enhancement of LTP if cocaine is administrated prior to nicotine. The facilitation induced by nicotine and cocaine can be blocked by oral administration of the dopamine D1/D5 receptor antagonist (SKF 83566) and enhanced by the D1/D5 agonist (SKF 38393). Application of the histone deacetylation inhibitor suberoylanilide hydroxamic acid (SAHA) simulates the priming effect of nicotine on cocaine. By contrast, the priming effect of nicotine on cocaine is blocked in genetically modified mice that are haploinsufficient for the CREB-binding protein (CBP) and possess only one functional CBP allele and therefore exhibit a reduction in histone acetylation. These results demonstrate that the DG of the hippocampus is an important brain region contributing to the priming effect of nicotine on cocaine. Moreover, both activation of dopamine-D1 receptor/PKA signaling pathway and histone deacetylation/CBP mediated transcription are required for the nicotine priming effect in the DG.

  18. Extracellular and intracellular cleavages of proBDNF required at two distinct stages of late-phase LTP

    NASA Astrophysics Data System (ADS)

    Pang, Petti T.; Nagappan, Guhan; Guo, Wei; Lu, Bai

    2016-05-01

    Although late-phase long-term potentiation (L-LTP) is implicated in long-term memory, its molecular mechanisms are largely unknown. Here we provide evidence that L-LTP can be divided into two stages: an induction stage (I) and a maintenance stage (II). Both stages require mature brain-derived neurotrophic factor (mBDNF), but involve distinct underlying mechanisms. Stage I requires secretion of existing proBDNF followed by extracellular cleavage by tPA/plasmin. Stage II depends on newly synthesized BDNF. Surprisingly, mBDNF at stage II is derived from intracellular cleavage of proBDNF by furin/PC1. Moreover, stage I involves BDNF-TrkB signaling mainly through MAP kinase, whereas all three signaling pathways (phospholipase C-γ, PI3 kinase, and MAP kinase) are required for the maintenance of L-LTP at stage II. These results reveal the molecular basis for two temporally distinct stages in L-LTP, and provide insights on how BDNF modulates this long-lasting synaptic alternation at two critical time windows.

  19. LTP in Hippocampal Area CA1 Is Induced by Burst Stimulation over a Broad Frequency Range Centered around Delta

    ERIC Educational Resources Information Center

    Grover, Lawrence M.; Kim, Eunyoung; Cooke, Jennifer D.; Holmes, William R.

    2009-01-01

    Long-term potentiation (LTP) is typically studied using either continuous high-frequency stimulation or theta burst stimulation. Previous studies emphasized the physiological relevance of theta frequency; however, synchronized hippocampal activity occurs over a broader frequency range. We therefore tested burst stimulation at intervals from 100…

  20. Coordinate High-Frequency Pattern of Stimulation and Calcium Levels Control the Induction of LTP in Striatal Cholinergic Interneurons

    ERIC Educational Resources Information Center

    Bonsi, Paola; De Persis, Cristiano; Calabresi, Paolo; Bernardi, Giorgio; Pisani, Antonio

    2004-01-01

    Current evidence appoints a central role to cholinergic interneurons in modulating striatal function. Recently, a long-term potentiation (LTP) of synaptic transmission has been reported to occur in these neurons. The relationship between the pattern of cortico/thalamostriatal fibers stimulation, the consequent changes in the intracellular calcium…

  1. Stability of sunflower 2S albumins and LTP to physiologically relevant in vitro gastrointestinal digestion.

    PubMed

    Berecz, Bernadett; Clare Mills, E N; Parádi, István; Láng, Ferenc; Tamás, László; Shewry, Peter R; Mackie, Alan R

    2013-06-15

    In order for a protein to elicit a systemic allergic response it must reach the circulatory system through the intestinal mucosa as a sufficiently large fragment with adequate structural integrity. Sunflower LTP and 2S albumins (SFA8 and three mixed fractions of Alb1 and Alb2) were digested in simulated gastric fluid (SGF) for 2h and the conditions were then changed to mimic the intestinal environment for a further 2h digestion. The effects of phosphatidylcholine (PC) and emulsification on the digestibility of the proteins were investigated. PC protected all of the proteins studied against both gastric and intestinal digestive enzymes but to different extents. Emulsification of SFA8 resulted in strong protection against digestion, which was further enhanced by the presence of PC in the SGF. These results highlight the importance of considering real food structures such as emulsified systems and also the gastrointestinal environment that proteins are exposed to once consumed when assessing allergenicity.

  2. A map of LTP-related synaptic changes in dorsal hippocampus following unsupervised learning.

    PubMed

    Cox, Conor D; Rex, Christopher S; Palmer, Linda C; Babayan, Alex H; Pham, Danielle T; Corwin, Samantha D; Trieu, Brian H; Gall, Christine M; Lynch, Gary

    2014-02-19

    Recent work showed that unsupervised learning of a complex environment activates synaptic proteins essential for the stabilization of long-term potentiation (LTP). The present study used automated methods to construct maps of excitatory synapses associated with high concentrations of one of these LTP-related proteins [CaMKII phosphorylated at T286/287, (pCaMKII)]. Labeling patterns across 42 sampling zones covering entire cross sections through rostral hippocampus were assessed for two groups of rats that explored a novel two-room arena for 30 min, with or without a response contingency involving mildly aversive cues. The number of pCaMKII-immunopositive (+) synapses was highly correlated between the two groups for the 21 sampling zones covering the dentate gyrus, CA3c/hilus, and apical dendrites of field CA1, but not for the remainder of the cross section. The distribution of pCaMKII+ synapses in the large uncorrelated segment differed markedly between the groups. Subtracting home-cage values removed high scores (i.e., sampling zones with a high percentage of pCaMKII+ contacts) in the negative contingency group, but not in the free-exploration animals. Three sites in the latter had values that were markedly elevated above other fields. These mapping results suggest that encoding of a form of memory that is dependent upon rostral hippocampus reliably occurs at high levels in discrete anatomical zones, and that this regionally differentiated response is blocked when animals are inhibited from freely exploring the environment by the introduction of a mildly aversive stimulus.

  3. Early visuomotor integration processes induce LTP/LTD-like plasticity in the human motor cortex.

    PubMed

    Suppa, A; Li Voti, P; Rocchi, L; Papazachariadis, O; Berardelli, A

    2015-03-01

    To investigate whether visuomotor integration processes induce long-term potentiation (LTP) and depression (LTD)-like plasticity in the primary motor cortex (M1), we designed a new paired associative stimulation (PAS) protocol coupling left primary visual area (V1) activation achieved by hemifield visual evoked potentials (VEPs) and transcranial magnetic stimulation (TMS) over the left M1, at specific interstimulus intervals (ISIs), delivered at 1 Hz (V-PAS). Before and after V-PAS, we measured motor evoked potentials (MEPs). To clarify the mechanisms underlying V-PAS, we tested the effect of 1-Hz repetitive TMS (rTMS), 0.25-Hz V-PAS and rTMS, and a shorter 0.25-Hz V-PAS protocol. To examine V-PAS with contralateral V1 activation, we delivered V-PAS activating the right V1. To clarify whether V-PAS increases V1 activity or parieto- and premotor-to-M1 connectivity, before and after V-PAS, we examined VEPs and MEPs evoked by paired-pulse techniques. V-PAS increased, decreased, or left MEPs unchanged according to the ISI used. After 1-Hz rTMS MEPs decreased. Although 0.25-Hz rTMS elicited no aftereffect, 0.25-Hz V-PAS modulated MEPs according to the ISI used. The short 0.25-Hz V-PAS protocol left MEPs unchanged. Contralateral V-PAS inhibited MEPs. After V-PAS, VEPs remained unchanged and the premotor-to-M1 inhibitory connections decreased. V-PAS induces M1 LTP/LTD-like plasticity by activating premotor-to-motor connections.

  4. Effects of raubasine stereoisomers on pre- and postsynaptic alpha-adrenoceptors in the rat vas deferens.

    PubMed Central

    Demichel, P.; Roquebert, J.

    1984-01-01

    The actions of raubasine, tetrahydroalstonine and akuammigine were studied on pre- and postsynaptic alpha-adrenoceptors of the rat vas deferens. These three drugs competitively antagonized the effect of noradrenaline on postsynaptic alpha-adrenoceptors, yielding pA2 values of 6.57, 4.56 and 4.68 respectively. The presynaptic alpha-adrenoceptor antagonist activity of the drugs was quantitatively determined by studying the effect of increasing concentrations on the clonidine dose-response curve in the electrically stimulated vas deferens. The inhibitory effect of clonidine could be competitively blocked by these three compounds and the pA2 values for raubasine, tetrahydroalstonine and akuammigine were 6.02, 7.71 and 5.64 respectively. These results indicate that: akuammigine is a very weak antagonist at pre- and postsynaptic sites; raubasine acts preferentially at postsynaptic sites; tetrahydroalstonine is a highly selective presynaptic alpha-adrenoceptor blocking agent. The ratio of the pre/postsynaptic potency declines in the order tetrahydroalstonine greater than akuammigine greater than raubasine. PMID:6091834

  5. Pre- and postsynaptic alpha-adrenoceptor blocking activity of raubasine in the rat vas deferens.

    PubMed Central

    Demichel, P.; Gomond, P.; Roquebert, J.

    1981-01-01

    1 The actions of raubasine, yohimbine and corynanthine at pre- and postsynaptic alpha-adrenoceptors were studied in the rat vas deferens. 2 Low frequency electrical stimulation of the isolated vas deferens of the rat produced regular contractions that were inhibited by low concentrations of clonidine. This inhibition was presynaptic in origin and involved alpha-adrenoceptors. 3 Presynaptic alpha-adrenoceptor antagonist activity was assessed by studying the effect of increasing antagonist concentrations on cumulative clonidine dose-response curves on the stimulated vas deferens. 4 Postsynaptic alpha-adrenoceptor antagonist activity in the isolated vas deferens was assessed by comparing control cumulative noradrenaline dose-response curves in the absence and in the presence of increasing concentrations of antagonists. 5 The results indicate that raubasine and corynanthine preferentially block postsynaptic alpha-adrenoceptors. Yohimbine is more potent in blocking pre- than postsynaptic alpha-adrenoceptors. The ration of the pre/postsynaptic potency declines in the order yohimbine less than raubasine less than corynanthine. PMID:6118191

  6. The potential role of postsynaptic phospholipase C activity in synaptic facilitation and behavioral sensitization in Aplysia.

    PubMed

    Fulton, Daniel; Condro, Michael C; Pearce, Kaycey; Glanzman, David L

    2008-07-01

    Previous findings indicate that synaptic facilitation, a cellular mechanism underlying sensitization of the siphon withdrawal response (SWR) in Aplysia, depends on a cascade of postsynaptic events, including activation of inositol triphosphate (IP3) receptors and release of Ca2+ from postsynaptic intracellular stores. These findings suggest that phospholipase C (PLC), the enzyme that catalyzes IP3 formation, may play an important role in postsynaptic signaling during facilitation and learning in Aplysia. Using the PLC inhibitor U73122, we found that PLC activity is required for synaptic facilitation following a 10-min treatment with 5-HT, as measured at 20 min after 5-HT washout. Prior work has indicated that facilitation at this time is supported primarily by postsynaptic processes. To determine whether postsynaptic PLC activity is involved in 5-HT-mediated facilitatory actions, we examined the effect of U73122 on enhancement of the response of motor neurons isolated in cell culture to glutamate, the sensory neuron transmitter. A 10-min application of 5-HT induced persistent (>40 min) enhancement of glutamate-evoked potentials (Glu-EPs) recorded from isolated motor neurons, and this enhancement was blocked by U73122. Finally, we showed that injecting U73122 into intact animals before behavioral training impaired intermediate-term sensitization, indicating that PLC activity contributes to this form of nonassociative learning.

  7. Cerebellar dentate nuclei lesions alter prefrontal cortex dendritic spine morphology.

    PubMed

    Bauer, David J; Peterson, Todd C; Swain, Rodney A

    2014-01-28

    Anatomical tracing studies in primates have revealed neural tracts from the cerebellar dentate nuclei to prefrontal cortex, implicating a cerebellar role in nonmotor processes. Experiments in rats examining the functional role of this cerebellothalamocortical pathway have demonstrated the development of visuospatial and motivational deficits following lesions of the dentate nuclei, in the absence of motor impairment. These behavioral deficits possibly occur due to structural modifications of the cerebral cortex secondary to loss of cerebellar input. The current study characterized morphological alterations in prefrontal cortex important for visuospatial and motivational processes following bilateral cerebellar dentate nuclei lesions. Rats received either bilateral electrolytic cerebellar dentate nuclei lesions or sham surgery followed by a 30-day recovery. Randomly selected Golgi-impregnated neurons in prefrontal cortex were examined for analysis. Measures of branch length and spine density revealed no differences between lesioned and sham rats in either apical or basilar arbors; however, the proportion of immature to mature spines significantly decreased in lesioned rats as compared to sham controls, with reductions of 33% in the basilar arbor and 28% in the apical arbor. Although expected pruning of branches and spines did not occur, the results are consistent with the hypothesis that cerebellar lesions influence prefrontal morphology and support the possibility that functional deficits following cerebellar dentate nuclei lesions are related to prefrontal morphological alteration.

  8. Abnormal cerebellar morphometry in abstinent adolescent marijuana users

    PubMed Central

    Medina, Krista Lisdahl; Nagel, Bonnie J.; Tapert, Susan F.

    2010-01-01

    Background Functional neuroimaging data from adults have, in general, found frontocerebellar dysfunction associated with acute and chronic marijuana (MJ) use (Loeber & Yurgelun-Todd, 1999). One structural neuroimaging study found reduced cerebellar vermis volume in young adult MJ users with a history of heavy polysubstance use (Aasly et al., 1993). The goal of this study was to characterize cerebellar volume in adolescent chronic MJ users following one month of monitored abstinence. Method Participants were MJ users (n=16) and controls (n=16) aged 16-18 years. Extensive exclusionary criteria included history of psychiatric or neurologic disorders. Drug use history, neuropsychological data, and structural brain scans were collected after 28 days of monitored abstinence. Trained research staff defined cerebellar volumes (including three cerebellar vermis lobes and both cerebellar hemispheres) on high-resolution T1-weighted magnetic resonance images. Results Adolescent MJ users demonstrated significantly larger inferior posterior (lobules VIII-X) vermis volume (p<.009) than controls, above and beyond effects of lifetime alcohol and other drug use, gender, and intracranial volume. Larger vermis volumes were associated with poorer executive functioning (p’s<.05). Conclusions Following one month of abstinence, adolescent MJ users had significantly larger posterior cerebellar vermis volumes than non-using controls. These greater volumes are suggested to be pathological based on linkage to poorer executive functioning. Longitudinal studies are needed to examine typical cerebellar development during adolescence and the influence of marijuana use. PMID:20413277

  9. Chronic nicotine treatment reverses hypothyroidism-induced impairment of L-LTP induction phase: critical role of CREB.

    PubMed

    Alzoubi, K H; Alkadhi, K A

    2014-06-01

    We have previously shown that adult onset hypothyroidism impairs late-phase long-term potentiation (L-LTP) and reduces basal protein levels of cyclic-AMP response element binding protein (CREB), mutagen-activated protein kinase (MAPKp42/44), and calcium calmodulin kinase IV (CaMKIV) in area Cornu Ammonis 1 (CA1) of the hippocampus. These changes were reversed by chronic nicotine treatment. In the present study, levels of signaling molecules important for L-LTP were determined in CA1 area of the hippocampus during the induction phase. Standard multiple high-frequency stimulation (MHFS) was used to evoke L-LTP in the CA1 area of the hippocampus of hypothyroid, nicotine-treated hypothyroid, nicotine, and sham control anaesthetized adult rats. Chronic nicotine treatment reversed hypothyroidism-induced impairment of L-LTP at the induction phase. Five minutes after MHFS, Western blotting showed an increase in the levels of P-CREB, and P-MAPKp42/44 in sham-operated control, nicotine, and nicotine-treated hypothyroid animals, but not in hypothyroid animals. The protein levels of total CREB, total MAPK p42/44, BDNF, and CaMKIV were not altered in all groups 5 min after MHFS. Therefore, normalized phosphorylation of essential kinases such as P-CREB and P-MAPK p42/44 in the CA1 area of nicotine-treated hypothyroid animals plays a crucial role in nicotine-induced rescue of L-LTP induction during hypothyroidism.

  10. Fatal remote cerebellar hemorrhage after supratentorial unruptured aneurysm surgery in patient with previous cerebellar infarction

    PubMed Central

    Koh, Eun-Jeong; Park, Jung-Soo

    2017-01-01

    Abstract Rationale: Remote cerebellar hemorrhage (RCH) is a rare complication of supratentorial and spinal surgeries, seldom requiring intervention but occasionally causing significant morbidity or even mortality. Although a number of theories have been proposed, the exact pathophysiology of RCH remains incompletely understood. Patient concerns: We present a 62-year-old patient with RCH encountered following surgical clipping of an unruptured middle cerebral artery bifurcation aneurysm in a patient with previous cerebellar infarction. Lessons: It is extremely rare, but sometimes, RCH can be life-threatening. It is necessary to check the patient's general condition, underlying diseases and medical history. And controlled drainage of the CSF seems to be most important. Arachnoidplasty may be a consideration and the position of the drain string might have to be carefully determined. PMID:28121936

  11. Developmental enhancement of alpha2-adrenoceptor-mediated suppression of inhibitory synaptic transmission onto mouse cerebellar Purkinje cells.

    PubMed

    Hirono, M; Matsunaga, W; Chimura, T; Obata, K

    2008-09-22

    Noradrenaline (NA) modulates glutamatergic and GABAergic transmission in various areas of the brain. It is reported that some alpha2-adrenoceptor subtypes are expressed in the cerebellar cortex and alpha2-adrenoceptors may play a role in motor coordination. Our previous study demonstrated that the selective alpha2-adrenoceptor agonist clonidine partially depresses spontaneous inhibitory postsynaptic currents (sIPSCs) in mouse cerebellar Purkinje cells (PCs). Here we found that the inhibitory effect of clonidine on sIPSCs was enhanced during postnatal development. The activation of alpha2-adrenoceptors by clonidine did not affect sIPSCs in PCs at postnatal days (P) 8-10, when PCs showed a few sIPSCs and interneurons in the molecular layer (MLIs) did not cause action potential (AP). In the second postnatal week, the frequency of sIPSCs increased temporarily and reached a plateau at P14. By contrast, MLIs began to fire at P11 with the firing rate gradually increasing thereafter and reaching a plateau at P21. In parallel with this rise in the rate of firing, the magnitude of the clonidine-mediated inhibition of sIPSCs increased during postnatal development. Furthermore, the magnitude of the clonidine-mediated firing suppression in MLIs, which seemed to be mediated by a reduction in amplitude of the hyperpolarization-activated nonselective cation current, I(h), was constant across development. Both alpha2A- and alpha2B-, but not alpha2C-, adrenoceptors were strongly expressed in MLIs at P13, and P31. Therefore, the developmental enhancement of the clonidine-mediated inhibition of sIPSCs is attributed to an age-dependent increase in AP-derived sIPSCs, which can be blocked by clonidine. Thus, presynaptic activation of alpha2-adrenoceptors inhibits cerebellar inhibitory synaptic transmission after the second postnatal week, leading to a restriction of NA signaling, which is mainly mediated by alpha1- and beta2-adrenoceptors in the adult cerebellar neuronal circuit.

  12. Cerebral venous thrombosis presenting with cerebellar ataxia and cortical blindness.

    PubMed

    Ben Sassi, Samia; Mizouni, Habiba; Nabli, Fatma; Kallel, Lamia; Kefi, Mounir; Hentati, Fayçal

    2010-01-01

    Venous infarction in the cerebellum has been reported only rarely, probably because of the abundant venous collateral drainage in this region. Bilateral occipital infarction is a rare cause of visual loss in cerebral venous thrombosis. We describe a 50-year-old woman with a history of ulcerative colitis who developed acute cerebellar ataxia and cortical blindness. She had bilateral cerebellar and occipital lesions related to sigmoid venous thrombosis and achieved complete recovery with anticoagulation therapy. Cerebral venous thrombosis should be considered in cases of simultaneous cerebellar and occipital vascular lesions.

  13. Cerebellar Mutism Following Closed Head Injury in a Child

    PubMed Central

    Kariyattil, Rajeev; Rahim, Mohamed I. A.; Muthukuttiparambil, Unnikrishnan

    2015-01-01

    Cerebellar mutism is a rare occurrence following paediatric trauma. Although it is quite common after posterior fossa surgery in children, this phenomenon has rarely been reported following other insults, such as trauma, and its pathophysiology remains poorly understood. We report a seven-year-old child who presented to the casualty department of Sultan Qaboos University Hospital in Muscat, Oman, in May 2013 with a traumatic right cerebellar contusion. The child presented with clinical features of cerebellar mutism but underwent a rapid and spontaneous recovery. The possible mechanism of this occurrence is discussed. PMID:25685374

  14. Lissencephaly with brainstem and cerebellar hypoplasia and congenital cataracts.

    PubMed

    Abumansour, Iman S; Wrogemann, Jens; Chudley, Albert E; Chodirker, Bernard N; Salman, Michael S

    2014-06-01

    Classical lissencephaly may be associated with cerebellar hypoplasia and when significant cerebellar abnormalities occur, defects in proteins encoded by TUBA1A, RELN, and very-low-density lipoprotein receptor (VLDLR) genes have been reported. We present a neonate with a severe neurologic phenotype associated with hypotonia, oropharyngeal incoordination that required a gastric tube for feeding, intractable epilepsy, and congenital cataracts. Her brain magnetic resonance imaging (MRI) showed classical lissencephaly, ventriculomegaly, absent corpus callosum, globular and vertical hippocampi, and severe cerebellar and brainstem hypoplasia. She died at 6 weeks of age. No specific molecular diagnosis was made. This likely represents a previously undescribed genetic lissencephaly syndrome.

  15. Enhanced Tolerance of Transgenic Potato Plants Over-Expressing Non-specific Lipid Transfer Protein-1 (StnsLTP1) against Multiple Abiotic Stresses

    PubMed Central

    Gangadhar, Baniekal H.; Sajeesh, Kappachery; Venkatesh, Jelli; Baskar, Venkidasamy; Abhinandan, Kumar; Yu, Jae W.; Prasad, Ram; Mishra, Raghvendra K.

    2016-01-01

    Abiotic stresses such as heat, drought, and salinity are major environmental constraints that limit potato (Solanum tuberosum L.) production worldwide. Previously, we found a potential thermo-tolerance gene, named StnsLTP1 from potato using yeast functional screening. Here, we report the functional characterization of StnsLTP1 and its role in multiple abiotic stresses in potato plants. Computational analysis of StnsLTP1 with other plant LTPs showed eight conserved cysteine residues, and four α-helices stabilized by four disulfide bridges. Expression analysis of StnsLTP1 gene showed differential expression under heat, water-deficit and salt stresses. Transgenic potato lines over-expressing StnsLTP1 gene displayed enhanced cell membrane integrity under stress conditions, as indicated by reduced membrane lipid per-oxidation, and hydrogen peroxide content relative to untransformed (UT) control plants. In addition, transgenic lines over-expressing StLTP1 also exhibited increased antioxidant enzyme activity with enhanced accumulation of ascorbates, and up-regulation of stress-related genes including StAPX, StCAT, StSOD, StHsfA3, StHSP70, and StsHSP20 compared with the UT plants. These results suggests that StnsLTP1 transgenic plants acquired improved tolerance to multiple abiotic stresses through enhanced activation of antioxidative defense mechanisms via cyclic scavenging of reactive oxygen species and regulated expression of stress-related genes. PMID:27597854

  16. The preventive effect of NR2B and NR2D-containing NMDAR antagonists on Aβ-induced LTP disruption in the dentate gyrus of rats.

    PubMed

    Zhang, Junfang; Wang, Chuang; Deng, Tianxiang; Xue, Zhancheng; Chen, Xiaowei; Chang, Lan; Wang, Qinwen

    2013-12-01

    Amyloid β-protein (Aβ) in the brain of Alzheimer's disease (AD) potently inhibits the synaptic plasticity subsequently causing the cognitive deficits. Long-term potentiation (LTP) of synaptic transmission is thought to be an important cellular mechanism underlying memory formation. Different NR2 subunits are involved in NMDA receptor-dependent LTP. In the present study, we investigated the roles of NR2B and NR2D-containing NMDAR on Aβ(1-42)-induced LTP deficits in the hippocampal slices of rats by using selective NMDAR antagonists. First, we found that Aβ(1-42) significantly inhibited the LTP in the dentate gyrus of slices as reported before. Following that the Aβ(1-42)-induced LTP inhibition was prevented by the pre-perfusion of the specific NR2B-containing NMDAR antagonists ifenprodil (approximately >200-fold selectivity for NR2B) and Ro25-6981 (>3,000-fold selectivity for NR2B), as well as PPDA, a specific NR2D receptor antagonist. Meanwhile, the antagonists on their own had no or only partial effects on the normal LTP in the same dose condition. These findings not only support the effects of NR2B and NR2D subunits on Aβ(1-42)-induced LTP deficits, but also imply that preferentially targeting NR2B- and NR2D-containing NMDARs may provide an effective means to prevent cognitive deficits in the early AD.

  17. Aging Drosophila melanogaster display altered pre- and postsynaptic ultrastructure at adult neuromuscular junctions.

    PubMed

    Wagner, Nicole; Laugks, Ulrike; Heckmann, Manfred; Asan, Esther; Neuser, Kirsa

    2015-11-01

    Although age-related changes in synaptic plasticity are an important focus within neuroscience, little is known about ultrastructural changes of synaptic morphology during aging. Here we report how aging affects synaptic ultrastructure by using fluorescence and electron microscopy at the adult Drosophila neuromuscular junction (NMJ) of ventral abdominal muscles. Mainly four striking morphological changes of aging NMJs were revealed. 1) Bouton size increases with proportionally rising number of active zones (AZs). 2) Synaptic vesicle density at AZs is increased in old flies. 3) Late endosomes, cisternae, and multivesicular bodies accumulate in the presynaptic terminal, and vesicles accumulate between membranes of the terminal bouton and the subsynaptic reticulum. 4) The electron-dense pre- and postsynaptic apposition is expanded in aging NMJs, which is accompanied by an expansion of the postsynaptic glutamate receptor fields. These findings suggest that aging is possibly accompanied by impaired synaptic vesicle release and recycling and a potentially compensatory expansion of AZs and postsynaptic densities.

  18. A Postsynaptic Role for Short-Term Neuronal Facilitation in Dendritic Spines

    PubMed Central

    Yang, Sunggu; Santos, Mariton D.; Tang, Cha-Min; Kim, Jae Geun; Yang, Sungchil

    2016-01-01

    Synaptic plasticity is a fundamental component of information processing in the brain. Presynaptic facilitation in response to repetitive stimuli, often referred to as paired-pulse facilitation (PPF), is a dominant form of short-term synaptic plasticity. Recently, an additional cellular mechanism for short-term facilitation, short-term postsynaptic plasticity (STPP), has been proposed. While a dendritic mechanism was described in hippocampus, its expression has not yet been demonstrated at the levels of the spine. Furthermore, it is unknown whether the mechanism can be expressed in other brain regions, such as sensory cortex. Here, we demonstrated that a postsynaptic response can be facilitated by prior spine excitation in both hippocampal and cortical neurons, using 3D digital holography and two-photon calcium imaging. The coordinated action of pre- and post-synaptic plasticity may provide a more thorough account of information processing in the brain. PMID:27746721

  19. Chronic THC intake modifies fundamental cerebellar functions

    PubMed Central

    Stella, Nephi

    2013-01-01

    Delta9-tetrahydrocannabinol (THC), the principal bioactive component in the Cannabis plant, is truly a captivating drug. Acute and chronic THC intake produces a spectrum of biological effects ranging from transient psychotropic effects to prolonged medicinal benefits, many of which have been fostered for centuries by our society. In the July 2013 issue of the JCI, Cutando et al. combined mouse genetics with classic mouse behavioral analysis to deepen our understanding of the physiological consequence of subchronic THC intake on eyeblink reflexes, a fundamental neuronal adaptive response, revealing that this regimen leads to downregulation of the cannabinoid CB1 receptor (referred to as CB1 in the Cutando et al. article) in cerebellar stress fibers and the activation of microglia, raising provocative new questions about the safety profile of regimented THC intake. PMID:23863631

  20. The Arabidopsis Lipid Transfer Protein 2 (AtLTP2) Is Involved in Cuticle-Cell Wall Interface Integrity and in Etiolated Hypocotyl Permeability.

    PubMed

    Jacq, Adélaïde; Pernot, Clémentine; Martinez, Yves; Domergue, Frédéric; Payré, Bruno; Jamet, Elisabeth; Burlat, Vincent; Pacquit, Valérie B

    2017-01-01

    Plant non-specific lipid transfer proteins (nsLTPs) belong to a complex multigenic family implicated in diverse physiological processes. However, their function and mode of action remain unclear probably because of functional redundancy. Among the different roles proposed for nsLTPs, it has long been suggested that they could transport cuticular precursor across the cell wall during the formation of the cuticle, which constitutes the first physical barrier for plant interactions with their aerial environment. Here, we took advantage of the Arabidopsis thaliana etiolated hypocotyl model in which AtLTP2 was previously identified as the unique and abundant nsLTP member in the cell wall proteome, to investigate its function. AtLTP2 expression was restricted to epidermal cells of aerial organs, in agreement with the place of cuticle deposition. Furthermore, transient AtLTP2-TagRFP over-expression in Nicotiana benthamiana leaf epidermal cells resulted in its localization to the cell wall, as expected, but surprisingly also to the plastids, indicating an original dual trafficking for a nsLTP. Remarkably, in etiolated hypocotyls, the atltp2-1 mutant displayed modifications in cuticle permeability together with a disorganized ultra-structure at the cuticle-cell wall interface completely recovered in complemented lines, whereas only slight differences in cuticular composition were observed. Thus, AtLTP2 may not play the historical purported nsLTP shuttling role across the cell wall, but we rather hypothesize that AtLTP2 could play a major structural role by maintaining the integrity of the adhesion between the mainly hydrophobic cuticle and the hydrophilic underlying cell wall. Altogether, these results gave new insights into nsLTP functions.

  1. The Arabidopsis Lipid Transfer Protein 2 (AtLTP2) Is Involved in Cuticle-Cell Wall Interface Integrity and in Etiolated Hypocotyl Permeability

    PubMed Central

    Jacq, Adélaïde; Pernot, Clémentine; Martinez, Yves; Domergue, Frédéric; Payré, Bruno; Jamet, Elisabeth; Burlat, Vincent; Pacquit, Valérie B.

    2017-01-01

    Plant non-specific lipid transfer proteins (nsLTPs) belong to a complex multigenic family implicated in diverse physiological processes. However, their function and mode of action remain unclear probably because of functional redundancy. Among the different roles proposed for nsLTPs, it has long been suggested that they could transport cuticular precursor across the cell wall during the formation of the cuticle, which constitutes the first physical barrier for plant interactions with their aerial environment. Here, we took advantage of the Arabidopsis thaliana etiolated hypocotyl model in which AtLTP2 was previously identified as the unique and abundant nsLTP member in the cell wall proteome, to investigate its function. AtLTP2 expression was restricted to epidermal cells of aerial organs, in agreement with the place of cuticle deposition. Furthermore, transient AtLTP2-TagRFP over-expression in Nicotiana benthamiana leaf epidermal cells resulted in its localization to the cell wall, as expected, but surprisingly also to the plastids, indicating an original dual trafficking for a nsLTP. Remarkably, in etiolated hypocotyls, the atltp2-1 mutant displayed modifications in cuticle permeability together with a disorganized ultra-structure at the cuticle-cell wall interface completely recovered in complemented lines, whereas only slight differences in cuticular composition were observed. Thus, AtLTP2 may not play the historical purported nsLTP shuttling role across the cell wall, but we rather hypothesize that AtLTP2 could play a major structural role by maintaining the integrity of the adhesion between the mainly hydrophobic cuticle and the hydrophilic underlying cell wall. Altogether, these results gave new insights into nsLTP functions. PMID:28289427

  2. Target recognition at the tips of postsynaptic filopodia: accumulation and function of Capricious.

    PubMed

    Kohsaka, Hiroshi; Nose, Akinao

    2009-04-01

    While much evidence suggests that postsynaptic dynamism contributes to the formation of synapses, few studies have addressed its possible role in target selection. Do postsynaptic motile structures seek specific synaptic partner cells, as does the presynaptic growth cone? Here we studied the dynamics of myopodia, postsynaptic filopodia in Drosophila muscles, and the role of Capricious (CAPS) during the process of synaptic matchmaking. CAPS is a target recognition molecule with an extracellular domain containing leucine-rich repeat sequences. It is expressed in specific subsets of embryonic/larval body wall muscles, including muscle 12 (M12). We provide evidence that implicates the tips of myopodia as loci of initial neuromuscular recognition: (1) CAPS, expressed as a GFP-fusion protein in M12, accumulated at the tips of myopodia; and (2) simultaneous live imaging of presynaptic motoneurons and postsynaptic myopodia revealed that initial neuromuscular contacts occur at the tips of myopodia. The live imaging also showed that individual postsynaptic myopodia appear to be able to discriminate partner and non-partner presynaptic cells: whereas many myopodial contacts with the partner motoneurons are stabilized to form synapses, those with non-partner neurons are retracted. In caps mutants, or in double mutants lacking both CAPS and the closely related protein Tartan, we observed fewer contacts between myopodia of M12 and the presynaptic growth cones during the process of initial neuromuscular interaction. The nascent synaptic sites of M12 were also reduced. These results provide evidence for the sensing function of postsynaptic filopodia, and implicate Caps-mediated recognition at the tips of myopodia in synaptic matching.

  3. Classically conditioned postural reflex in cerebellar patients.

    PubMed

    Kolb, F P; Lachauer, S; Maschke, M; Timmann, D

    2004-09-01

    The aim of the current study was to compare postural responses to repetitive platform-evoked perturbations in cerebellar patients with those of healthy subjects using a classical conditioning paradigm. The perturbations consisted of tilting of the platform (unconditioned stimulus: US) at random time intervals, preceded by an auditory signal that represented the conditioning stimulus (CS). Physiological reactions were recorded biomechanically by measuring the vertical ground forces, yielding the center of vertical pressure (CVP), and electrophysiologically by EMG measurements of the main muscle groups of both legs. The recording session consisted of a control section with US-alone trials, a testing section with paired stimuli and a brief final section with US-alone trials. Healthy control subjects were divided into those establishing conditioned responses (CR) in all muscles tested (strategy I) and those with CR in the gastrocnemius muscles only (strategy II), suggesting an associative motor-related process is involved. Patients with a diffuse, non-localized disease were almost unable to establish CR. This was also true for a patient with a focal surgical lesion with no CR on the affected side but who, simultaneously, showed an essentially normal CR incidence on the intact side. During US-alone trials healthy controls exhibited a remarkable decay of the UR amplitude due to a non-associative motor-related process such as habituation. The decay was most prominent in the paired trials section. In contrast, patients showed no significant differences in the UR amplitude throughout the entire recording session. Analysis of the CVP supported the electrophysiological findings, showing CR in the controls only. The differences between the responses of control subjects and those of the cerebellar patients imply strongly that the cerebellum is involved critically in controlling associative and non-associative motor-related processes.

  4. Memory impairment following right cerebellar infarction: a case study.

    PubMed

    Nakamoto, Fumiko Kusunoki; Tsutsumiuchi, Michiko; Maeda, Meiko Hashimoto; Uesaka, Yoshikazu; Takeda, Katsuhiko

    2015-01-01

    We reported a patient with a right cerebellar infarction who showed anterograde amnesia. Cognitive dysfunction caused by cerebellar lesions was called cerebellar cognitive affective syndrome, and deactivation of the contralateral prefrontal cortex function due to disconnections of cerebello-cerebral fiber tracts have been hypothesized as mechanism underlying the syndrome. The episodic memory impairment, however, could not be supported by the same mechanism because the prefrontal lesions cannot cause amnesia syndrome. The feature of the impairment of our patient was similar to that of diencephalic amnesia, and a single photon emission computed tomography study showed a relative hypoperfusion in the right cerebellar hemisphere and left anterior thalamus. We considered that the memory deficit was caused by the dysfunction of the thalamus, which is a relay center of the cerebello-cerebral connectivity network.

  5. Past, Present and Future Therapeutics for Cerebellar Ataxias

    PubMed Central

    Marmolino, D; Manto, M

    2010-01-01

    Cerebellar ataxias are a group of disabling neurological disorders. Patients exhibit a cerebellar syndrome and can also present with extra-cerebellar deficits, namely pigmentary retinopathy, extrapyramidal movement disorders, pyramidal signs, cortical symptoms (seizures, cognitive impairment/behavioural symptoms), and peripheral neuropathy. Recently, deficits in cognitive operations have been unraveled. Cerebellar ataxias are heterogeneous both at the phenotypic and genotypic point of view. Therapeutical trials performed during these last 4 decades have failed in most cases, in particular because drugs were not targeting a deleterious pathway, but were given to counteract putative defects in neurotransmission. The identification of the causative mutations of many hereditary ataxias, the development of relevant animal models and the recent identifications of the molecular mechanisms underlying ataxias are impacting on the development of new drugs. We provide an overview of the pharmacological treatments currently used in the clinical practice and we discuss the drugs under development. PMID:20808545

  6. Asterixis as a Presentation of Cerebellar Ischemic Stroke

    PubMed Central

    Siniscalchi, Antonio; Gallelli, Luca; Di Benedetto, Olindo; De Sarro, Giovambattista

    2012-01-01

    Asterixis is not yet considered a common neurological sign of cerebellum infarction, and the pathogenic mechanism for asterixis remains elusive. We report a 58-year-old male with moderate hypertension who presented to our emergency department for acute headache in both cervical and occipital regions of the left side. About 2 hours later the patient developed ipsilateral asterixis in the upper left limb; 3 days later the asterixis disappeared. Magnetic resonance imaging of the brain disclosed cerebellar infarctions at the left superior cerebellar artery. In conclusion, we observed that a transitory asterixis associated with ipsilateral headache can be an initial clinical manifestation of ipsilateral cerebellar infarctions in the superior cerebellar artery area. PMID:23359270

  7. Hypocupremia: A Possible Association with Late Cortical Cerebellar Atrophy

    PubMed Central

    Mittal, Shivam Om; Machado, Duarte G.

    2014-01-01

    Background We report a patient, diagnosed with late cortical cerebellar atrophy, who had persistent low serum copper levels. Case report A 48-year-old male developed progressive difficulty with balance, frequent falls, and dysarthric speech, which worsened over a short time span. He had an extensive ataxia work-up, which was unremarkable except for persistent low serum copper levels despite adequate supplementation. Magnetic resonance imaging of the brain showed marked cerebellar atrophy. The patient experienced progressive worsening of symptoms, which did not improve with either oral or parenteral copper supplementation. Discussion To our knowledge, ours is the first case report of late cortical cerebellar atrophy in the setting of low serum copper levels. The current report should trigger further research in mechanisms leading to copper deficiency and its possible role in cerebellar disease. PMID:25247109

  8. Cerebellar blood flow in methylmercury poisoning (Minamata disease).

    PubMed

    Itoh, K; Korogi, Y; Tomiguchi, S; Takahashi, M; Okajima, T; Sato, H

    2001-04-01

    We looked at regional cerebellar blood flow in patients with Minamata disease (MD) using technetium-99m ethyl cysteinate dimer (99m-Tc-ECD). We carried out single-photon emission computed tomography (SPECT) on 15 patients with MD (eight men, seven women, aged 51-78 years, mean 70.5 years) and 11 control subjects (eight men, three women, aged 62-80 years, mean 72.5 years). Regional blood flow was measured in the superior, middle, and inferior portions of the cerebellar hemispheres, and the frontal, temporal and occipital cerebral lobes. The degree of cerebellar atrophy was assessed on MRI. There were significant differences in regional blood flow in all parts of the cerebellum between patients and control, but no significant decrease was observed in the cerebrum. Blood flow was lower in the inferior cerebellum than in the other parts. Even in patients without cerebellar atrophy, flow was significantly decreased regional blood flow in the inferior part.

  9. Anomalous Cerebellar Anatomy in Chinese Children with Dyslexia

    PubMed Central

    Yang, Yang; Chen, Bao-Guo; Zhang, Yi-Wei; Bi, Hong-Yan

    2016-01-01

    The cerebellar deficit hypothesis for developmental dyslexia claims that cerebellar dysfunction causes the failures in the acquisition of visuomotor skills and automatic reading and writing skills. In people with dyslexia in the alphabetic languages, the abnormal activation and structure of the right or bilateral cerebellar lobes have been identified. Using a typical implicit motor learning task, however, one neuroimaging study demonstrated the left cerebellar dysfunction in Chinese children with dyslexia. In the present study, using voxel-based morphometry, we found decreased gray matter volume in the left cerebellum in Chinese children with dyslexia relative to age-matched controls. The positive correlation between reading performance and regional gray matter volume suggests that the abnormal structure in the left cerebellum is responsible for reading disability in Chinese children with dyslexia. PMID:27047403

  10. Malignant cerebellar peduncle lesions - rapid progression and poor outcome

    PubMed Central

    Singla, Navneet; Kapoor, Ankur; Savardekar, Amey; Radotra, B. D.; Chatterjee, Debjyoti; Gupta, Sunil K.

    2016-01-01

    Background: Tumors arising from cerebellar peduncle are extremely rare and behave aggressively. The inclusion of these into either cerebellar or brainstem gliomas is contentious. Case Description: We performed clinicopathological review of three patients treated at our institute and surveyed the literature for previous such reported cases. Mean duration of symptoms in our patients was 2 weeks. Subtotal tumor resection was performed in two patients while the third underwent stereotactic biopsy followed by chemoradiotherapy. Histopathology revealed glioblastoma in initial two patients and medulloblastoma Grade IV in the third. The two patients who underwent surgical excision succumbed to the illness within 2 days and a month, respectively. Conclusion: Malignant cerebellar peduncular lesions have poor overall survival despite surgical debulking. It is not confirmed whether these tumors should be considered as cerebellar lesions or brainstem gliomas due to aggressive clinical behavior, and so the ideal line of management is not yet known. PMID:27057396

  11. Metabotropic Glutamate Receptors Induce a Form of LTP Controlled by Translation and Arc Signaling in the Hippocampus

    PubMed Central

    Wang, Hui; Ardiles, Alvaro O.; Yang, Sunggu; Tran, Trinh; Posada-Duque, Rafael; Valdivia, Gonzalo; Baek, Min; Chuang, Yang-An; Palacios, Adrian G.; Gallagher, Michela; Worley, Paul

    2016-01-01

    Activity-dependent bidirectional modifications of excitatory synaptic strength are essential for learning and storage on new memories. Research on bidirectional synaptic plasticity has largely focused on long-term potentiation (LTP) and long-term depression (LTD) mechanisms that rely on the activation of NMDA receptors. In principle, metabotropic glutamate receptors (mGluRs) are also suitable to convert synaptic activity into intracellular signals for synaptic modification. Indeed, dysfunction of a form of LTD that depends on Type I mGluRs (mGluR-LTD), but not NMDARs, has been implicated in learning deficits in aging and mouse models of several neurological conditions, including Fragile X syndrome and Alzheimer's disease. To determine whether mGluR activation can also induce LTP in the absence of NMDAR activation, we examined in hippocampal slices from rats and mice, an NMDAR-independent form of LTP previously characterized as dependent on voltage-gated Ca2+ channels. We found that this form of LTP requires activation of Type I mGluRs and, like mGluR-LTD but unlike NMDAR-dependent plasticity, depends crucially on protein synthesis controlled by fragile X mental retardation protein and on Arc signaling. Based on these observations, we propose the coexistence of two distinct activity-dependent systems of bidirectional synaptic plasticity: one that is based on the activity of NMDARs and the other one based on the activation of mGluRs. SIGNIFICANCE STATEMENT Bidirectional changes of synaptic strength are crucial for the encoding of new memories. Currently, the only activity-dependent mechanism known to support such bidirectional changes are long-term potentiation (LTP) and long-term depression (LTD) forms that relay on the activation of NMDA receptors. Metabotropic glutamate receptors (mGluRs) are, in principle, also suitable to trigger bidirectional synaptic modifications. However, only the mGluR-dependent form of LTD has been characterized. Here we report that an

  12. Non-invasive cerebellar stimulation--a consensus paper.

    PubMed

    Grimaldi, G; Argyropoulos, G P; Boehringer, A; Celnik, P; Edwards, M J; Ferrucci, R; Galea, J M; Groiss, S J; Hiraoka, K; Kassavetis, P; Lesage, E; Manto, M; Miall, R C; Priori, A; Sadnicka, A; Ugawa, Y; Ziemann, U

    2014-02-01

    The field of neurostimulation of the cerebellum either with transcranial magnetic stimulation (TMS; single pulse or repetitive (rTMS)) or transcranial direct current stimulation (tDCS; anodal or cathodal) is gaining popularity in the scientific community, in particular because these stimulation techniques are non-invasive and provide novel information on cerebellar functions. There is a consensus amongst the panel of experts that both TMS and tDCS can effectively influence cerebellar functions, not only in the motor domain, with effects on visually guided tracking tasks, motor surround inhibition, motor adaptation and learning, but also for the cognitive and affective operations handled by the cerebro-cerebellar circuits. Verbal working memory, semantic associations and predictive language processing are amongst these operations. Both TMS and tDCS modulate the connectivity between the cerebellum and the primary motor cortex, tuning cerebellar excitability. Cerebellar TMS is an effective and valuable method to evaluate the cerebello-thalamo-cortical loop functions and for the study of the pathophysiology of ataxia. In most circumstances, DCS induces a polarity-dependent site-specific modulation of cerebellar activity. Paired associative stimulation of the cerebello-dentato-thalamo-M1 pathway can induce bidirectional long-term spike-timing-dependent plasticity-like changes of corticospinal excitability. However, the panel of experts considers that several important issues still remain unresolved and require further research. In particular, the role of TMS in promoting cerebellar plasticity is not established. Moreover, the exact positioning of electrode stimulation and the duration of the after effects of tDCS remain unclear. Future studies are required to better define how DCS over particular regions of the cerebellum affects individual cerebellar symptoms, given the topographical organization of cerebellar symptoms. The long-term neural consequences of non

  13. Isolated cerebellar toxoplasmosis as a complication of HIV infection.

    PubMed

    Pott, H; Castelo, A

    2013-01-01

    Isolated cerebellar mass lesion is an uncommon presentation of toxoplasmosis. The authors report one rare case in a 50-year-old HIV-infected male patient who presented with clipped speech, gait ataxia and incoordination. The cerebellar toxoplasmosis was suspected based on imaging findings, despite the atypical location. This case highlights the need for a high index of clinical suspicion among HIV-infected patients with neurological manifestations and suspicious neuroimaging findings.

  14. Primary cerebellopontine progressive multifocal leukoencephalopathy diagnosed premortem by cerebellar biopsy.

    PubMed

    Jones, H R; Hedley-Whyte, E T; Freidberg, S R; Kelleher, J E; Krolikowski, J

    1982-02-01

    A subacute progressive cerebellar brainstem syndrome developed in a patient with systemic lupus erythematosus in remission. Cerebellar biopsy documented the diagnosis of progressive multifocal leukoencephalopathy (PML). Data from this patient and 10 others in the literature emphasize the need to consider this diagnosis when ataxia develops in any patient with underlying malignancy, chronic infection, or other disease that involves immunological incompetence. Although the ataxic form of PML is not of nosological relevance, early diagnosis may eventually have therapeutic importance.

  15. Glucose utilization in the inferior cerebellar vermis and ocular myoclonus.

    PubMed

    Yakushiji, Y; Otsubo, R; Hayashi, T; Fukuchi, K; Yamada, N; Hasegawa, Y; Minematsu, K

    2006-07-11

    In a patient with symptomatic ocular myoclonus, the authors observed the regional cerebral metabolic rate of glucose use (rCMRGlu) before and after successful treatment with clonazepam. Even after the symptoms resolved, the rCMRGlu in the hypertrophic olive increased persistently, whereas that in the inferior cerebellar vermis contralateral to the hypertrophic olive decreased. The inferior cerebellar vermis, belonging to the vestibulocerebellar system, may be associated with the generation of symptomatic ocular myoclonus.

  16. Neurochondrin is a neuronal target antigen in autoimmune cerebellar degeneration

    PubMed Central

    Miske, Ramona; Gross, Catharina C.; Scharf, Madeleine; Golombeck, Kristin S.; Hartwig, Marvin; Bhatia, Urvashi; Schulte-Mecklenbeck, Andreas; Bönte, Kathrin; Strippel, Christine; Schöls, Ludger; Synofzik, Matthis; Lohmann, Hubertus; Dettmann, Inga Madeleine; Deppe, Michael; Mindorf, Swantje; Warnecke, Tobias; Denno, Yvonne; Teegen, Bianca; Probst, Christian; Brakopp, Stefanie; Wandinger, Klaus-Peter; Wiendl, Heinz; Stöcker, Winfried; Meuth, Sven G.

    2016-01-01

    Objective: To report on a novel neuronal target antigen in 3 patients with autoimmune cerebellar degeneration. Methods: Three patients with subacute to chronic cerebellar ataxia and controls underwent detailed clinical and neuropsychological assessment together with quantitative high-resolution structural MRI. Sera and CSF were subjected to comprehensive autoantibody screening by indirect immunofluorescence assay (IFA) and immunoblot. Immunoprecipitation with lysates of hippocampus and cerebellum combined with mass spectrometric analysis was used to identify the autoantigen, which was verified by recombinant expression in HEK293 cells and use in several immunoassays. Multiparameter flow cytometry was performed on peripheral blood and CSF, and peripheral blood was subjected to T-cell receptor spectratyping. Results: Patients presented with a subacute to chronic cerebellar and brainstem syndrome. MRI was consistent with cortical and cerebellar gray matter atrophy associated with subsequent neuroaxonal degeneration. IFA screening revealed strong immunoglobulin G1 reactivity in sera and CSF with hippocampal and cerebellar molecular and granular layers, but not with a panel of 30 recombinantly expressed established neural autoantigens. Neurochondrin was subsequently identified as the target antigen, verified by IFA and immunoblot with HEK293 cells expressing human neurochondrin as well as the ability of recombinant neurochondrin to neutralize the autoantibodies' tissue reaction. Immune phenotyping revealed intrathecal accumulation and activation of B and T cells during the acute but not chronic phase of the disease. T-cell receptor spectratyping suggested an antigen-specific T-cell response accompanying the formation of antineurochondrin autoantibodies. No such neurochondrin reactivity was found in control cohorts of various neural autoantibody-associated neurologic syndromes, relapsing-remitting multiple sclerosis, cerebellar type of multiple system atrophy, hereditary

  17. Proprioceptive Localization Deficits in People With Cerebellar Damage.

    PubMed

    Weeks, Heidi M; Therrien, Amanda S; Bastian, Amy J

    2017-04-01

    It has been hypothesized that an important function of the cerebellum is predicting the state of the body during movement. Yet, the extent of cerebellar involvement in perception of limb state (i.e., proprioception, specifically limb position sense) has yet to be determined. Here, we investigated whether patients with cerebellar damage have deficits when trying to locate their hand in space (i.e., proprioceptive localization), which is highly important for everyday movements. By comparing performance during passive robot-controlled and active self-made multi-joint movements, we were able to determine that some cerebellar patients show improved precision during active movement (i.e., active benefit), comparable to controls, whereas other patients have reduced active benefit. Importantly, the differences in patient performance are not explained by patient diagnosis or clinical ratings of impairment. Furthermore, a subsequent experiment confirmed that active deficits in proprioceptive localization occur during both single-joint and multi-joint movements. As such, it is unlikely that localization deficits can be explained by the multi-joint coordination deficits occurring after cerebellar damage. Our results suggest that cerebellar damage may cause varied impairments to different elements of proprioceptive sense. It follows that proprioceptive localization should be adequately accounted for in clinical testing and rehabilitation of people with cerebellar damage.

  18. Transplantation and Stem Cell Therapy for Cerebellar Degenerations.

    PubMed

    Cendelin, Jan

    2016-02-01

    Stem cell-based and regenerative therapy may become a hopeful treatment for neurodegenerative diseases including hereditary cerebellar degenerations. Neurotransplantation therapy mainly aims to substitute lost cells, but potential effects might include various mechanisms including nonspecific trophic effects and stimulation of endogenous regenerative processes and neural plasticity. Nevertheless, currently, there remain serious limitations. There is a wide spectrum of human hereditary cerebellar degenerations as well as numerous cerebellar mutant mouse strains that serve as models for the development of effective therapy. By now, transplantation has been shown to ameliorate cerebellar function, e.g. in Purkinje cell degeneration mice, Lurcher mutant mice and mouse models of spinocerebellar ataxia type 1 and type 2 and Niemann-Pick disease type C. Despite the lack of direct comparative studies, it appears that there might be differences in graft development and functioning between various types of cerebellar degeneration. Investigation of the relation of graft development to specific morphological, microvascular or biochemical features of the diseased host tissue in various cerebellar degenerations may help to identify factors determining the fate of grafted cells and potential of their functional integration.

  19. Neurodevelopmental Malformations of the Cerebellar Vermis in Genetically Engineered Rats.

    PubMed

    Ramos, Raddy L; Van Dine, Sarah E; Gilbert, Mary E; Leheste, Joerg R; Torres, German

    2015-12-01

    The cerebellar vermis is particularly vulnerable to neurodevelopmental malformations in humans and rodents. Sprague-Dawley, and Long-Evans rats exhibit spontaneous cerebellar malformations consisting of heterotopic neurons and glia in the molecular layer of the vermis. Malformations are almost exclusively found along the primary fissure and are indicative of deficits of neuronal migration during cerebellar development. In the present report, we test the prediction that genetically engineered rats on Sprague-Dawley or Long-Evans backgrounds will also exhibit the same cerebellar malformations. Consistent with our hypothesis, we found that three different transgenic lines on two different backgrounds had cerebellar malformations. Heterotopia in transgenic rats had identical cytoarchitecture as that observed in wild-type rats including altered morphology of Bergmann glia. In light of the possibility that heterotopia could affect results from behavioral studies, these data suggest that histological analyses be performed in studies of cerebellar function or development when using genetically engineered rats on these backgrounds in order to have more careful interpretation of experimental findings.

  20. Clumsiness and disturbed cerebellar development: insights from animal experiments.

    PubMed

    Gramsbergen, Albert

    2003-01-01

    Cerebellar functioning has been implied in the fine adjustments of muscle tone, in the coordination and the feed-forward control of movements and posture, as well as in the establishment and performance of motor skills. The cerebellar cortex in mammals develops late in neuro-ontogeny and an extrapolation from experimental results indicates that in the human the proliferation of the granule cells and the development of circuitry in the cerebellar cortex starts only in the last trimester of pregnancy and lasts until beyond the first birthday. This late development makes the cerebellar development particularly vulnerable to situations like an insufficient supply of nutrients, which may follow placental dysfunction, or to side effects of pharmacological treatments like the administration of corticosteroids in the postnatal period. We studied whether such situations might also lead to motor impairments. In rats, the effects of undernutrition during the brain growth spurt were investigated as well as those of corticosteroids administered in a period that is analogous to the 7th to 8th month of pregnancy in the human. Both these interferences affect cerebellar development and our results in rats indicate that they also lead to retardations in the emergence of certain reflexes, as well as to longer lasting motor impairments during locomotion. Extrapolation of these results strongly suggests that a disturbed cerebellar development should be considered as an important etiological factor in clumsiness in human children.

  1. Voltage-gated calcium channel autoimmune cerebellar degeneration

    PubMed Central

    McKasson, Marilyn; Clawson, Susan A.; Hill, Kenneth E.; Wood, Blair; Carlson, Noel; Bromberg, Mark; Greenlee, John E.

    2016-01-01

    Objectives: To describe response to treatment in a patient with autoantibodies against voltage-gated calcium channels (VGCCs) who presented with autoimmune cerebellar degeneration and subsequently developed Lambert-Eaton myasthenic syndrome (LEMS), and to study the effect of the patient's autoantibodies on Purkinje cells in rat cerebellar slice cultures. Methods: Case report and study of rat cerebellar slice cultures incubated with patient VGCC autoantibodies. Results: A 53-year-old man developed progressive incoordination with ataxic speech. Laboratory evaluation revealed VGCC autoantibodies without other antineuronal autoantibodies. Whole-body PET scans 6 and 12 months after presentation detected no malignancy. The patient improved significantly with IV immunoglobulin G (IgG), prednisone, and mycophenolate mofetil, but worsened after IV IgG was halted secondary to aseptic meningitis. He subsequently developed weakness with electrodiagnostic evidence of LEMS. The patient's IgG bound to Purkinje cells in rat cerebellar slice cultures, followed by neuronal death. Reactivity of the patient's autoantibodies with VGCCs was confirmed by blocking studies with defined VGCC antibodies. Conclusions: Autoimmune cerebellar degeneration associated with VGCC autoantibodies may precede onset of LEMS and may improve with immunosuppressive treatment. Binding of anti-VGCC antibodies to Purkinje cells in cerebellar slice cultures may be followed by cell death. Patients with anti-VGCC autoantibodies may be at risk of irreversible neurologic injury over time, and treatment should be initiated early. PMID:27088118

  2. Altered cerebellar connectivity in Parkinson's patients ON and OFF L-DOPA medication

    PubMed Central

    Festini, Sara B.; Bernard, Jessica A.; Kwak, Youngbin; Peltier, Scott; Bohnen, Nicolaas I.; Müller, Martijn L. T. M.; Dayalu, Praveen; Seidler, Rachael D.

    2015-01-01

    Although nigrostriatal changes are most commonly affiliated with Parkinson's disease, the role of the cerebellum in Parkinson's has become increasingly apparent. The present study used lobule-based cerebellar resting state functional connectivity to (1) compare cerebellar-whole brain and cerebellar-cerebellar connectivity in Parkinson's patients both ON and OFF L-DOPA medication and controls, and to (2) relate variations in cerebellar connectivity to behavioral performance. Results indicated that, when contrasted to the control group, Parkinson's patients OFF medication had increased levels of cerebellar-whole brain and cerebellar-cerebellar connectivity, whereas Parkinson's patients ON medication had decreased levels of cerebellar-whole brain and cerebellar-cerebellar connectivity. Moreover, analyses relating levels of cerebellar connectivity to behavioral measures demonstrated that, within each group, increased levels of connectivity were most often associated with improved cognitive and motor performance, but there were several instances where increased connectivity was related to poorer performance. Overall, the present study found medication-variant cerebellar connectivity in Parkinson's patients, further demonstrating cerebellar changes associated with Parkinson's disease and the moderating effects of medication. PMID:25954184

  3. Cerebellar-Motor Dysfunction in Schizophrenia and Psychosis-Risk: The Importance of Regional Cerebellar Analysis Approaches

    PubMed Central

    Bernard, Jessica A.; Mittal, Vijay A.

    2014-01-01

    Motor abnormalities in individuals with schizophrenia and those at-risk for psychosis are well documented. An accumulating body of work has also highlighted motor abnormalities related to cerebellar dysfunction in schizophrenia including eye-blink conditioning, timing, postural control, and motor learning. We have also recently found evidence for motor dysfunction in individuals at ultra high-risk for psychosis (1–3). This is particularly relevant as the cerebellum is thought to be central to the cognitive dysmetria model of schizophrenia, and these overt motor signs may point to more general cerebellar dysfunction in the etiology of psychotic disorders. While studies have provided evidence indicative of motor cerebellar dysfunction in at-risk populations and in schizophrenia, findings with respect to the cerebellum have been mixed. One factor potentially contributing to these mixed results is the whole-structure approach taken when investigating the cerebellum. In non-human primates, there are distinct closed-loop circuits between the cerebellum, thalamus, and brain with motor and non-motor cortical regions. Recent human neuroimaging has supported this finding and indicates that there is a cerebellar functional topography (4), and this information is being missed with whole-structure approaches. Here, we review cerebellar-motor dysfunction in individuals with schizophrenia and those at-risk for psychosis. We also discuss cerebellar abnormalities in psychosis, and the cerebellar functional topography. Because of the segregated functional regions of the cerebellum, we propose that it is important to look at the structure regionally in order to better understand its role in motor dysfunction in these populations. This is analogous to approaches taken with the basal ganglia, where each region is considered separately. Such an approach is necessary to better understand cerebellar pathophysiology on a macro-structural level with respect to the pathogenesis of

  4. Dopamine synapse is a neuroligin-2-mediated contact between dopaminergic presynaptic and GABAergic postsynaptic structures.

    PubMed

    Uchigashima, Motokazu; Ohtsuka, Toshihisa; Kobayashi, Kazuto; Watanabe, Masahiko

    2016-04-12

    Midbrain dopamine neurons project densely to the striatum and form so-called dopamine synapses on medium spiny neurons (MSNs), principal neurons in the striatum. Because dopamine receptors are widely expressed away from dopamine synapses, it remains unclear how dopamine synapses are involved in dopaminergic transmission. Here we demonstrate that dopamine synapses are contacts formed between dopaminergic presynaptic and GABAergic postsynaptic structures. The presynaptic structure expressed tyrosine hydroxylase, vesicular monoamine transporter-2, and plasmalemmal dopamine transporter, which are essential for dopamine synthesis, vesicular filling, and recycling, but was below the detection threshold for molecules involving GABA synthesis and vesicular filling or for GABA itself. In contrast, the postsynaptic structure of dopamine synapses expressed GABAergic molecules, including postsynaptic adhesion molecule neuroligin-2, postsynaptic scaffolding molecule gephyrin, and GABAA receptor α1, without any specific clustering of dopamine receptors. Of these, neuroligin-2 promoted presynaptic differentiation in axons of midbrain dopamine neurons and striatal GABAergic neurons in culture. After neuroligin-2 knockdown in the striatum, a significant decrease of dopamine synapses coupled with a reciprocal increase of GABAergic synapses was observed on MSN dendrites. This finding suggests that neuroligin-2 controls striatal synapse formation by giving competitive advantage to heterologous dopamine synapses over conventional GABAergic synapses. Considering that MSN dendrites are preferential targets of dopamine synapses and express high levels of dopamine receptors, dopamine synapse formation may serve to increase the specificity and potency of dopaminergic modulation of striatal outputs by anchoring dopamine release sites to dopamine-sensing targets.

  5. Pre- and postsynaptic changes in the neuromuscular junction in dystrophic mice

    PubMed Central

    Pratt, Stephen J. P.; Valencia, Ana P.; Le, Gloribel K.; Shah, Sameer B.; Lovering, Richard M.

    2015-01-01

    Duchenne muscular dystrophy (DMD) is a devastating neuromuscular disease in which weakness, increased susceptibility to muscle injury, and inadequate repair appear to underlie the pathology. While most attention has focused within the muscle fiber, we recently demonstrated in mdx mice (murine model for DMD) significant morphologic alterations at the motor endplate of the neuromuscular junction (NMJ) and corresponding NMJ transmission failure after injury. Here we extend these initial observations at the motor endplate to gain insight into the pre- vs. postsynaptic morphology, as well as the subsynaptic nuclei in healthy (WT) vs. mdx mice. We quantified the discontinuity and branching of the terminal nerve in adult mice. We report mdx- and age-dependent changes for discontinuity and an increase in branching when compared to WT. To examine mdx- and age-dependent changes in the relative localization of pre- and postsynaptic structures, we calculated NMJ occupancy, defined as the ratio of the footprint occupied by presynaptic vesicles vs. that of the underlying motor endplate. The normally congruent coupling between presynaptic and postsynaptic morphology was altered in mdx mice, independent of age. Finally we found an almost two-fold increase in the number of nuclei and an increase in density (nuclei/area) underlying the NMJ. These outcomes suggest substantial remodeling of the NMJ during dystrophic progression. This remodeling reflects plasticity in both pre- and postsynaptic contributors to NMJ structure, and thus perhaps also NM transmission and muscle function. PMID:26441672

  6. The Glutamatergic Aspects of Schizophrenia Molecular Pathophysiology: Role of the Postsynaptic Density, and Implications for Treatment

    PubMed Central

    Iasevoli, Felice; Tomasetti, Carmine; Buonaguro, Elisabetta F.; de Bartolomeis, Andrea

    2014-01-01

    Schizophrenia is one of the most debilitating psychiatric diseases with a lifetime prevalence of approximately 1%. Although the specific molecular underpinnings of schizophrenia are still unknown, evidence has long linked its pathophysiology to postsynaptic abnormalities. The postsynaptic density (PSD) is among the molecular structures suggested to be potentially involved in schizophrenia. More specifically, the PSD is an electron-dense thickening of glutamatergic synapses, including ionotropic and metabotropic glutamate receptors, cytoskeletal and scaffolding proteins, and adhesion and signaling molecules. Being implicated in the postsynaptic signaling of multiple neurotransmitter systems, mostly dopamine and glutamate, the PSD constitutes an ideal candidate for studying dopamine-glutamate disturbances in schizophrenia. Recent evidence suggests that some PSD proteins, such as PSD-95, Shank, and Homer are implicated in severe behavioral disorders, including schizophrenia. These findings, further corroborated by genetic and animal studies of schizophrenia, offer new insights for the development of pharmacological strategies able to overcome the limitations in terms of efficacy and side effects of current schizophrenia treatment. Indeed, PSD proteins are now being considered as potential molecular targets against this devastating illness. The current paper reviews the most recent hypotheses on the molecular mechanisms underlying schizophrenia pathophysiology. First, we review glutamatergic dysfunctions in schizophrenia and we provide an update on postsynaptic molecules involvement in schizophrenia pathophysiology by addressing both human and animal studies. Finally, the possibility that PSD proteins may represent potential targets for new molecular interventions in psychosis will be discussed. PMID:24851087

  7. NMDA-induced accumulation of Shank at the postsynaptic density is mediated by CaMKII

    SciTech Connect

    Tao-Cheng, Jung-Hwa; Yang, Yijung; Bayer, K. Ulrich; Reese, Thomas S.; Dosemeci, Ayse

    2014-07-18

    Highlights: • NMDA-induces accumulation of Shank at the postsynaptic density. • Shank accumulation is preferential to the distal region of the postsynaptic density. • Shank accumulation is mediated by CaMKII. - Abstract: Shank is a specialized scaffold protein present in high abundance at the postsynaptic density (PSD). Using pre-embedding immunogold electron microscopy on cultured hippocampal neurons, we had previously demonstrated further accumulation of Shank at the PSD under excitatory conditions. Here, using the same experimental protocol, we demonstrate that a cell permeable CaMKII inhibitor, tatCN21, blocks NMDA-induced accumulation of Shank at the PSD. Furthermore we show that NMDA application changes the distribution pattern of Shank at the PSD, promoting a 7–10 nm shift in the median distance of Shank labels away from the postsynaptic membrane. Inhibition of CaMKII with tatCN21 also blocks this shift in the distribution of Shank. Altogether these results imply that upon activation of NMDA receptors, CaMKII mediates accumulation of Shank, preferentially at the distal regions of the PSD complex extending toward the cytoplasm.

  8. Postsynaptic PDLIM5 / Enigma Homolog binds SPAR and causes dendritic spine shrinkage

    PubMed Central

    Herrick, Scott; Evers, Danielle M.; Lee, Ji-Yun; Udagawa, Noriko; Pak, Daniel T.S.

    2009-01-01

    Dendritic spine morphology is thought to play important roles in synaptic development and plasticity, and morphological derangements in spines are correlated with several neurological disorders. Here, we identified an interaction between Spine-Associated RapGAP (SPAR), a postsynaptic protein that reorganizes actin cytoskeleton and drives dendritic spine head growth, and PDLIM5 / Enigma Homolog (ENH), a PDZ-LIM (postsynaptic density-95/Discs large/zona occludens 1-Lin11/Isl-1/Mec3) family member. PDLIM5 has been implicated in susceptibility to bipolar disorder, major depression and schizophrenia but its function in neurological disease is poorly understood. We show that PDLIM5 is present in the postsynaptic density, where it promotes decreased dendritic spine head size and longer, filopodia-like morphology. Conversely, RNA interference against PDLIM5 or loss of PDLIM5 interaction with SPAR caused increased spine head diameter. Furthermore, PKC activation promoted delivery of PDLIM5 into dendritic spines and increased its spine colocalization with SPAR. These data reveal new postsynaptic functions for PDLIM5 in shrinkage of dendritic spines that may be relevant to its association with psychiatric illness. PMID:19900557

  9. The lipid transfer proteins (LTP) essentially concentrate in the skin of Rosaceae fruits as cell surface exposed allergens.

    PubMed

    Borges, J-P; Jauneau, A; Brulé, C; Culerrier, R; Barre, A; Didier, A; Rougé, P

    2006-10-01

    The localization and distribution of non-specific lipid transfer proteins (nsLTP) allergens in the skin and pulp of Rosaceae fruits (apple, peach, apricot, plum) has been investigated. nsLTP essentially concentrate in the pericarp of the fruits whereas the pulp contains lower amounts of allergens. Immunolocalization showed they are primarily located in the cytosol but are subsequently excreted and finally accumulate at the plasmalemma-cell wall interface and in the cell wall. However, high discrepancies were observed in the content of allergens among, e.g. different cultivars of apple. As a consequence, the consumption of peeled-off fruits is recommended to reduce the risk of severe allergic reactions (anaphylactic shock) in individuals sensitized to Rosaceae fruits.

  10. D1/D5 receptors and histone deacetylation mediate the Gateway Effect of LTP in hippocampal dentate gyrus

    PubMed Central

    Huang, Yan-You; Levine, Amir; Kandel, Denise B.; Yin, Deqi; Colnaghi, Luca; Drisaldi, Bettina; Kandel, Eric R.

    2014-01-01

    The dentate gyrus (DG) of the hippocampus is critical for spatial memory and is also thought to be involved in the formation of drug-related associative memory. Here, we attempt to test an aspect of the Gateway Hypothesis, by studying the effect of consecutive exposure to nicotine and cocaine on long-term synaptic potentiation (LTP) in the DG. We find that a single injection of cocaine does not alter LTP. However, pretreatment with nicotine followed by a single injection of cocaine causes a substantial enhancement of LTP. This priming effect of nicotine is unidirectional: There is no enhancement of LTP if cocaine is administrated prior to nicotine. The facilitation induced by nicotine and cocaine can be blocked by oral administration of the dopamine D1/D5 receptor antagonist (SKF 83566) and enhanced by the D1/D5 agonist (SKF 38393). Application of the histone deacetylation inhibitor suberoylanilide hydroxamic acid (SAHA) simulates the priming effect of nicotine on cocaine. By contrast, the priming effect of nicotine on cocaine is blocked in genetically modified mice that are haploinsufficient for the CREB-binding protein (CBP) and possess only one functional CBP allele and therefore exhibit a reduction in histone acetylation. These results demonstrate that the DG of the hippocampus is an important brain region contributing to the priming effect of nicotine on cocaine. Moreover, both activation of dopamine-D1 receptor/PKA signaling pathway and histone deacetylation/CBP mediated transcription are required for the nicotine priming effect in the DG. PMID:24549570

  11. Prenatal exposures to LTP-patterned magnetic fields: quantitative effects on specific limbic structures and acquisition of contextually conditioned fear.

    PubMed

    Whissell, P D; Tsang, E W; Mulligan, B P; Persinger, M A

    2009-01-01

    Weak (<1 microT) complex magnetic fields (CMFs) may exert their behavioral influences through the hippocampus by resonating by accident or design with intrinsic electrical patterns. Rats were exposed prenatally to one of four intensities of a CMF (either <5 nanoTesla [nT], 10-50 nT, 50-500 nT, or 500-1000 nT) designed to interact with the process of Long-Term Potentiation (LTP) in the hippocampus. Rats then underwent testing in the forced swim, open field, and fear-conditioning procedures. The cell densities of all amygdaloid nuclei, specific hypothalamic structures, and the major regions of the hippocampus were quantified. Results showed that acquisition of conditioned fear was strongly inhibited in animals exposed to LTP-CMFs. Rats exposed to intensities above 10 nT showed decreased cell density in the CA2 fields of the hippocampus; more neurons were present in the CA1 fields of rats exposed to the 10-50 nT intensities compared to all other groups. A decrease in cell density in the medial preoptic nucleus was linearly dependent on field intensity. In the forced-swim test, swimming was decreased in rats that had been exposed to low (10-50 nT) and medium intensity (50-500 nT) LTP-CMFs in a manner consistent with monoamine modulation. In the open field, exposed rats were indistinguishable from controls. These findings support the hypothesis that continuous exposure during prenatal development to CMFs designed to simulate intrinsic LTP within the hippocampus can affect adult behaviors specific to this structure and produce quantitative alterations in neuronal density.

  12. Gating of Long-Term Potentiation by Nicotinic Acetylcholine Receptors at the Cerebellum Input Stage

    PubMed Central

    Prestori, Francesca; Bonardi, Claudia; Mapelli, Lisa; Lombardo, Paola; Goselink, Rianne; De Stefano, Maria Egle; Gandolfi, Daniela; Mapelli, Jonathan; Bertrand, Daniel; Schonewille, Martijn; De Zeeuw, Chris; D’Angelo, Egidio

    2013-01-01

    The brain needs mechanisms able to correlate plastic changes with local circuit activity and internal functional states. At the cerebellum input stage, uncontrolled induction of long-term potentiation or depression (LTP or LTD) between mossy fibres and granule cells can saturate synaptic capacity and impair cerebellar functioning, which suggests that neuromodulators are required to gate plasticity processes. Cholinergic systems innervating the cerebellum are thought to enhance procedural learning and memory. Here we show that a specific subtype of acetylcholine receptors, the α7-nAChRs, are distributed both in cerebellar mossy fibre terminals and granule cell dendrites and contribute substantially to synaptic regulation. Selective α7-nAChR activation enhances the postsynaptic calcium increase, allowing weak mossy fibre bursts, which would otherwise cause LTD, to generate robust LTP. The local microperfusion of α7-nAChR agonists could also lead to in vivo switching of LTD to LTP following sensory stimulation of the whisker pad. In the cerebellar flocculus, α7-nAChR pharmacological activation impaired vestibulo-ocular-reflex adaptation, probably because LTP was saturated, preventing the fine adjustment of synaptic weights. These results show that gating mechanisms mediated by specific subtypes of nicotinic receptors are required to control the LTD/LTP balance at the mossy fibre-granule cell relay in order to regulate cerebellar plasticity and behavioural adaptation. PMID:23741401

  13. Involvement of pre- and postsynaptic NMDA receptors at local circuit interneuron connections in rat neocortex.

    PubMed

    De-May, C L; Ali, A B

    2013-01-03

    To investigate the involvement of N-Methyl-D-aspartate (NMDA) receptors in local neocortical synaptic transmission, dual whole-cell recordings - combined with biocytin labelling - were obtained from bitufted adapting, multipolar adapting or multipolar non-adapting interneurons and pyramidal cells in layers II-V of rat (postnatal days 17-22) sensorimotor cortex. The voltage dependency of the amplitude of Excitatory postsynaptic potentials (EPSPs) received by the three types of interneuron appeared to coincide with the interneuron subclass; upon depolarisation, EPSPs received by multipolar non-adapting interneurons either decreased in amplitude or appeared insensitive, multipolar adapting interneuron EPSP amplitudes increased or appeared insensitive, whereas bitufted interneuron EPSP amplitudes increased or decreased. Connections were challenged with the NMDA receptor antagonist d-(-)-2-amino-5-phosphonopentanoic acid (d-AP5) (50μM) revealing NMDA receptors to contribute to EPSPs received by all cell types, this also abolished the non-conventional voltage dependency. Reciprocal connections were frequent between pyramidal cells and multipolar interneurons, and inhibitory postsynaptic potentials (IPSPs) elicited in pyramidal cells by both multipolar adapting and multipolar non-adapting interneurons were sensitive to a significant reduction in amplitude by d-AP5. The involvement of presynaptic NMDA receptors was indicated by coefficient of variation analysis and an increase in the failures of transmission. Furthermore, by loading MK-801 into the pre- or postsynaptic neurons, we observed that a reduction in inhibition requires presynaptic and not postsynaptic NMDA receptors. These results suggest that NMDA receptors possess pre- and postsynaptic roles at selective neocortical synapses that are probably important in governing spike-timing and information flow.

  14. Postsynaptic target specific synaptic dysfunctions in the CA3 area of BACE1 knockout mice.

    PubMed

    Wang, Hui; Megill, Andrea; Wong, Philip C; Kirkwood, Alfredo; Lee, Hey-Kyoung

    2014-01-01

    Beta-amyloid precursor protein cleaving enzyme 1 (BACE1), a major neuronal β-secretase critical for the formation of β-amyloid (Aβ) peptide, is considered one of the key therapeutic targets that can prevent the progression of Alzheimer's disease (AD). Although a complete ablation of BACE1 gene prevents Aβ formation, we previously reported that BACE1 knockouts (KOs) display presynaptic deficits, especially at the mossy fiber (MF) to CA3 synapses. Whether the defect is specific to certain inputs or postsynaptic targets in CA3 is unknown. To determine this, we performed whole-cell recording from pyramidal cells (PYR) and the stratum lucidum (SL) interneurons in the CA3, both of which receive excitatory MF terminals with high levels of BACE1 expression. BACE1 KOs displayed an enhancement of paired-pulse facilitation at the MF inputs to CA3 PYRs without changes at the MF inputs to SL interneurons, which suggests postsynaptic target specific regulation. The synaptic dysfunction in CA3 PYRs was not restricted to excitatory synapses, as seen by an increase in the paired-pulse ratio of evoked inhibitory postsynaptic currents from SL to CA3 PYRs. In addition to the changes in evoked synaptic transmission, BACE1 KOs displayed a reduction in the frequency of miniature excitatory and inhibitory postsynaptic currents (mEPSCs and mIPSCs) in CA3 PYRs without alteration in mEPSCs recorded from SL interneurons. This suggests that the impairment may be more global across diverse inputs to CA3 PYRs. Our results indicate that the synaptic dysfunctions seen in BACE1 KOs are specific to the postsynaptic target, the CA3 PYRs, independent of the input type.

  15. Postsynaptic Receptors for Amyloid-β Oligomers as Mediators of Neuronal Damage in Alzheimer's Disease.

    PubMed

    Dinamarca, Margarita C; Ríos, Juvenal A; Inestrosa, Nibaldo C

    2012-01-01

    The neurotoxic effect of amyloid-β peptide (Aβ) over the central synapses has been described and is reflected in the decrease of some postsynaptic excitatory proteins, the alteration in the number and morphology of the dendritic spines, and a decrease in long-term potentiation. Many studies has been carried out to identify the putative Aβ receptors in neurons, and is still no clear why the Aβ oligomers only affect the excitatory synapses. Aβ oligomers bind to neurite and preferentially to the postsynaptic region, where the postsynaptic protein-95 (PSD-95) is present in the glutamatergic synapse, and interacts directly with the N-methyl-D-aspartate receptor (NMDAR) and neuroligin (NL). NL is a postsynaptic protein which binds to the presynaptic protein, neurexin to form a heterophilic adhesion complex, the disruption of this interaction affects the integrity of the synaptic contact. Structurally, NL has an extracellular domain homolog to acetylcholinesterase, the first synaptic protein that was found to interact with Aβ. In the present review we will document the interaction between Aβ and the extracellular domain of NL-1 at the excitatory synapse, as well as the interaction with other postsynaptic components, including the glutamatergic receptors (NMDA and mGluR5), the prion protein, the neurotrophin receptor, and the α7-nicotinic acetylcholine receptor. We conclude that several Aβ oligomers receptors exist at the excitatory synapse, which could be the responsible for the neurotoxic effect described for the Aβ oligomers. The characterization of the interaction between Aβ receptors and Aβ oligomers could help to understand the source of the neurologic damage observed in the brain of the Alzheimer's disease patients.

  16. Heterogeneity of postsynaptic receptor occupancy fluctuations among glycinergic inhibitory synapses in the zebrafish hindbrain

    PubMed Central

    Rigo, Jean-Michel; Badiu, Carmen Ionela; Legendre, Pascal

    2003-01-01

    The amplitude of glycinergic miniature inhibitory postsynaptic currents (mIPSCs) varies considerably in neurons recorded in the isolated hindbrain of 50-h-old zebrafish larvae. At this age, glycinergic synapses are functionally mature. In order to measure the occupancy level of postsynaptic glycine receptors (GlyRs) and to determine the pre- and/or postsynaptic origin of its variability, we analysed mIPSCs within bursts evoked by α-latrotoxin (0.1–1 nm). Two types of burst were observed according to their mIPSC frequencies: ‘slow’ bursts with clearly spaced mIPSCs and ‘fast’ bursts characterised by superimposed events. Non-stationary noise analysis of mIPSCs in some ‘slow’ bursts recorded in the presence or in the absence of Ca2+ denoted that mIPSC amplitude variance did not depend on the quantity of neurotransmitters released (presynaptic origin), but rather on intrinsic stochastic behaviour of the same group of GlyRs (postsynaptic origin). In these bursts, the open probability measured at the peak of the mIPSCs was close to 0.5 while the maximum open probability is close to 0.9 for the synaptic isoform of GlyRs (heteromeric α1/β GlyRs). In ‘fast’ bursts with superimposed events, a correlation was found between the amplitude of mIPSCs and the basal current level measured at their onset, which could suggest that the same group of GlyRs is activated during such bursts. Altogether, our results indicate that glycine synapses can display different release modes in the presence of α-latrotoxin. They also indicate that, in our model, postsynaptic GlyRs cannot be saturated by the release of a single vesicle. PMID:14500774

  17. Activation-Dependent Rapid Postsynaptic Clustering of Glycine Receptors in Mature Spinal Cord Neurons

    PubMed Central

    Eto, Kei; Murakoshi, Hideji; Watanabe, Miho; Hirata, Hiromi; Moorhouse, Andrew J.; Ishibashi, Hitoshi

    2017-01-01

    Abstract Inhibitory synapses are established during development but continue to be generated and modulated in strength in the mature nervous system. In the spinal cord and brainstem, presynaptically released inhibitory neurotransmitter dominantly switches from GABA to glycine during normal development in vivo. While presynaptic mechanisms of the shift of inhibitory neurotransmission are well investigated, the contribution of postsynaptic neurotransmitter receptors to this shift is not fully elucidated. Synaptic clustering of glycine receptors (GlyRs) is regulated by activation-dependent depolarization in early development. However, GlyR activation induces hyperpolarization after the first postnatal week, and little is known whether and how presynaptically released glycine regulates postsynaptic receptors in a depolarization-independent manner in mature developmental stage. Here we developed spinal cord neuronal culture of rodents using chronic strychnine application to investigate whether initial activation of GlyRs in mature stage could change postsynaptic localization of GlyRs. Immunocytochemical analyses demonstrate that chronic blockade of GlyR activation until mature developmental stage resulted in smaller clusters of postsynaptic GlyRs that could be enlarged upon receptor activation for 1 h in the mature stage. Furthermore, live cell-imaging techniques show that GlyR activation decreases its lateral diffusion at synapses, and this phenomenon is dependent on PKC, but neither Ca2+ nor CaMKII activity. These results suggest that the GlyR activation can regulate receptor diffusion and cluster size at inhibitory synapses in mature stage, providing not only new insights into the postsynaptic mechanism of shifting inhibitory neurotransmission but also the inhibitory synaptic plasticity in mature nervous system. PMID:28197549

  18. Removal of FKBP12 enhances mTOR-Raptor interactions, LTP, memory, and perseverative/repetitive behavior.

    PubMed

    Hoeffer, Charles A; Tang, Wei; Wong, Helen; Santillan, Arturo; Patterson, Richard J; Martinez, Luis A; Tejada-Simon, Maria V; Paylor, Richard; Hamilton, Susan L; Klann, Eric

    2008-12-10

    FK506-binding protein 12 (FKBP12) binds the immunosuppressant drugs FK506 and rapamycin and regulates several signaling pathways, including mammalian target of rapamycin (mTOR) signaling. We determined whether the brain-specific disruption of the FKBP12 gene in mice altered mTOR signaling, synaptic plasticity, and memory. Biochemically, the FKBP12-deficient mice displayed increases in basal mTOR phosphorylation, mTOR-Raptor interactions, and p70 S6 kinase (S6K) phosphorylation. Electrophysiological experiments revealed that FKBP12 deficiency was associated with an enhancement in long-lasting hippocampal long-term potentiation (LTP). The LTP enhancement was resistant to rapamycin, but not anisomycin, suggesting that altered translation control is involved in the enhanced synaptic plasticity. Behaviorally, FKBP12 conditional knockout (cKO) mice displayed enhanced contextual fear memory and autistic/obsessive-compulsive-like perseveration in several assays including the water maze, Y-maze reversal task, and the novel object recognition test. Our results indicate that FKBP12 plays a critical role in the regulation of mTOR-Raptor interactions, LTP, memory, and perseverative behaviors.

  19. Discovery, identification and comparative analysis of non-specific lipid transfer protein (nsLtp) family in Solanaceae.

    PubMed

    Liu, Wanfei; Huang, Dawei; Liu, Kan; Hu, Songnian; Yu, Jun; Gao, Gang; Song, Shuhui

    2010-12-01

    Plant non-specific lipid transfer proteins (nsLtps) have been reported to be involved in plant defense activity against bacterial and fungal pathogens. In this study, we identified 135 (122 putative and 13 previously identified) Solanaceae nsLtps, which are clustered into 8 different groups. By comparing with Boutrot's nsLtp classification, we classified these eight groups into five types (I, II, IV, IX and X). We compared Solanaceae nsLtps with Arabi-dopsis and Gramineae nsLtps and found that (1) Types I, II and IV are shared by Solanaceae, Gramineae and Arabidopsis; (2) Types III, V, VI and VIII are shared by Gramineae and Arabidopsis but not detected in Solanaceae so far; (3) Type VII is only found in Gramineae whereas type IX is present only in Arabidopsis and Solanaceae; (4) Type X is a new type that accounts for 52.59% Solanaceae nsLtps in our data, and has not been reported in any other plant so far. We further built and compared the three-dimensional structures of the eight groups, and found that the major functional diversification within the nsLtp family could be predated to the monocot/dicot divergence, and many gene duplications and sequence variations had happened in the nsLtp family after the monocot/dicot divergence, especially in Solanaceae.

  20. Identification of european allergy patterns to the allergen families PR-10, LTP, and profilin from Rosaceae fruits.

    PubMed

    Andersen, Maj-Britt Schmidt; Hall, Sharon; Dragsted, Lars Ove

    2011-08-01

    High fruit intakes are associated with significant health benefits but fruit allergy sufferers may be discouraged from eating fruit due to the symptoms they experience. Knowledge about allergens involved in fruit allergy and the frequent cross-reactions to other allergens is essential to (a) design the best strategy for fruit allergy testing (b) prescribe optimal avoidance diets, and (c) design technological solutions for development of hypoallergenic fruits. The objective of this review was to investigate whether some characteristic disease entities could be identified in Europe for allergy to Rosaceae fruits. Five allergy patterns were found involving the allergen families PR-10, LTP, and profilin. In the Western Mediterranean area allergies to Rosaceae fruits are caused by monosensitization to LTP, monosensitization to profilin, or co-sensitization to both these allergens. On the contrary, monosensitization to PR-10 and, to a lesser degree, co-sensitization to profilin and PR-10 is dominant in Northern and Central Europe. LTP sensitization is present both in pollinosis and non-pollinosis patients and is associated with peach allergy in particular. The disease pattern for patients sensitized to profilin is characterized by several concomitant allergies including grass and other pollens, Rosaceae and non-Rosaceae fruits. Finally, PR-10 sensitization is primarily associated to concomitant birch pollen and apple allergy.

  1. Autonomous CaMKII mediates both LTP and LTD using a mechanism for differential substrate site selection.

    PubMed

    Coultrap, Steven J; Freund, Ronald K; O'Leary, Heather; Sanderson, Jennifer L; Roche, Katherine W; Dell'Acqua, Mark L; Bayer, K Ulrich

    2014-02-13

    Traditionally, hippocampal long-term potentiation (LTP) of synaptic strength requires Ca(2+)/calmodulin (CaM)-dependent protein kinase II (CaMKII) and other kinases, whereas long-term depression (LTD) requires phosphatases. Here, we found that LTD also requires CaMKII and its phospho-T286-induced "autonomous" (Ca(2+)-independent) activity. However, whereas LTP is known to induce phosphorylation of the AMPA-type glutamate receptor (AMPAR) subunit GluA1 at S831, LTD instead induced CaMKII-mediated phosphorylation at S567, a site known to reduce synaptic GluA1 localization. GluA1 S831 phosphorylation by "autonomous" CaMKII was further stimulated by Ca(2+)/CaM, as expected for traditional substrates. By contrast, GluA1 S567 represents a distinct substrate class that is unaffected by such stimulation. This differential regulation caused GluA1 S831 to be favored by LTP-type stimuli (strong but brief), whereas GluA1 S567 was favored by LTD-type stimuli (weak but prolonged). Thus, requirement of autonomous CaMKII in opposing forms of plasticity involves distinct substrate classes that are differentially regulated to enable stimulus-dependent substrate-site preference.

  2. Fennel allergy is a lipid-transfer protein (LTP)-related food hypersensitivity associated with peach allergy.

    PubMed

    Pastorello, Elide A; Farioli, Laura; Stafylaraki, Chrysi; Scibilia, Joseph; Giuffrida, Maria G; Mascheri, Ambra; Piantanida, Marta; Baro, Cristina; Primavesi, Laura; Nichelatti, Michele; Schroeder, Jan W; Pravettoni, Valerio

    2013-01-23

    Fennel allergy has been rarely reported, and the association with peach allergy has never been described. Our aim was to (i) study the correlation between symptom severity of peach and fennel and (ii) identify fennel allergens and the role of rPru p 3 antibodies in severe reactions to fennel. In 148 patients with peach allergy, we investigated 58 patients with symptoms and IgE antibodies positive to fennel. IgE to rPru p 1, 3, and 4 and rBet v 1, 2, and 4 were measured by immunoblotting, and the N-terminal amino acid sequences and relevant allergens were determined. We found significant association between severe reactions to fennel and peach (p = 0.0009). A major allergen was ~9 kDa lipid-transfer protein (LTP), cross-reactive with Pru p 3, a 15 kDa protein identified as a pathogenesis-related protein 1 of the Bet v 1 family. In conclusion, peach and fennel severe allergic symptoms are significantly related, and LTP is a major fennel allergen. Fennel should be included in the LTP syndrome.

  3. BDNF-induced LTP is associated with rapid Arc/Arg3.1-dependent enhancement in adult hippocampal neurogenesis

    PubMed Central

    Kuipers, Sjoukje D.; Trentani, Andrea; Tiron, Adrian; Mao, Xiaosong; Kuhl, Dietmar; Bramham, Clive R.

    2016-01-01

    Adult neurogenesis in the hippocampus is a remarkable phenomenon involved in various aspects of learning and memory as well as disease pathophysiology. Brain-derived neurotrophic factor (BDNF) represents a major player in the regulation of this unique form of neuroplasticity, yet the mechanisms underlying its pro-neurogenic actions remain unclear. Here, we examined the effects associated with brief (25 min), unilateral infusion of BDNF in the rat dentate gyrus. Acute BDNF infusion induced long-term potentiation (LTP) of medial perforant path-evoked synaptic transmission and, concomitantly, enhanced hippocampal neurogenesis bilaterally, reflected by increased dentate gyrus BrdU + cell numbers. Importantly, inhibition of activity-regulated cytoskeleton-associated protein (Arc/Arg3.1) translation through local, unilateral infusion of anti-sense oligodeoxynucleotides (ArcAS) prior to BDNF infusion blocked both BDNF-LTP induction and the associated pro-neurogenic effects. Notably, basal rates of proliferation and newborn cell survival were unaltered in homozygous Arc/Arg3.1 knockout mice. Taken together these findings link the pro-neurogenic effects of acute BDNF infusion to induction of Arc/Arg3.1-dependent LTP in the adult rodent dentate gyrus. PMID:26888068

  4. eIF2α-mediated translational control regulates the persistence of cocaine-induced LTP in midbrain dopamine neurons.

    PubMed

    Placzek, Andon N; Prisco, Gonzalo Viana Di; Khatiwada, Sanjeev; Sgritta, Martina; Huang, Wei; Krnjević, Krešimir; Kaufman, Randal J; Dani, John A; Walter, Peter; Costa-Mattioli, Mauro

    2016-12-13

    Recreational drug use leads to compulsive substance abuse in some individuals. Studies on animal models of drug addiction indicate that persistent long-term potentiation (LTP) of excitatory synaptic transmission onto ventral tegmental area (VTA) dopamine (DA) neurons is a critical component of sustained drug seeking. However, little is known about the mechanism regulating such long-lasting changes in synaptic strength. Previously, we identified that translational control by eIF2α phosphorylation (p-eIF2α) regulates cocaine-induced LTP in the VTA (Huang et al., 2016). Here we report that in mice with reduced p-eIF2α-mediated translation, cocaine induces persistent LTP in VTA DA neurons. Moreover, selectively inhibiting eIF2α-mediated translational control with a small molecule ISRIB, or knocking down oligophrenin-1-an mRNA whose translation is controlled by p-eIF2α-in the VTA also prolongs cocaine-induced LTP. This persistent LTP is mediated by the insertion of GluR2-lacking AMPARs. Collectively, our findings suggest that eIF2α-mediated translational control regulates the progression from transient to persistent cocaine-induced LTP.

  5. eIF2α-mediated translational control regulates the persistence of cocaine-induced LTP in midbrain dopamine neurons

    PubMed Central

    Placzek, Andon N; Prisco, Gonzalo Viana Di; Khatiwada, Sanjeev; Sgritta, Martina; Huang, Wei; Krnjević, Krešimir; Kaufman, Randal J; Dani, John A; Walter, Peter; Costa-Mattioli, Mauro

    2016-01-01

    Recreational drug use leads to compulsive substance abuse in some individuals. Studies on animal models of drug addiction indicate that persistent long-term potentiation (LTP) of excitatory synaptic transmission onto ventral tegmental area (VTA) dopamine (DA) neurons is a critical component of sustained drug seeking. However, little is known about the mechanism regulating such long-lasting changes in synaptic strength. Previously, we identified that translational control by eIF2α phosphorylation (p-eIF2α) regulates cocaine-induced LTP in the VTA (Huang et al., 2016). Here we report that in mice with reduced p-eIF2α-mediated translation, cocaine induces persistent LTP in VTA DA neurons. Moreover, selectively inhibiting eIF2α-mediated translational control with a small molecule ISRIB, or knocking down oligophrenin-1—an mRNA whose translation is controlled by p-eIF2α—in the VTA also prolongs cocaine-induced LTP. This persistent LTP is mediated by the insertion of GluR2-lacking AMPARs. Collectively, our findings suggest that eIF2α-mediated translational control regulates the progression from transient to persistent cocaine-induced LTP. DOI: http://dx.doi.org/10.7554/eLife.17517.001 PMID:27960077

  6. Stability of barley and malt lipid transfer protein 1 (LTP1) toward heating and reducing agents: relationships with the brewing process.

    PubMed

    Perrocheau, Ludivine; Bakan, Benedicte; Boivin, Patrick; Marion, Didier

    2006-04-19

    Barley lipid transfer protein (LTP1) is a heat-stable and protease-resistant albumin that concentrates in beer, where it participates in the formation and stability of beer foam. Whereas the barley LTP1 does not display any foaming properties, the corresponding beer protein is surface-active. Such an improvement is related to glycation by Maillard reactions on malting, acylation on mashing, and structural unfolding on brewing. The structural stability of purified barley and glycated malt LTP1 toward heating has been analyzed. Whatever the modification, lipid adduction or glycation, barley LTP1s are highly stable proteins that resisted temperatures up to 100 degrees C. Unfolding of LTP1 occurred only when heating was conducted in the presence of a reducing agent. In the presence of sodium sulfite, the lipid-adducted barley and malt LTP1 displayed higher heat stability than the nonadducted protein. Glycation had no or weak effect on heat-induced unfolding. Finally, it was shown that unfolding occurred on wort boiling before fermentation and that the reducing conditions are provided by malt extract.

  7. The toxicity of a lipid transfer protein (Cc-LTP1) from Coffea canephora Seeds on the larval development of Callosobruchus maculatus (Coleoptera: Bruchidae).

    PubMed

    Zottich, Umberto; Da Cunha, Maura; Dias, Germana B; Rabelo, Guilherme R; Oliveira, Antonia Elenir A; Carvalho, André O; Fernandes, Kátia Valevski S; do Nascimento, Viviane V; Gomes, Valdirene M

    2014-10-01

    In this work, we analyzed the effects of coffee seed proteins, especially Cc-LTP1 on the larval development of Callosobruchus maculatus (F.) (Coleoptera: Bruchidae), a bruchid pest of beans and the most important insect pest of Vigna unguiculata (L.) Walp. Artificial seed assay, which incorporated the F/0-90 fraction from Coffea canephora seeds, resulted in the reduction of oviposition and caused an inhibition of C. maculatus larval development in a dose-dependent manner. The F/0-90 fraction used at a 4 % concentration resulted in the survival of no larvae. The purified Cc-LTP1, at a concentration of 0.5 %, also demonstrated effective inhibition of larval development, reducing both females oviposition and the weight and number of larvae. Cc-LTP1 was also able to inhibit the C. maculatus gut α-amylase activity, and immunolabeling by an anti-LTP serum was observed in the midgut tissues of the C. maculatus larvae. Cc-LTP1 has shown binding affinity towards microvillar cells, endoplasmic reticulum and mitochondria, as demonstrated by micrographic images taken by a transmission electron microscope. The results from this study indicate that Cc-LTP1 has insecticidal actions toward C. maculatus and exerts anti-nutritional effects with direct actions on intestinal tissues.

  8. Autosomal dominant cerebellar ataxia deafness and narcolepsy.

    PubMed

    Melberg, A; Hetta, J; Dahl, N; Nennesmo, I; Bengtsson, M; Wibom, R; Grant, C; Gustavson, K H; Lundberg, P O

    1995-12-01

    A new autosomal dominant syndrome in a Swedish pedigree is described. Five patients were affected with cerebellar ataxia and sensorineural deafness. Four of these patients had symptoms of narcolepsy. Optic atrophy, other neurological abnormalities and psychiatric symptoms developed with increasing disease duration. Three patients had non-neurological disease in addition, including diabetes mellitus in two and hypertrophic cardiomyopathy in one. Autopsy with neuropathological examination was performed in one case. Molecular studies focused on the short arm of chromosome 6, including the HLA DR2 locus associated with narcolepsy and the (CAG)n repeat at the spinocerebellar ataxia type 1 (SCA1) locus. Biochemical investigation of muscle biopsy of one case indicated mitochondrial dysfunction with selective decrease in ATP production for substrates that normally give the highest rates. The activity of glutamate dehydrogenase was reduced, indicating a low mitochondrial density. We postulate an autosomal dominant genetic factor responsible for this syndrome. Linkage was excluded to HLA DR2, and a normal sized SCA1 repeat was observed. We conclude that a locus predisposing to ataxia, deafness and narcolepsy exists outside this region of chromosome 6.

  9. Imaging calcium waves in cerebellar Bergmann glia.

    PubMed

    Beierlein, Michael

    2013-01-01

    This protocol describes methods for recording synaptically evoked Ca(2+) waves from individual Bergmann glia (BG) in slices of cerebellar cortex. Unlike protoplasmic, star-shaped astrocytes, whose thin processes pose a serious challenge to stable Ca(2+) measurements, BG are large radial cells, with several main processes that run over distances of several hundred micrometers toward the pia and ensheathe thousands of parallel fiber (PF) synapses. Stimulation of PF synapses with brief bursts can trigger long-lasting Ca(2+) responses in BG processes, which can be reliably recorded using a cooled charge-coupled device (CCD) camera. This protocol was developed to enable measurements of Ca(2+) waves in individual BG loaded with a high-affinity Ca(2+) indicator such as Fura-2 for up to 2 h. Because BG recorded in slices rarely display spontaneous (i.e., tetrodotoxin [TTX]-sensitive) or intrinsic Ca(2+) transients, Ca(2+) waves can be evoked repeatedly and reliably, which permits quantitative studies using pharmacological tools. Fluorescence measurements obtained using CCD technology offer a straightforward means of characterizing the mechanisms and potential functional consequences of widespread and long-lasting, store-mediated Ca(2+) increases in astrocytes.

  10. Understanding and modulating motor learning with Cerebellar stimulation

    PubMed Central

    Celnik, Pablo

    2014-01-01

    Non-invasive brain stimulation techniques are a powerful approach to investigate the physiology and function of the central nervous system. Recent years have seen numerous investigations delivering transcranial magnetic stimulation (TMS) and or transcranial direct current stimulation (tDCS) to the cerebellum to determine its role in motor, cognitive and emotional behaviours. Early studies have shown that it is possible to assess cerebellar-motor cortex (CB-M1) connectivity using a paired-pulse TMS paradigm called cerebellar inhibition (CBI), and indirectly infer the state of cerebellar excitability. Thus, it has been shown that CBI changes proportionally to the magnitude of locomotor learning and in association with reaching adaption tasks. In addition, CBI has been used to demonstrate at a physiological level the effects of applying TMS or tDCS to modulate, up or down, the excitability of cerebellar-M1 connectivity. These studies became the fundamental substrate to newer investigations showing that we can affect motor, cognitive and emotional behaviour when TMS or tDCS targeting the cerebellum is delivered in the context of performance. Furthermore, newer investigations are starting to report the effects of cerebellar non-invasive stimulation to treat symptoms associated with neurological conditions such as stroke and dystonia. Altogether, non-invasive cerebellar stimulation can potentially become a game changer for the management of conditions that affect the cerebellum given the scarcity of current effective therapeutic options. In this brief manuscript, some of the current evidence demonstrating the effects of cerebellar stimulation to modulate motor behaviour and its use to assess physiological processes underlying motor learning are presented. PMID:25283180

  11. Effect of Valsartan on Cerebellar Adrenomedullin System Dysregulation During Hypertension.

    PubMed

    Figueira, Leticia; Israel, Anita

    2017-02-01

    Adrenomedullin (AM) and its receptors components, calcitonin-receptor-like receptor (CRLR), and receptor activity-modifying protein (RAMP1, RAMP2, and RAMP3) are expressed in cerebellum. Cerebellar AM, AM binding sites and receptor components are altered during hypertension, suggesting a role for cerebellar AM in blood pressure regulation. Thus, we assessed the effect of valsartan, on AM and its receptor components expression in the cerebellar vermis of Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats. Additionally, we evaluated AM action on superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) activity, and thiobarbituric acid reactive substances (TBARS) production in cerebellar vermis. Animals were treated with valsartan or vehicle for 11 days. Rats were sacrificed by decapitation; cerebellar vermis was dissected; and AM, CRLR, RAMP1, RAMP2, and RAMP3 expression was quantified by Western blot analysis. CAT, SOD, and GPx activity was determined spectrophotometrically and blood pressure by non-invasive plethysmography. We demonstrate that AM and RAMP2 expression was lower in cerebellum of SHR rats, while CRLR, RAMP1, and RAMP3 expression was higher than those of WKY rats. AM reduced cerebellar CAT, SOD, GPx activities, and TBARS production in WKY rats, but not in SHR rats. Valsartan reduced blood pressure and reversed the altered expression of AM and its receptors components, as well the loss of AM capacity to reduce antioxidant enzyme activity and TBARS production in SHR rats. These findings demonstrate that valsartan is able to reverse the dysregulation of cerebellar adrenomedullinergic system; and they suggest that altered AM system in the cerebellum could represent the primary abnormality leading to hypertension.

  12. A Cerebellar Neuroprosthetic System: Computational Architecture and in vivo Test

    PubMed Central

    Herreros, Ivan; Giovannucci, Andrea; Taub, Aryeh H.; Hogri, Roni; Magal, Ari; Bamford, Sim; Prueckl, Robert; Verschure, Paul F. M. J.

    2014-01-01

    Emulating the input–output functions performed by a brain structure opens the possibility for developing neuroprosthetic systems that replace damaged neuronal circuits. Here, we demonstrate the feasibility of this approach by replacing the cerebellar circuit responsible for the acquisition and extinction of motor memories. Specifically, we show that a rat can undergo acquisition, retention, and extinction of the eye-blink reflex even though the biological circuit responsible for this task has been chemically inactivated via anesthesia. This is achieved by first developing a computational model of the cerebellar microcircuit involved in the acquisition of conditioned reflexes and training it with synthetic data generated based on physiological recordings. Secondly, the cerebellar model is interfaced with the brain of an anesthetized rat, connecting the model’s inputs and outputs to afferent and efferent cerebellar structures. As a result, we show that the anesthetized rat, equipped with our neuroprosthetic system, can be classically conditioned to the acquisition of an eye-blink response. However, non-stationarities in the recorded biological signals limit the performance of the cerebellar model. Thus, we introduce an updated cerebellar model and validate it with physiological recordings showing that learning becomes stable and reliable. The resulting system represents an important step toward replacing lost functions of the central nervous system via neuroprosthetics, obtained by integrating a synthetic circuit with the afferent and efferent pathways of a damaged brain region. These results also embody an early example of science-based medicine, where on the one hand the neuroprosthetic system directly validates a theory of cerebellar learning that informed the design of the system, and on the other one it takes a step toward the development of neuro-prostheses that could recover lost learning functions in animals and, in the longer term, humans. PMID:25152887

  13. Inhibition of Ca2+-activated large-conductance K+ channel activity alters synaptic AMPA receptor phenotype in mouse cerebellar stellate cells.

    PubMed

    Liu, Yu; Savtchouk, Iaroslav; Acharjee, Shoana; Liu, Siqiong June

    2011-07-01

    Many fast-spiking inhibitory interneurons, including cerebellar stellate cells, fire brief action potentials and express α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-type glutamate receptors (AMPAR) that are permeable to Ca(2+) and do not contain the GluR2 subunit. In a recent study, we found that increasing action potential duration promotes GluR2 gene transcription in stellate cells. We have now tested the prediction that activation of potassium channels that control the duration of action potentials can suppress the expression of GluR2-containing AMPARs at stellate cell synapses. We find that large-conductance Ca(2+)-activated potassium (BK) channels mediate a large proportion of the depolarization-evoked noninactivating potassium current in stellate cells. Pharmacological blockade of BK channels prolonged the action potential duration in postsynaptic stellate cells and altered synaptic AMPAR subtype from GluR2-lacking to GluR2-containing Ca(2+)-impermeable AMPARs. An L-type channel blocker abolished an increase in Ca(2+) entry that was associated with spike broadening and also prevented the BK channel blocker-induced switch in AMPAR phenotype. Thus blocking BK potassium channels prolongs the action potential duration and increases the expression of GluR2-containing receptors at the synapse by enhancing Ca(2+) entry in cerebellar stellate cells.

  14. Inhibition of Ca2+-activated large-conductance K+ channel activity alters synaptic AMPA receptor phenotype in mouse cerebellar stellate cells

    PubMed Central

    Liu, Yu; Savtchouk, Iaroslav; Acharjee, Shoana

    2011-01-01

    Many fast-spiking inhibitory interneurons, including cerebellar stellate cells, fire brief action potentials and express α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-type glutamate receptors (AMPAR) that are permeable to Ca2+ and do not contain the GluR2 subunit. In a recent study, we found that increasing action potential duration promotes GluR2 gene transcription in stellate cells. We have now tested the prediction that activation of potassium channels that control the duration of action potentials can suppress the expression of GluR2-containing AMPARs at stellate cell synapses. We find that large-conductance Ca2+-activated potassium (BK) channels mediate a large proportion of the depolarization-evoked noninactivating potassium current in stellate cells. Pharmacological blockade of BK channels prolonged the action potential duration in postsynaptic stellate cells and altered synaptic AMPAR subtype from GluR2-lacking to GluR2-containing Ca2+-impermeable AMPARs. An L-type channel blocker abolished an increase in Ca2+ entry that was associated with spike broadening and also prevented the BK channel blocker-induced switch in AMPAR phenotype. Thus blocking BK potassium channels prolongs the action potential duration and increases the expression of GluR2-containing receptors at the synapse by enhancing Ca2+ entry in cerebellar stellate cells. PMID:21562198

  15. Distributed Cerebellar Motor Learning: A Spike-Timing-Dependent Plasticity Model.

    PubMed

    Luque, Niceto R; Garrido, Jesús A; Naveros, Francisco; Carrillo, Richard R; D'Angelo, Egidio; Ros, Eduardo

    2016-01-01

    Deep cerebellar nuclei neurons receive both inhibitory (GABAergic) synaptic currents from Purkinje cells (within the cerebellar cortex) and excitatory (glutamatergic) synaptic currents from mossy fibers. Those two deep cerebellar nucleus inputs are thought to be also adaptive, embedding interesting properties in the framework of accurate movements. We show that distributed spike-timing-dependent plasticity mechanisms (STDP) located at different cerebellar sites (parallel fibers to Purkinje cells, mossy fibers to deep cerebellar nucleus cells, and Purkinje cells to deep cerebellar nucleus cells) in close-loop simulations provide an explanation for the complex learning properties of the cerebellum in motor learning. Concretely, we propose a new mechanistic cerebellar spiking model. In this new model, deep cerebellar nuclei embed a dual functionality: deep cerebellar nuclei acting as a gain adaptation mechanism and as a facilitator for the slow memory consolidation at mossy fibers to deep cerebellar nucleus synapses. Equipping the cerebellum with excitatory (e-STDP) and inhibitory (i-STDP) mechanisms at deep cerebellar nuclei afferents allows the accommodation of synaptic memories that were formed at parallel fibers to Purkinje cells synapses and then transferred to mossy fibers to deep cerebellar nucleus synapses. These adaptive mechanisms also contribute to modulate the deep-cerebellar-nucleus-output firing rate (output gain modulation toward optimizing its working range).

  16. Distributed Cerebellar Motor Learning: A Spike-Timing-Dependent Plasticity Model

    PubMed Central

    Luque, Niceto R.; Garrido, Jesús A.; Naveros, Francisco; Carrillo, Richard R.; D'Angelo, Egidio; Ros, Eduardo

    2016-01-01

    Deep cerebellar nuclei neurons receive both inhibitory (GABAergic) synaptic currents from Purkinje cells (within the cerebellar cortex) and excitatory (glutamatergic) synaptic currents from mossy fibers. Those two deep cerebellar nucleus inputs are thought to be also adaptive, embedding interesting properties in the framework of accurate movements. We show that distributed spike-timing-dependent plasticity mechanisms (STDP) located at different cerebellar sites (parallel fibers to Purkinje cells, mossy fibers to deep cerebellar nucleus cells, and Purkinje cells to deep cerebellar nucleus cells) in close-loop simulations provide an explanation for the complex learning properties of the cerebellum in motor learning. Concretely, we propose a new mechanistic cerebellar spiking model. In this new model, deep cerebellar nuclei embed a dual functionality: deep cerebellar nuclei acting as a gain adaptation mechanism and as a facilitator for the slow memory consolidation at mossy fibers to deep cerebellar nucleus synapses. Equipping the cerebellum with excitatory (e-STDP) and inhibitory (i-STDP) mechanisms at deep cerebellar nuclei afferents allows the accommodation of synaptic memories that were formed at parallel fibers to Purkinje cells synapses and then transferred to mossy fibers to deep cerebellar nucleus synapses. These adaptive mechanisms also contribute to modulate the deep-cerebellar-nucleus-output firing rate (output gain modulation toward optimizing its working range). PMID:26973504

  17. Changes in Neuronal Oscillations Accompany the Loss of Hippocampal LTP that Occurs in an Animal Model of Psychosis

    PubMed Central

    Kalweit, Alexander N.; Amanpour-Gharaei, Bezhad; Colitti-Klausnitzer, Jens; Manahan-Vaughan, Denise

    2017-01-01

    The first-episode of psychosis is followed by a transient time-window of ca. 60 days during which therapeutic interventions have a higher likelihood of being effective than interventions that are started with a greater latency. This suggests that, in the immediate time-period after first-episode psychosis, functional changes occur in the brain that render it increasingly resistant to intervention. The precise mechanistic nature of these changes is unclear, but at the cognitive level, sensory and hippocampus-based dysfunctions become increasingly manifest. In an animal model of first-episode psychosis that comprises acute treatment of rats with the irreversible N-methyl-D-aspartate receptor (NMDAR)-antagonist, MK801, acute but also chronic deficits in long-term potentiation (LTP) and spatial memory occur. Neuronal oscillations, especially in the form of information transfer through θ and γ frequency oscillations are an intrinsic component of normal information processing in the hippocampus. Changes in θ-γ coupling and power are known to accompany deficits in hippocampal plasticity. Here, we examined whether changes in δ, θ, α, β and γ oscillations, or θ-γ coupling accompany the chronic loss of LTP that is observed in the MK801-animal model of psychosis. One and 4 weeks after acute systemic treatment of adult rats with MK801, a potent loss of hippocampal in vivo LTP was evident compared to vehicle-treated controls. Overall, the typical pattern of θ-γ oscillations that are characteristic for the successful induction of LTP was altered. In particular, θ-power was lower and an uncoupling of θ-γ oscillations was evident in MK801-treated rats. The alterations in network oscillations that accompany LTP deficits in this animal model may comprise a mechanism through which disturbances in sensory information processing and hippocampal function occur in psychosis. These data suggest that the hippocampus is likely to comprise a very early locus of functional

  18. Cellular and Metabolic Origins of Flavoprotein Autofluorescence in the Cerebellar Cortex in vivo

    PubMed Central

    Reinert, Kenneth C.; Gao, Wangcai; Chen, Gang; Wang, Xinming; Peng, Yu-Ping

    2013-01-01

    Flavoprotein autofluorescence imaging, an intrinsic mitochondrial signal, has proven useful for monitoring neuronal activity. In the cerebellar cortex, parallel fiber stimulation evokes a beam-like response consisting of an initial, short-duration increase in fluorescence (on-beam light phase) followed by a longer duration decrease (on-beam dark phase). Also evoked are parasagittal bands of decreased fluorescence due to molecular layer inhibition. Previous work suggests that the on-beam light phase is due to oxidative metabolism in neurons. The present study further investigated the metabolic and cellular origins of the flavoprotein signal in vivo, testing the hypotheses that the dark phase is mediated by glia activation and the inhibitory bands reflect decreased flavoprotein oxidation and increased glycolysis in neurons. Blocking postsynaptic ionotropic and metabotropic glutamate receptors abolished the onbeam light phase and the parasagittal bands without altering the on-beam dark phase. Adding glutamate transporter blockers reduced the dark phase. Replacing glucose with lactate (or pyruvate) or adding lactate to the bathing media abolished the on-beam dark phase and reduced the inhibitory bands without affecting the light phase. Blocking monocarboxylate transporters eliminated the on-beam dark phase and increased the light phase. These results confirm that the on-beam light phase is due primarily to increased oxidative metabolism in neurons. They also show that the on-beam dark phase involves activation of glycolysis in glia resulting in the generation of lactate that is transferred to neurons. Oxidative savings in neurons contributes to the decrease in fluorescence characterizing the inhibitory bands. These findings provide strong in vivo support for the astrocyte–neuron lactate shuttle hypothesis. PMID:21503591

  19. Cerebellar cortex and cerebellar nuclei are concomitantly activated during eyeblink conditioning: a 7T fMRI study in humans.

    PubMed

    Thürling, Markus; Kahl, Fabian; Maderwald, Stefan; Stefanescu, Roxana M; Schlamann, Marc; Boele, Henk-Jan; De Zeeuw, Chris I; Diedrichsen, Jörn; Ladd, Mark E; Koekkoek, Sebastiaan K E; Timmann, Dagmar

    2015-01-21

    There are controversies whether learning of conditioned eyeblink responses primarily takes place within the cerebellar cortex, the interposed nuclei, or both. It has also been suggested that the cerebellar cortex may be important during early stages of learning, and that there is a shift to the cerebellar nuclei during later stages. As yet, human studies have provided little to resolve this question. In the present study, we established a setup that allows ultra-high-field 7T functional magnetic resonance imaging (fMRI) of the cerebellar cortex and interposed cerebellar nuclei simultaneously during delay eyeblink conditioning in humans. Event-related fMRI signals increased concomitantly in the cerebellar cortex and nuclei during early acquisition of conditioned eyeblink responses in 20 healthy human subjects. ANOVAs with repeated-measures showed significant effects of time across five blocks of 20 conditioning trials in the cortex and nuclei (p < 0.05, permutation corrected). Activations were most pronounced in, but not limited to, lobules VI and interposed nuclei. Increased activations were most prominent at the first time the maximum number of conditioned responses was achieved. Our data are consistent with a simultaneous and synergistic two-site model of learning during acquisition of classically conditioned eyeblinks. Because increased MRI signal reflects synaptic activity, concomitantly increased signals in the cerebellar nuclei and cortex are consistent with findings of learning related potentiation at the mossy fiber to nuclear cell synapse and mossy fiber to granule cell synapse. Activity related to the expression of conditioned responses, however, cannot be excluded.

  20. Thalamic, brainstem, and cerebellar glucose metabolism in the hemiplegic monkey

    SciTech Connect

    Shimoyama, I.; Dauth, G.W.; Gilman, S.; Frey, K.A.; Penney, J.B. Jr.

    1988-12-01

    Unilateral ablation of cerebral cortical areas 4 and 6 of Brodmann in the macaque monkey results in a contralateral hemiplegia that resolves partially with time. During the phase of dense hemiplegia, local cerebral metabolic rate for glucose (1CMRG1c) is decreased significantly in most of the thalamic nuclei ipsilateral to the ablation, and there are slight contralateral decreases. The lCMRGlc is reduced bilaterally in most of the brainstem nuclei and bilaterally in the deep cerebellar nuclei, but only in the contralateral cerebellar cortex. During the phase of partial motor recovery, lCMRGlc is incompletely restored in many of the thalamic nuclei ipsilateral to the ablation and completely restored in the contralateral nuclei. In the brainstem and deep cerebellar nuclei, poor to moderate recovery occurs bilaterally. Moderate recovery occurs in the contralateral cerebellar cortex. The findings demonstrate that a unilateral cerebral cortical lesion strongly affects lCMRGlc in the thalamus ipsilaterally and in the cerebellar cortex contralaterally, but in the brainstem bilaterally. Partial recovery of lCMRGlc accompanies the progressive motor recovery. The structures affected include those with direct, and also those with indirect, connections to the areas ablated.

  1. Cerebellar network plasticity: from genes to fast oscillation.

    PubMed

    Cheron, G; Servais, L; Dan, B

    2008-04-22

    The role of the cerebellum has been increasingly recognized not only in motor control but in sensory, cognitive and emotional learning and regulation. Purkinje cells, being the sole output from the cerebellar cortex, occupy an integrative position in this network. Plasticity at this level is known to critically involve calcium signaling. In the last few years, electrophysiological study of genetically engineered mice has demonstrated the topical role of several genes encoding calcium-binding proteins (calretinin, calbindin, parvalbumin). Specific inactivation of these genes results in the emergence of a fast network oscillation (ca. 160 Hz) throughout the cerebellar cortex in alert animals, associated with ataxia. This oscillation is produced by synchronization of Purkinje cells along the parallel fiber beam. It behaves as an electrophysiological arrest rhythm, being blocked by sensorimotor stimulation. Pharmacological manipulations showed that the oscillation is blocked by GABA(A) and NMDA antagonists as well as gap junction blockers. This cerebellar network oscillation has also been documented in mouse models of human conditions with complex developmental cerebellar dysfunction, such as Angelman syndrome and fetal alcohol syndrome. Recent evidence suggests a relationship between fast oscillation and cerebellar long term depression (LTD). This may have major implications for future therapeutic targeting.

  2. Motor learning of mice lacking cerebellar Purkinje cells

    PubMed Central

    Porras-García, M. Elena; Ruiz, Rocío; Pérez-Villegas, Eva M.; Armengol, José Á.

    2013-01-01

    The cerebellum plays a key role in the acquisition and execution of motor tasks whose physiological foundations were postulated on Purkinje cells' long-term depression (LTD). Numerous research efforts have been focused on understanding the cerebellum as a site of learning and/or memory storage. However, the controversy on which part of the cerebellum participates in motor learning, and how the process takes place, remains unsolved. In fact, it has been suggested that cerebellar cortex, deep cerebellar nuclei, and/or their combination with some brain structures other than the cerebellum are responsible for motor learning. Different experimental approaches have been used to tackle this question (cerebellar lesions, pharmacological agonist and/or antagonist of cerebellar neurotransmitters, virus tract tracings, etc.). One of these approaches is the study of spontaneous mutations affecting the cerebellar cortex and depriving it of its main input–output organizer (i.e., the Purkinje cell). In this review, we discuss the results obtained in our laboratory in motor learning of both Lurcher (Lc/+) and tambaleante (tbl/tbl) mice as models of Purkinje-cell-devoid cerebellum. PMID:23630472

  3. Motor learning of mice lacking cerebellar Purkinje cells.

    PubMed

    Porras-García, M Elena; Ruiz, Rocío; Pérez-Villegas, Eva M; Armengol, José Á

    2013-01-01

    The cerebellum plays a key role in the acquisition and execution of motor tasks whose physiological foundations were postulated on Purkinje cells' long-term depression (LTD). Numerous research efforts have been focused on understanding the cerebellum as a site of learning and/or memory storage. However, the controversy on which part of the cerebellum participates in motor learning, and how the process takes place, remains unsolved. In fact, it has been suggested that cerebellar cortex, deep cerebellar nuclei, and/or their combination with some brain structures other than the cerebellum are responsible for motor learning. Different experimental approaches have been used to tackle this question (cerebellar lesions, pharmacological agonist and/or antagonist of cerebellar neurotransmitters, virus tract tracings, etc.). One of these approaches is the study of spontaneous mutations affecting the cerebellar cortex and depriving it of its main input-output organizer (i.e., the Purkinje cell). In this review, we discuss the results obtained in our laboratory in motor learning of both Lurcher (Lc/+) and tambaleante (tbl/tbl) mice as models of Purkinje-cell-devoid cerebellum.

  4. Modeling the Generation of Output by the Cerebellar Nuclei

    PubMed Central

    Steuber, Volker; Jaeger, Dieter

    2012-01-01

    Functional aspects of network integration in the cerebellar cortex have been studied experimentally and modeled in much detail ever since the early work by theoreticians such as Marr, Albus and Braitenberg more than 40 years ago. In contrast, much less is known about cerebellar processing at the output stage, namely in the cerebellar nuclei (CN). Here, input from Purkinje cells converges to control CN neuron spiking via GABAergic inhibition, before the output from the CN reaches cerebellar targets such as the brainstem and the motor thalamus. In this article we review modeling studies that address how the CN may integrate cerebellar cortical inputs, and what kind of signals may be transmitted. Specific hypotheses in the literature contrast rate coding and temporal coding of information in the spiking output from the CN. One popular hypothesis states that postinhibitory rebound spiking may be an important mechanism by which Purkinje cell inhibition is turned into CN output spiking, but this hypothesis remains controversial. Rate coding clearly does take place, but in what way it may be augmented by temporal codes remains to be more clearly established. Several candidate mechanisms distinct from rebound spiking are discussed, such as the significance of spike time correlations between Purkinje cell pools to determine CN spike timing, irregularity of Purkinje cell spiking as a determinant of CN firing rate, and shared brief pauses between Purkinje cell pools that may trigger individual CN spikes precisely. PMID:23200193

  5. Upregulation of cortico-cerebellar functional connectivity after motor learning.

    PubMed

    Mehrkanoon, Saeid; Boonstra, Tjeerd W; Breakspear, Michael; Hinder, Mark; Summers, Jeffery J

    2016-03-01

    Interactions between the cerebellum and primary motor cortex are crucial for the acquisition of new motor skills. Recent neuroimaging studies indicate that learning motor skills is associated with subsequent modulation of resting-state functional connectivity in the cerebellar and cerebral cortices. The neuronal processes underlying the motor-learning-induced plasticity are not well understood. Here, we investigate changes in functional connectivity in source-reconstructed electroencephalography (EEG) following the performance of a single session of a dynamic force task in twenty young adults. Source activity was reconstructed in 112 regions of interest (ROIs) and the functional connectivity between all ROIs was estimated using the imaginary part of coherence. Significant changes in resting-state connectivity were assessed using partial least squares (PLS). We found that subjects adapted their motor performance during the training session and showed improved accuracy but with slower movement times. A number of connections were significantly upregulated after motor training, principally involving connections within the cerebellum and between the cerebellum and motor cortex. Increased connectivity was confined to specific frequency ranges in the mu- and beta-bands. Post hoc analysis of the phase spectra of these cerebellar and cortico-cerebellar connections revealed an increased phase lag between motor cortical and cerebellar activity following motor practice. These findings show a reorganization of intrinsic cortico-cerebellar connectivity related to motor adaptation and demonstrate the potential of EEG connectivity analysis in source space to reveal the neuronal processes that underpin neural plasticity.

  6. Cellular and Subcellular Localization of the RGS7/Gβ5/R7BP Complex in the Cerebellar Cortex

    PubMed Central

    Aguado, Carolina; Orlandi, Cesare; Fajardo-Serrano, Ana; Gil-Minguez, Mercedes; Martemyanov, Kirill A.; Luján, Rafael

    2016-01-01

    A member of regulator of G-protein signaling family, RGS7, is an essential modulator of signaling through GABAB receptors. RGS7 functions as a macromolecular complex with type 5 G protein β (Gβ5) and R7 binding protein (R7BP) to control the localization and function of the resultant heterotrimeric complexes. Here, we used co-immunoprecipitation, in situ hybridization, histoblot and immunohistochemical techniques at the light and electron microscopic level to advance understanding of RGS7-Gβ5-R7BP complexes in the central nervous system, focusing on distinct neuronal populations in the cerebellar cortex. Histoblot analysis showed that RGS7, Gβ5 and R7BP proteins were widely expressed in the brain, with mostly an overlapping pattern and showing a high expression level in the molecular layer of the cerebellar cortex. Co-immunoprecipitation experiments established that the RGS7/Gβ5 forms complexes with R7BP in the cerebellum. At the cellular level, RGS7 and R7BP mRNAs were expressed at the highest level in Purkinje cells (PCs) and Golgi cells, and at low levels in granule cells. Immunohistochemistry confirmed that labeling for RGS7, Gβ5 and R7BP were present in the three neuronal populations and concentrated in dendrites and spines. At the electron microscopic level, immunolabeling for RGS7, Gβ5 and R7BP proteins was found both at postsynaptic and presynaptic sites and showed similar distribution patterns. Immunoreactivity for the three proteins was mostly localized along the extrasynaptic plasma membrane of dendritic shafts and spines of PCs and to a lesser extent, in axon terminals (AT) establishing excitatory synapses. Quantitative analysis of immunogold particles for RGS7, Gβ5 and R7BP revealed that they are non-uniformly distributed along the surface of PCs, and show enrichment around excitatory synapses on dendritic spines. We further report that deletion of R7BP in mice reduced the targeting of both RGS7 and Gβ5 to the plasma membrane. Altogether, these

  7. Presynaptic Calcium Signalling in Cerebellar Mossy Fibres

    PubMed Central

    Thomsen, Louiza B.; Jörntell, Henrik; Midtgaard, Jens

    2009-01-01

    Whole-cell recordings were obtained from mossy fibre terminals in adult turtles in order to characterize the basic membrane properties. Calcium imaging of presynaptic calcium signals was carried out in order to analyse calcium dynamics and presynaptic GABA B inhibition. A tetrodotoxin (TTX)-sensitive fast Na+ spike faithfully followed repetitive depolarizing pulses with little change in spike duration or amplitude, while a strong outward rectification dominated responses to long-lasting depolarizations. High-threshold calcium spikes were uncovered following addition of potassium channel blockers. Calcium imaging using Calcium-Green dextran revealed a stimulus-evoked all-or-none TTX-sensitive calcium signal in simple and complex rosettes. All compartments of a complex rosette were activated during electrical activation of the mossy fibre, while individual simple and complex rosettes along an axon appeared to be isolated from one another in terms of calcium signalling. CGP55845 application showed that GABA B receptors mediated presynaptic inhibition of the calcium signal over the entire firing frequency range of mossy fibres. A paired-pulse depression of the calcium signal lasting more than 1 s affected burst firing in mossy fibres; this paired-pulse depression was reduced by GABA B antagonists. While our results indicated that a presynaptic rosette electrophysiologically functioned as a unit, topical GABA application showed that calcium signals in the branches of complex rosettes could be modulated locally, suggesting that cerebellar glomeruli may be dynamically sub-compartmentalized due to ongoing inhibition mediated by Golgi cells. This could provide a fine-grained control of mossy fibre-granule cell information transfer and synaptic plasticity within a mossy fibre rosette. PMID:20162034

  8. Behavioral effects of neonatal lesions on the cerebellar system.

    PubMed

    Lalonde, Robert; Strazielle, Catherine

    2015-06-01

    Several rodent models with spontaneous mutations causing cerebellar pathology are impaired in motor functions during the neonatal period, including Grid2(Lc), Rora(sg), Dab1(scm), Girk2(Wv), Lmx1a(dr-sst), Myo5a(dn), Inpp4a(wbl), and Cacna1a(rol) mice as well as shaker and dystonic rats. Deficits are also evident in murine null mutants such as Zic1, Fgfr1/FgFr2, and Xpa/Ercc8. Behavioral deficits are time-dependent following X-irradiated- or aspiration-induced lesions of the cerebellum in rats. In addition, motor functions are deficient after lesions in cerebellar-related pathways. As in animal subjects, sensorimotor disturbances have been described in children with cerebellar lesions. These results underline the importance of the cerebellum and its connections in the development of motor functions.

  9. Excitatory Cerebellar Nucleocortical Circuit Provides Internal Amplification during Associative Conditioning

    PubMed Central

    Gao, Zhenyu; Proietti-Onori, Martina; Lin, Zhanmin; ten Brinke, Michiel M.; Boele, Henk-Jan; Potters, Jan-Willem; Ruigrok, Tom J.H.; Hoebeek, Freek E.; De Zeeuw, Chris I.

    2016-01-01

    Summary Closed-loop circuitries between cortical and subcortical regions can facilitate precision of output patterns, but the role of such networks in the cerebellum remains to be elucidated. Here, we characterize the role of internal feedback from the cerebellar nuclei to the cerebellar cortex in classical eyeblink conditioning. We find that excitatory output neurons in the interposed nucleus provide efference-copy signals via mossy fibers to the cerebellar cortical zones that belong to the same module, triggering monosynaptic responses in granule and Golgi cells and indirectly inhibiting Purkinje cells. Upon conditioning, the local density of nucleocortical mossy fiber terminals significantly increases. Optogenetic activation and inhibition of nucleocortical fibers in conditioned animals increases and decreases the amplitude of learned eyeblink responses, respectively. Our data show that the excitatory nucleocortical closed-loop circuitry of the cerebellum relays a corollary discharge of premotor signals and suggests an amplifying role of this circuitry in controlling associative motor learning. PMID:26844836

  10. Preterm cerebellar growth impairment after postnatal exposure to glucocorticoids.

    PubMed

    Tam, Emily W Y; Chau, Vann; Ferriero, Donna M; Barkovich, A James; Poskitt, Kenneth J; Studholme, Colin; Fok, Eric D-Y; Grunau, Ruth E; Glidden, David V; Miller, Steven P

    2011-10-19

    As survival rates of preterm newborns improve as a result of better medical management, these children increasingly show impaired cognition. These adverse cognitive outcomes are associated with decreases in the volume of the cerebellum. Because animals exhibit reduced preterm cerebellar growth after perinatal exposure to glucocorticoids, we sought to determine whether glucocorticoid exposure and other modifiable factors increased the risk for these adverse outcomes in human neonates. We studied 172 preterm neonatal infants from two medical centers, the University of British Columbia and the University of California, San Francisco, by performing serial magnetic resonance imaging examinations near birth and again near term-equivalent age. After we adjusted for associated clinical factors, antenatal betamethasone was not associated with changes in cerebellar volume. Postnatal exposure to clinically routine doses of hydrocortisone or dexamethasone was associated with impaired cerebellar, but not cerebral, growth. Alterations in treatment after preterm birth, particularly glucocorticoid exposure, may help to decrease risk for adverse neurological outcome after preterm birth.

  11. Cerebellar Development and Autism Spectrum Disorder in Tuberous Sclerosis Complex.

    PubMed

    Sundberg, Maria; Sahin, Mustafa

    2015-12-01

    Approximately 50% of patients with the genetic disease tuberous sclerosis complex present with autism spectrum disorder. Although a number of studies have investigated the link between autism and tuberous sclerosis complex, the etiology of autism spectrum disorder in these patients remains unclear. Abnormal cerebellar function during critical phases of development could disrupt functional processes in the brain, leading to development of autistic features. Accordingly, the authors review the potential role of cerebellar dysfunction in the pathogenesis of autism spectrum disorder in tuberous sclerosis complex. The authors also introduce conditional knockout mouse models of Tsc1 and Tsc2 that link cerebellar circuitry to the development of autistic-like features. Taken together, these preclinical and clinical investigations indicate the cerebellum has a profound regulatory role during development of social communication and repetitive behaviors.

  12. Cholinergic afferents to the locus coeruleus and noradrenergic afferents to the medial septum mediate LTP-reinforcement in the dentate gyrus by stimulation of the amygdala.

    PubMed

    Bergado, Jorge A; Frey, Sabine; López, Jeffrey; Almaguer-Melian, William; Frey, Julietta U

    2007-10-01

    Transient long-term potentiation (E-LTP) can be transformed into a long-lasting LTP (L-LTP) in the dentate gyrus (DG) by behavioral stimuli with high motivational content. Previous research from our group has identified several brain structures, such as the basolateral amygdala (BLA), the locus coeruleus (LC), the medial septum (MS) and transmitters as noradrenaline (NA) and acetylcholine (ACh) that are involved in these processes. Here we have investigated the functional interplay among brain structures and systems which result in the conversion of a E-LTP into a L-LTP (reinforcement) by stimulation of the BLA (BLA-R). We used topical application of specific drugs into DG, and other targets, while following the time course of LTP induced by stimulation of the perforant pathway (PP) to study their specific contribution to BLA-R. One injection cannula, a recording electrode in the DG and stimulating electrodes in the PP and the BLA were stereotactically implanted one week before electrophysiological experiments. Topical application of atropine or propranolol into the DG blocked BLA-R in both cases, but the effect of propranolol occurred earlier, suggesting a role of NA within the DG during an intermediate stage of LTP maintenance. The injection of lidocaine into the LC abolished BLA-R indicating that the LC is part of the functional neural reinforcing system. The effect on the LC is mediated by cholinergic afferents because application of atropine into the LC produced the same effect. Injection of lidocaine inactivating the MS also abolished BLA-R. This effect was mediated by noradrenergic afferents (probably from the LC) because the application of propranolol into the MS prevented BLA-R. These findings suggest a functional loop for BLA-R involving cholinergic afferents to the LC, a noradrenergic projection from the LC to the DG and the MS, and finally, the cholinergic projection from the MS to the DG.

  13. Postsynaptic, not presynaptic NMDA receptors are required for spike timing dependent LTD induction

    PubMed Central

    Carter, Brett C.; Jahr, Craig E.

    2016-01-01

    Long-term depression (LTD) between cortical layer 4 spiny stellate cells and layer 2/3 pyramidal cells requires the activation of NMDA receptors (NMDARs). In young rodents, this form of LTD has been repeatedly reported to require presynaptic NMDARs for its induction. Here we show that at this synapse in the somatosensory cortex of 2 to 3 week old rats and mice, postsynaptic, not presynaptic NMDARs are required for LTD induction. First, we find no evidence for functional NMDARs in L4 neuron axons using 2 photon laser scanning microscopy and 2 photon glutamate uncaging. Second, we find that genetic deletion of postsynaptic, but not presynaptic NMDARs prevents LTD induction. Finally, the pharmacology of the NMDAR requirement is consistent with a non-ionic signaling mechanism. PMID:27399842

  14. Influences of morphine on the spontaneous and evoked excitatory postsynaptic currents in lateral amygdala of rats.

    PubMed

    Zhang, J-J; Liu, X-D; Yu, L-C

    2016-01-01

    Acute morphine exposure induces antinociceptive activity, but the underlying mechanisms in the central nervous system are unclear. Using whole-cell patch clamp recordings, we explore the role of morphine in the modulation of excitatory synaptic transmission in lateral amygdala neurons of rats. The results demonstrate that perfusion of 10 microM of morphine to the lateral amygdala inhibits the discharge frequency significantly. We further find that there are no significant influences of morphine on the amplitude of spontaneous excitatory postsynaptic currents (sEPSCs). Interestingly, morphine shows no marked influence on the evoked excitatory postsynaptic currents (eEPSCs) in the lateral amygdala neurons. These results indicate that acute morphine treatment plays an important role in the modulation on the excitatory synaptic transmission in lateral amygdala neurons of rats.

  15. [Properties of spontaneous and miniature excitatory postsynaptic currents of rat prefrontal cortex neurons].

    PubMed

    Malkin, S L; Kim, K Kh; Tikhonov, D B; Zaitsev, A V

    2014-01-01

    Quantum analysis of postsynaptic currents is important for fundamental and applied studies of synaptic transmission. In the present work, we investigated the possibility of using the characteristics of spontaneous excitatory postsynaptic currents (EPSCs) for estimation of quantum parameters of excitatory synaptic transmission in different types of neurons from rat prefrontal cortex slices. By blocking spontaneous spiking activity in slices by tetrodotoxin, we showed that spontaneous and miniature EPSCs in prefrontal cortex neurons did not differ by their properties. Thereby, both spontaneous and miniature responses can be used for estimation of quantum parameters of excitatory synaptic transmission in this preparation. We also revealed that excitatory spontaneous responses of pyramidal cells were 2 times lower by amplitude, had twice lower the coefficient of variation and exhibited much slower kinetics than responses of the fast-spiking and regular-spiking interneurons. Possible mechanisms of these differences are considered.

  16. [The features of postsynaptic currents in primary culture of rat cortical neurons].

    PubMed

    Sibarov, D A; Antonov, S M

    2013-06-01

    The generation features of postsynaptic currents were studied in primary culture of cortical neurons at 7-20 days in vitro (DIV). The use of specific blockers of postsynaptic ion channels after 10 DIV revealed all types of electrical activity found in adult cortex including miniature inhibitory (mIPSCs), excitatory (mEPSCs) and spontaneous giant excitatory currents and spikes. The frequency of mEPSCs increased exponentially from 7 to 20 DIV doubling every 2.2 days in parallel with changes in action potentials generation. The mEPSCs generated by NMDA and AMPA or by only AMPA receptor activation were found. The inhibition of NMDA receptors by magnesium ions or AP5 were shown to modulate the frequency and amplitude of mEPSCs, which differ primary culture from brain slices possibly because of the lack of glial control of synaptic transmission.

  17. Presence of a voltage-dependent anion channel 1 in the rat postsynaptic density fraction.

    PubMed

    Moon, J I; Jung, Y W; Ko, B H; De Pinto, V; Jin, I; Moon, I S

    1999-02-25

    Little is known about the molecular organization and functions of the postsynaptic density (PSD), a cytoskeletal specialization on the postsynaptic membrane. In an attempt to elucidate the protein composition of PSD, we have sequenced a 35 kDa protein of the rat forebrain PSD fraction. Amino acid sequence information of the tryptic peptides and immunoblot analyses revealed that the protein is a voltage-dependent anion channel 1 (VDAC1). VDAC1 was enriched in the PSD fraction and was partially soluble in 1% n-octyl glucoside (NOG) or Triton X-100. Our data indicate that VDAC1, which is originally found in the outer mitochondrial membrane, is also present in the central nervous system (CNS) synapses in association with the PSD 'core'.

  18. [The correlation between postsynaptic inhibition and GABA, opioid peptides, SP in electroacupuncture].

    PubMed

    Fang, Z; Yu, Q; Li, Y

    1993-01-01

    Identified tract cells in lumbar enlargement were recorded from intact anaesthetized rats. The prolongation of the latency of antidromic action potential was a measure of postsynaptic inhibition. Both ST 36 and SP 6 were stimulated electrically. In EA group (N = 12) EA prolonged the latency for 0.111 +/- 0.022 ms (P < 0.001). In bicuculline group (N = 12) the prolongation of the latency for 0.010 +/- 0.004 ms (P < 0.05) by EA was less than that of EA group with statistical significance. In naloxone group (N = 12) and SP antiserum group (N = 12) EA did not induce a significant prolongation of the latency. It suggested that GABA, opioides and SP might be involved in postsynaptic inhibition induced by EA.

  19. A composite neurobehavioral test to evaluate acute functional deficits after cerebellar haemorrhage in rats.

    PubMed

    McBride, Devin W; Nowrangi, Derek; Kaur, Harpreet; Wu, Guangyong; Huang, Lei; Lekic, Tim; Tang, Jiping; Zhang, John H

    2017-01-01

    Cerebellar haemorrhage accounts for 5-10% of all intracerebral haemorrhages and leads to severe, long-lasting functional deficits. Currently, there is limited research on this stroke subtype, which may be due to the lack of a suitable composite neuroscoring system specific for cerebellar injury in rodents. The purpose of this study is to develop a comprehensive composite neuroscore test for cerebellar injury using a rat model of cerebellar haemorrhage. Sixty male Sprague-Dawley rats were subjected to either sham surgery or cerebellar haemorrhage. Twenty-four hours post-injury, neurological behaviour was evaluated using 17 cost-effective and easy-to-perform tests, and a composite neuroscore was developed. The composite neuroscore was then used to assess functional recovery over seven days after cerebellar haemorrhage. Differences in the composite neuroscore deficits for the mild and moderate cerebellar haemorrhage models were observed for up to five days post-ictus. Until now, a composite neuroscore for cerebellar injury was not available for rodent studies. Herein, using mild and moderate cerebellar haemorrhage rat models a composite neuroscore for cerebellar injury was developed and used to assess functional deficits after cerebellar haemorrhage. This composite neuroscore may also be useful for other cerebellar injury models.

  20. 3D morphometric analysis of human fetal cerebellar development.

    PubMed

    Scott, Julia A; Hamzelou, Kia S; Rajagopalan, Vidya; Habas, Piotr A; Kim, Kio; Barkovich, A James; Glenn, Orit A; Studholme, Colin

    2012-09-01

    To date, growth of the human fetal cerebellum has been estimated primarily from linear measurements from ultrasound and 2D magnetic resonance imaging (MRI). In this study, we use 3D analytical methods to develop normative growth trajectories for the cerebellum in utero. We measured cerebellar volume, linear dimensions, and local surface curvature from 3D reconstructed MRI of the human fetal brain (N = 46). We found that cerebellar volume increased approximately 7-fold from 20 to 31 gestational weeks. The better fit of the exponential curve (R (2) = 0.96) compared to the linear curve (R (2) = 0.92) indicated acceleration in growth. Within-subject cerebellar and cerebral volumes were highly correlated (R (2) = 0.94), though the cerebellar percentage of total brain volume increased from approximately 2.4% to 3.7% (R (2) = 0.63). Right and left hemispheric volumes did not significantly differ. Transcerebellar diameter, vermal height, and vermal anterior to posterior diameter increased significantly at constant rates. From the local curvature analysis, we found that expansion along the inferior and superior aspects of the hemispheres resulted in decreased convexity, which is likely due to the physical constraints of the dura surrounding the cerebellum and the adjacent brainstem. The paired decrease in convexity along the inferior vermis and increased convexity of the medial hemisphere represents development of the paravermian fissure, which becomes more visible during this period. In this 3D morphometric analysis of the human fetal cerebellum, we have shown that cerebellar growth is accelerating at a greater pace than the cerebrum and described how cerebellar growth impacts the shape of the structure.

  1. 3D Morphometric Analysis of Human Fetal Cerebellar Development

    PubMed Central

    Hamzelou, Kia S.; Rajagopalan, Vidya; Habas, Piotr A.; Kim, Kio; Barkovich, A. James; Glenn, Orit A.; Studholme, Colin

    2012-01-01

    To date, growth of the human fetal cerebellum has been estimated primarily from linear measurements from ultrasound and 2D magnetic resonance imaging (MRI). In this study, we use 3D analytical methods to develop normative growth trajectories for the cerebellum in utero. We measured cerebellar volume, linear dimensions, and local surface curvature from 3D reconstructed MRI of the human fetal brain (N = 46). We found that cerebellar volume increased approximately 7-fold from 20 to 31 gestational weeks. The better fit of the exponential curve (R2 = 0.96) compared to the linear curve (R2 = 0.92) indicated acceleration in growth. Within-subject cerebellar and cerebral volumes were highly correlated (R2 = 0.94), though the cerebellar percentage of total brain volume increased from approximately 2.4% to 3.7% (R2 = 0.63). Right and left hemispheric volumes did not significantly differ. Transcerebellar diameter, vermal height, and vermal anterior to posterior diameter increased significantly at constant rates. From the local curvature analysis, we found that expansion along the inferior and superior aspects of the hemispheres resulted in decreased convexity, which is likely due to the physical constraints of the dura surrounding the cerebellum and the adjacent brainstem. The paired decrease in convexity along the inferior vermis and increased convexity of the medial hemisphere represents development of the paravermian fissure, which becomes more visible during this period. In this 3D morphometric analysis of the human fetal cerebellum, we have shown that cerebellar growth is accelerating at a greater pace than the cerebrum and described how cerebellar growth impacts the shape of the structure. PMID:22198870

  2. Intrinsic conductances actively shape excitatory and inhibitory postsynaptic responses in olfactory bulb external tufted cells.

    PubMed

    Liu, Shaolin; Shipley, Michael T

    2008-10-08

    The initial synapse in the olfactory system is from olfactory nerve (ON) terminals to postsynaptic targets in olfactory bulb glomeruli. Recent studies have disclosed multiple presynaptic factors that regulate this important linkage, but less is known about the contribution of postsynaptic intrinsic conductances to integration at these synapses. The present study demonstrates voltage-dependent amplification of EPSPs in external tufted (ET) cells in response to monosynaptic (ON) inputs. This amplification is mainly exerted by persistent Na(+) conductance. Larger EPSPs, which bring the membrane potential to a relatively depolarized level, are further boosted by the low-voltage-activated Ca(2+) conductance. In contrast, the hyperpolarization-activated nonselective cation conductance (I(h)) attenuates EPSPs mainly by reducing EPSP duration; this also reduces temporal summation of multiple EPSPs. Regulation of EPSPs by these subthreshold, voltage-dependent conductances can enhance both the signal-to-noise ratio and the temporal summation of multiple synaptic inputs and thus help ET cells differentiate high- and low-frequency synaptic inputs. I(h) can also transform inhibitory inputs to postsynaptic excitation. When the ET cell membrane potential is relatively depolarized, as during a burst of action potentials, IPSPs produce classic inhibition. However, near resting membrane potentials where I(h) is engaged, IPSPs produce rebound bursts of action potentials. ET cells excite GABAergic PG cells. Thus, the transformation of inhibitory inputs to postsynaptic excitation in ET cells may enhance intraglomerular inhibition of mitral/tufted cells, the main output neurons in the olfactory bulb, and hence shape signaling to olfactory cortex.

  3. Release probability-dependent scaling of the postsynaptic responses at single hippocampal GABAergic synapses.

    PubMed

    Biró, Agota A; Holderith, Noémi B; Nusser, Zoltan

    2006-11-29

    The amount of neurotransmitter released after the arrival of an action potential affects the strength and the trial-to-trial variability of postsynaptic responses. Most studies examining the dependence of synaptic neurotransmitter concentration on the release probability (P(r)) have focused on glutamatergic synapses. Here we asked whether univesicular or multivesicular release characterizes transmission at hippocampal GABAergic synapses. We used multiple probability functional analysis to derive quantal parameters at inhibitory connections between cannabinoid receptor- and cholecystokinin (CCK)-expressing interneurons and CA3 pyramidal cells. After the recordings, the cells were visualized and reconstructed at the light-microscopic level, and the number of boutons mediating the IPSCs was determined using electron microscopy (EM). The number of active zones (AZs) per CCK-immunopositive bouton was determined from three-dimensional EM reconstructions, thus allowing the calculation of the total number of AZs for each pair. Our results reveal an approximate fivefold discrepancy between the numbers of functionally determined release sites (17.4 +/- 3.2) and structurally identified AZs (3.7 +/- 0.9). Channel modeling predicts that a fivefold to sevenfold increase in the peak synaptic GABA concentration is required for the fivefold enhancement of the postsynaptic responses. Kinetic analysis of the unitary IPSCs indicates that the increase in synaptic GABA concentration is most likely attributable to multivesicular release. This change in the synaptic GABA concentration transient together with extremely low postsynaptic receptor occupancy permits a P(r)-dependent scaling of the postsynaptic response generated at a single hippocampal GABAergic synaptic contact.

  4. Postsynaptic glutamate receptors regulate local BMP signaling at the Drosophila neuromuscular junction.

    PubMed

    Sulkowski, Mikolaj; Kim, Young-Jun; Serpe, Mihaela

    2014-01-01

    Effective communication between pre- and postsynaptic compartments is required for proper synapse development and function. At the Drosophila neuromuscular junction (NMJ), a retrograde BMP signal functions to promote synapse growth, stability and homeostasis and coordinates the growth of synaptic structures. Retrograde BMP signaling triggers accumulation of the pathway effector pMad in motoneuron nuclei and at synaptic termini. Nuclear pMad, in conjunction with transcription factors, modulates the expression of target genes and instructs synaptic growth; a role for synaptic pMad remains to be determined. Here, we report that pMad signals are selectively lost at NMJ synapses with reduced postsynaptic sensitivities. Despite this loss of synaptic pMad, nuclear pMad persisted in motoneuron nuclei, and expression of BMP target genes was unaffected, indicating a specific impairment in pMad production/maintenance at synaptic termini. During development, synaptic pMad accumulation followed the arrival and clustering of ionotropic glutamate receptors (iGluRs) at NMJ synapses. Synaptic pMad was lost at NMJ synapses developing at suboptimal levels of iGluRs and Neto, an auxiliary subunit required for functional iGluRs. Genetic manipulations of non-essential iGluR subunits revealed that synaptic pMad signals specifically correlated with the postsynaptic type-A glutamate receptors. Altering type-A receptor activities via protein kinase A (PKA) revealed that synaptic pMad depends on the activity and not the net levels of postsynaptic type-A receptors. Thus, synaptic pMad functions as a local sensor for NMJ synapse activity and has the potential to coordinate synaptic activity with a BMP retrograde signal required for synapse growth and homeostasis.

  5. Burst firing induces postsynaptic LTD at developing mossy fibre–CA3 pyramid synapses

    PubMed Central

    Ho, T M; Pelkey, K A; Pelletier, J G; Huganir, R L; Lacaille, J-C; McBain, C J

    2009-01-01

    Synaptic development is an activity-dependent process utilizing coordinated network activity to drive synaptogenesis and subsequent refinement of immature connections. Hippocampal CA3 pyramidal neurons (PYRs) exhibit intense burst firing (BF) early in development, concomitant with the period of mossy fibre (MF) development. However, whether developing MF–PYR synapses utilize PYR BF to promote MF synapse maturation remains unknown. Recently, we demonstrated that transient tonic depolarization of postsynaptic PYRs induces a persistent postsynaptic form of long-term depression (depolarization-induced long-term depression, DiLTD) at immature MF–PYR synapses. DiLTD induction is NMDAR independent but does require postsynaptic Ca2+ influx through L-type voltage gated Ca2+ channels (L-VGCCs), and is expressed as a reduction in AMPAR function through the loss of GluR2-lacking AMPARs present at immature MF–PYR synapses. Here we examined whether more physiologically relevant phasic L-VGCC activation by PYR action potential (AP) BF activity patterns can trigger DiLTD. Using combined electrophysiological and Ca2+ imaging approaches we demonstrate that PYR BF effectively drives L-VGCC activation and that brief periods of repetitive PYR BF, produced by direct current injection or intrinsic network activity induces NMDAR-independent LTD by promoting Ca2+ influx through the activated L-VGCCs. This BF induced LTD, just like DiLTD, is specific for developing MF–PYR synapses, is PICK1 dependent, and is expressed postsynaptically. Our results demonstrate that DiLTD can be induced by phasic L-VGCC activation driven by PYR BF, suggesting the engagement of natural PYR network activity patterns for MF synapse maturation. PMID:19635819

  6. Ca2+ signalling in postsynaptic dendrites and spines of mammalian neurons in brain slice.

    PubMed

    Müller, W; Connor, J A

    1992-01-01

    Postsynaptic Ca2+ changes are involved in control of cellular excitability and induction of synaptic long-term changes. We monitored Ca2+ changes in dendrites and spines during synaptic and direct stimulation using high resolution microfluorometry of fura-2 injected into CA3 pyramidal neurons in guinea pig hippocampal slice. When driven by current injection from an intracellular electrode or with synaptic stimulation, postsynaptic Ca2+ accumulations were highest in the proximal dendrites with a pronounced fall-off towards the soma and some fall-off towards more distal dendrites. Muscarinic activation by low concentrations of carbachol strongly increased intradendritic Ca2+ accumulation during directly-evoked repetitive firing. This enhancement occurred in large part because muscarinic activation suppressed the normal Ca(2+)-dependent activation of K-channels that mediates adaptation of firing. Repetitive firing of cholinergic fibers in the slice reproduced the effects of carbachol. Inhibition of acetylcholine-esterase activity by eserine enhanced the effects of repetitive stimulation of chlolinergic fibers. All effects were reversible and were blocked by the muscarinic antagonist atropine. Ca2+ accumulations in postsynaptic spines might be the basis of specificity of synaptic plasticity. With selective stimulation of few associative/comissural fibers, Ca2+ accumulated in single postsynaptic spines but not in the parent dendrite. With strong stimulation, dendrite levels also increased but spine levels were considerably higher. The NMDA-receptor antagonist AP-5 blocked Ca(2+)-peaks in spines, but left Ca2+ changes in dendrite shafts largely unaffected. Sustained steep Ca2+ gradients between single spines and the parent dendrite, often lasting several minutes, developed with repeated stimulation. Our results demonstrate a spine entity that can act independent from the dendrite with respect to Ca(2+)-dependent processes. Muscarinic augmentation of dendritic Ca2+ levels

  7. ATP P2X receptors downregulate AMPA receptor trafficking and postsynaptic efficacy in hippocampal neurons.

    PubMed

    Pougnet, Johan-Till; Toulme, Estelle; Martinez, Audrey; Choquet, Daniel; Hosy, Eric; Boué-Grabot, Eric

    2014-07-16

    P2X receptors (P2XRs) are ATP-gated cation channels widely expressed in the brain where they mediate action of extracellular ATP released by neurons or glia. Although purinergic signaling has multiple effects on synaptic transmission and plasticity, P2XR function at brain synapses remains to be established. Here, we show that activation of postsynaptic P2XRs by exogenous ATP or noradrenaline-dependent glial release of endogenous ATP decreases the amplitude of miniature excitatory postsynaptic currents and AMPA-evoked currents in cultured hippocampal neurons. We also observed a P2X-mediated depression of field potentials recorded in CA1 region from brain slices. P2X2Rs trigger dynamin-dependent internalization of AMPA receptors (AMPARs), leading to reduced surface AMPARs in dendrites and at synapses. AMPAR alteration required calcium influx through opened ATP-gated channels and phosphatase or CamKII activities. These findings indicate that postsynaptic P2XRs play a critical role in regulating the surface expression of AMPARs and thereby regulate the synaptic strength.

  8. Fast, automated implementation of temporally precise blind deconvolution of multiphasic excitatory postsynaptic currents.

    PubMed

    Andor-Ardó, Daniel; Keen, Erica C; Hudspeth, A J; Magnasco, Marcelo O

    2012-01-01

    Records of excitatory postsynaptic currents (EPSCs) are often complex, with overlapping signals that display a large range of amplitudes. Statistical analysis of the kinetics and amplitudes of such complex EPSCs is nonetheless essential to the understanding of transmitter release. We therefore developed a maximum-likelihood blind deconvolution algorithm to detect exocytotic events in complex EPSC records. The algorithm is capable of characterizing the kinetics of the prototypical EPSC as well as delineating individual release events at higher temporal resolution than other extant methods. The approach also accommodates data with low signal-to-noise ratios and those with substantial overlaps between events. We demonstrated the algorithm's efficacy on paired whole-cell electrode recordings and synthetic data of high complexity. Using the algorithm to align EPSCs, we characterized their kinetics in a parameter-free way. Combining this approach with maximum-entropy deconvolution, we were able to identify independent release events in complex records at a temporal resolution of less than 250 µs. We determined that the increase in total postsynaptic current associated with depolarization of the presynaptic cell stems primarily from an increase in the rate of EPSCs rather than an increase in their amplitude. Finally, we found that fluctuations owing to postsynaptic receptor kinetics and experimental noise, as well as the model dependence of the deconvolution process, explain our inability to observe quantized peaks in histograms of EPSC amplitudes from physiological recordings.

  9. [Postsynaptic reactions of cerebral cortex neurons, activated by nociceptive afferents during stimulation of the Raphe nuclei].

    PubMed

    Labakhua, T Sh; Dzhanashiia, T K; Gedevanishvili, G I; Dzhokhadze, L D; Tkemaladze, T T; Abzianidze, I V

    2012-01-01

    On cats, we studied the influence of stimulation of the Raphe nuclei (RN) on postsynaptic processes evoked in neurons of the somatosensory cortex by stimulation of nociceptive (intensive stimulation of the tooth pulp) and non-nociceptive (moderate stimulation of the ventroposteromedial--VPN--nucleus of the thalamus) afferent inputs. 6 cells, selectively excited by stimulation of nocciceptors and 9 cells, activated by both the above nociceptive and non-nociceptive influences (nociceptive and convergent neurons, respectively) were recorded intracellular. In neurons of both groups, responses to nociceptive stimulation (of sufficient intensity) looked like an EPSP-spike-IPSP (the letter of significant duration, up to 200-300 ms) compleх. Conditioning stimulation of the RN which preceded test stimulus applied to the tooth pulp or VPM nucleus by 100 to 800 ms, induced 40-60 % decrease of the IPSP amplitude only, while maхimal effect of influence, in both cases, was noted within intervals of 300-800 ms between conditioning and test stimulus. During stimulation of the RN, serotonin released via receptor and second messengers, provides postsynaptic modulation of GABAergic system, decreasing the IPSP amplitude which occurs after stimulation of both the tooth pulp and VPM thalamic nucleus. This process may be realized trough either pre- or postsynaptic mechanisms.

  10. Redundant Postsynaptic Functions of SynCAMs 1–3 during Synapse Formation

    PubMed Central

    Fowler, Daniel K.; Peters, James H.; Williams, Carly; Washbourne, Philip

    2017-01-01

    Investigating the roles of synaptogenic adhesion molecules during synapse formation has proven challenging, often due to compensatory functions between additional family members. The synaptic cell adhesion molecules 1–3 (SynCAM1–3) are expressed both pre- and postsynaptically, share highly homologous domains and are synaptogenic when ectopically presented to neurons; yet their endogenous functions during synaptogenesis are unclear. Here we report that SynCAM1–3 are functionally redundant and collectively necessary for synapse formation in cultured hippocampal neurons. Only triple knockdown (KD) of SynCAM1–3 using highly efficient, chained artificial microRNAs (amiRNAs) reduced synapse density and increased synapse area. Electrophysiological recordings of quantal release events supported an increase in synapse size caused by SynCAM1–3 depletion. Furthermore, a combinatorial, mosaic lentiviral approach comparing wild type (WT) and SynCAM1–3 KD neurons in the same culture demonstrate that SynCAM1–3 set synapse number and size through postsynaptic mechanisms. The results demonstrate that the redundancy between SynCAM1–3 has concealed their synaptogenic function at the postsynaptic terminal. PMID:28197078

  11. Ral mediates activity-dependent growth of postsynaptic membranes via recruitment of the exocyst

    PubMed Central

    Teodoro, Rita O; Pekkurnaz, Gulçin; Nasser, Abdullah; Higashi-Kovtun, Misao E; Balakireva, Maria; McLachlan, Ian G; Camonis, Jacques; Schwarz, Thomas L

    2013-01-01

    Remodelling neuronal connections by synaptic activity requires membrane trafficking. We present evidence for a signalling pathway by which synaptic activity and its consequent Ca2+ influx activate the small GTPase Ral and thereby recruit exocyst proteins to postsynaptic zones. In accord with the ability of the exocyst to direct delivery of post-Golgi vesicles, constitutively active Ral expressed in Drosophila muscle causes the exocyst to be concentrated in the region surrounding synaptic boutons and consequently enlarges the membrane folds of the postsynaptic plasma membrane (the subsynaptic reticulum, SSR). SSR growth requires Ral and the exocyst component Sec5 and Ral-induced enlargement of these membrane folds does not occur in sec5−/− muscles. Chronic changes in synaptic activity influence the plastic growth of this membrane in a manner consistent with activity-dependent activation of Ral. Thus, Ral regulation of the exocyst represents a control point for postsynaptic plasticity. This pathway may also function in mammals as expression of activated RalA in hippocampal neurons increases dendritic spine density in an exocyst-dependent manner and increases Sec5 in spines. PMID:23812009

  12. Activity-dependent Protein Dynamics Define Interconnected Cores of Co-regulated Postsynaptic Proteins*

    PubMed Central

    Trinidad, Jonathan C.; Thalhammer, Agnes; Burlingame, Alma L.; Schoepfer, Ralf

    2013-01-01

    Synapses are highly dynamic structures that mediate cell–cell communication in the central nervous system. Their molecular composition is altered in an activity-dependent fashion, which modulates the efficacy of subsequent synaptic transmission events. Whereas activity-dependent trafficking of individual key synaptic proteins into and out of the synapse has been characterized previously, global activity-dependent changes in the synaptic proteome have not been studied. To test the feasibility of carrying out an unbiased large-scale approach, we investigated alterations in the molecular composition of synaptic spines following mass stimulation of the central nervous system induced by pilocarpine. We observed widespread changes in relative synaptic abundances encompassing essentially all proteins, supporting the view that the molecular composition of the postsynaptic density is tightly regulated. In most cases, we observed that members of gene families displayed coordinate regulation even when they were not known to physically interact. Analysis of correlated synaptic localization revealed a tightly co-regulated cluster of proteins, consisting of mainly glutamate receptors and their adaptors. This cluster constitutes a functional core of the postsynaptic machinery, and changes in its size affect synaptic strength and synaptic size. Our data show that the unbiased investigation of activity-dependent signaling of the postsynaptic density proteome can offer valuable new information on synaptic plasticity. PMID:23035237

  13. Laminins promote postsynaptic maturation by an autocrine mechanism at the neuromuscular junction.

    PubMed

    Nishimune, Hiroshi; Valdez, Gregorio; Jarad, George; Moulson, Casey L; Müller, Ulrich; Miner, Jeffrey H; Sanes, Joshua R

    2008-09-22

    A prominent feature of synaptic maturation at the neuromuscular junction (NMJ) is the topological transformation of the acetylcholine receptor (AChR)-rich postsynaptic membrane from an ovoid plaque into a complex array of branches. We show here that laminins play an autocrine role in promoting this transformation. Laminins containing the alpha4, alpha5, and beta2 subunits are synthesized by muscle fibers and concentrated in the small portion of the basal lamina that passes through the synaptic cleft at the NMJ. Topological maturation of AChR clusters was delayed in targeted mutant mice lacking laminin alpha5 and arrested in mutants lacking both alpha4 and alpha5. Analysis of chimeric laminins in vivo and of mutant myotubes cultured aneurally demonstrated that the laminins act directly on muscle cells to promote postsynaptic maturation. Immunohistochemical studies in vivo and in vitro along with analysis of targeted mutants provide evidence that laminin-dependent aggregation of dystroglycan in the postsynaptic membrane is a key step in synaptic maturation. Another synaptically concentrated laminin receptor, Bcam, is dispensable. Together with previous studies implicating laminins as organizers of presynaptic differentiation, these results show that laminins coordinate post- with presynaptic maturation.

  14. Measurement and analysis of postsynaptic potentials using a novel voltage-deconvolution method.

    PubMed

    Richardson, Magnus J E; Silberberg, Gilad

    2008-02-01

    Accurate measurement of postsynaptic potential amplitudes is a central requirement for the quantification of synaptic strength, dynamics of short-term and long-term plasticity, and vesicle-release statistics. However, the intracellular voltage is a filtered version of the underlying synaptic signal and so a method of accounting for the distortion caused by overlapping postsynaptic potentials must be used. Here a voltage-deconvolution technique is demonstrated that defilters the entire voltage trace to reveal an underlying signal of well-separated synaptic events. These isolated events can be cropped out and reconvolved to yield a set of isolated postsynaptic potentials from which voltage amplitudes may be measured directly-greatly simplifying this common task. The method also has the significant advantage of providing a higher temporal resolution of the dynamics of the underlying synaptic signal. The versatility of the method is demonstrated by a variety of experimental examples, including excitatory and inhibitory connections to neurons with passive membranes and those with activated voltage-gated currents. The deconvolved current-clamp voltage has many features in common with voltage-clamp current measurements. These similarities are analyzed using cable theory and a multicompartment cell reconstruction, as well as direct comparison to voltage-clamp experiments.

  15. Colocalization of retinal dystrophin and actin in postsynaptic dendrites of rod and cone photoreceptor synapses.

    PubMed

    Schmitz, F; Holbach, M; Drenckhahn, D

    1993-12-01

    In this paper we demonstrate immunostaining specific for dystrophin in photoreceptor synapses of human, bovine and rat retinas. Cryosections of retinas incubated with dystrophin-specific monoclonal antibodies displayed a punctuate staining pattern in the outer plexiform layer. This pattern resulted from binding of the antibodies to synaptic complexes of both rods and cones, shown by double-labelling with antibodies to either synaptophysin or actin. Confocal laser fluorescence microscopy demonstrated that dystrophin staining colocalized predominantly with actin, which is concentrated in the postsynaptic portions of the synaptic complex. No significant dystrophin immunolabel was seen in the presynaptic terminals labelled with antibodies to synaptophysin, a marker of synaptic vesicles. Immunoblot analysis confirmed the presence of approximately 420 kDa and approximately 360 kDa dystrophin-like polypeptide bands associated with membranes of the bovine retina. We speculate that retinal dystrophin is involved in the linkage of actin filaments to the postsynaptic plasma membrane. Such a linkage may be important for the generation of synaptic microdomains and for certain phenomena of synaptic plasticity. The absence of dystrophin in patients suffering from Duchenne's muscular dystrophy is accompanied by visual problems and abnormalities of the electroretinogram. Therefore it is likely that retinal dystrophin plays a role in certain stages of synaptic transmission between photoreceptors and the postsynaptic dendritic complex formed by horizontal and bipolar cells.

  16. Postsynaptic Depolarization Enhances GABA Drive to Dorsomedial Hypothalamic Neurons through Somatodendritic Cholecystokinin Release.

    PubMed

    Crosby, Karen M; Baimoukhametova, Dinara V; Bains, Jaideep S; Pittman, Quentin J

    2015-09-23

    Somatodendritically released peptides alter synaptic function through a variety of mechanisms, including autocrine actions that liberate retrograde transmitters. Cholecystokinin (CCK) is a neuropeptide expressed in neurons in the dorsomedial hypothalamic nucleus (DMH), a region implicated in satiety and stress. There are clear demonstrations that exogenous CCK modulates food intake and neuropeptide expression in the DMH, but there is no information on how endogenous CCK alters synaptic properties. Here, we provide the first report of somatodendritic release of CCK in the brain in male Sprague Dawley rats. CCK is released from DMH neurons in response to repeated postsynaptic depolarizations, and acts in an autocrine fashion on CCK2 receptors to enhance postsynaptic NMDA receptor function and liberate the retrograde transmitter, nitric oxide (NO). NO subsequently acts presynaptically to enhance GABA release through a soluble guanylate cyclase-mediated pathway. These data provide the first demonstration of synaptic actions of somatodendritically released CCK in the hypothalamus and reveal a new form of retrograde plasticity, depolarization-induced potentiation of inhibition. Significance statement: Somatodendritic signaling using endocannabinoids or nitric oxide to alter the efficacy of afferent transmission is well established. Despite early convincing evidence for somatodendritic release of neurohypophysial peptides in the hypothalamus, there is only limited evidence for this mode of release for other peptides. Here, we provide the first evidence for somatodendritic release of the satiety peptide cholecystokinin (CCK) in the brain. We also reveal a new form of synaptic plasticity in which postsynaptic depolarization results in enhancement of inhibition through the somatodendritic release of CCK.

  17. Shisa6 traps AMPA receptors at postsynaptic sites and prevents their desensitization during synaptic activity

    PubMed Central

    Klaassen, Remco V.; Stroeder, Jasper; Coussen, Françoise; Hafner, Anne-Sophie; Petersen, Jennifer D.; Renancio, Cedric; Schmitz, Leanne J. M.; Normand, Elisabeth; Lodder, Johannes C.; Rotaru, Diana C.; Rao-Ruiz, Priyanka; Spijker, Sabine; Mansvelder, Huibert D.; Choquet, Daniel; Smit, August B.

    2016-01-01

    Trafficking and biophysical properties of AMPA receptors (AMPARs) in the brain depend on interactions with associated proteins. We identify Shisa6, a single transmembrane protein, as a stable and directly interacting bona fide AMPAR auxiliary subunit. Shisa6 is enriched at hippocampal postsynaptic membranes and co-localizes with AMPARs. The Shisa6 C-terminus harbours a PDZ domain ligand that binds to PSD-95, constraining mobility of AMPARs in the plasma membrane and confining them to postsynaptic densities. Shisa6 expressed in HEK293 cells alters GluA1- and GluA2-mediated currents by prolonging decay times and decreasing the extent of AMPAR desensitization, while slowing the rate of recovery from desensitization. Using gene deletion, we show that Shisa6 increases rise and decay times of hippocampal CA1 miniature excitatory postsynaptic currents (mEPSCs). Shisa6-containing AMPARs show prominent sustained currents, indicating protection from full desensitization. Accordingly, Shisa6 prevents synaptically trapped AMPARs from depression at high-frequency synaptic transmission. PMID:26931375

  18. Long-term enhancement (LTE) of postsynaptic potentials following neural conditioning, in mammalian sympathetic ganglia.

    PubMed

    Libet, B; Mochida, S

    1988-11-15

    Orthodromic, preganglionic conditioning stimulation can consistently induce long-term enhancement (LTE) (greater than 3 h) of the muscarinically mediated slow excitatory postsynaptic potential and the slow inhibitory postsynaptic potential. This was shown for superior cervical ganglia of rabbit and rat. Effective conditioning stimuli are in a physiologically observed range (3/s for 7 min, 5/s for 4 min, 10/s for 2 min, 20/s for 1 min). LTE was producible both homosynaptically and heterosynaptically. LTE can thus be associative, with conditioning synaptic input in one line inducing long-term changes in postsynaptic responses to another (heterosynaptic) input. The dopamine antagonist butaclamol depressed LTE, particularly that following the initial postconditioning period of 30 min. Adrenergic antagonists had no effect. This pharmacological evidence, coupled with the heterosynaptic induction of LTE, supports the view that neurally induced LTE may be at least partly mediated by endogenous dopamine. Another non-cholinergic but non-adrenergic transmitter (possibly a peptide) might contribute to the LTE seen in the initial 30 min postconditioning. The present, orthodromically induced LTE is clearly different from the long-term potentiation widely studied in hippocampus, etc., in the modes of induction and synaptic mediation.

  19. Cerebellar cysts in children: a pattern recognition approach.

    PubMed

    Boltshauser, Eugen; Scheer, Ianina; Huisman, Thierry A G M; Poretti, Andrea

    2015-06-01

    Cerebellar cysts may be seen in selected genetic disorders and acquired anomalies. Here, we review our experience, excluding cystic tumors and parasitic cysts. The pathogenesis is heterogeneous: Cysts may involve/represent normal structures (e.g., Virchow-Robin spaces), be "destructive" (such as in some types of pontocerebellar hypoplasias), "malformative" (such as in some forms of congenital muscular dystrophies and GPR56-related migration disorders), or "disruptive" (such as in some cerebellar dysplasias). The provided checklist may be useful in deciding targeted diagnostic workup.

  20. Paraneoplastic cerebellar degeneration as a marker of endometrial cancer recurrence.

    PubMed

    Lie, Geoffrey; Morley, Thomas; Chowdhury, Muhammad

    2016-05-18

    An 84-year-old woman developed a cerebellar syndrome having undergone a total abdominal hysterectomy and bilateral salpingo-oophorectomy for endometrial cancer 1 year previously. She was found to be anti-Yo antibody positive and was diagnosed with paraneoplastic cerebellar degeneration (PCD). A subsequent positron emission tomography scan and lymph node biopsy identified recurrence of her endometrial cancer. This case illustrates how PCD can be an indicator of cancer recurrence, underlines the significance of PCD as a prompt to search for underlying malignancy, and highlights the difficulties PCD poses to the clinician in terms of diagnosis and management.

  1. [Type I Chiari malformation associated with cerebellar atrophy. Case report].

    PubMed

    Moscote-Salazar, Luis Rafael; Calderón-Miranda, Willem Guillermo; Alvis-Miranda, Hernando Raphael; Lee-Aguirre, Ángel; Alcalá-Cerra, Gabriel

    2017-01-01

    Chiari malformation is characterized by caudal displacement of the cerebellar tonsils that penetrate into the spinal cana