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Sample records for alters neuronal excitability

  1. Altered neuronal and circuit excitability in Fragile X Syndrome

    PubMed Central

    Contractor, Anis; Klyachko, Vitaly A.; Portera-Cailliau, Carlos

    2015-01-01

    Fragile X syndrome (FXS) results from a genetic mutation in a single gene, yet produces a phenotypically complex disorder with a range of neurological and psychiatric problems. Efforts to decipher how perturbations in signaling pathways lead to the myriad alterations in synaptic and cellular functions have provided insights into the molecular underpinnings of this disorder. From this large body of data the theme of circuit hyperexcitability has emerged as a potential explanation for many of the neurological and psychiatric symptoms in FXS. The mechanisms for hyperexcitability range from alterations in the expression or activity of ion channels to changes in neurotransmitters and receptors. Contributions of these processes are often brain region- and cell type-specific, resulting in complex effects on circuit function that manifest as altered excitability. Here, we review the current state of knowledge of the molecular, synaptic and circuit-level mechanisms underlying hyperexcitability and their contributions to the FXS phenotypes. PMID:26291156

  2. Altered Neuronal and Circuit Excitability in Fragile X Syndrome.

    PubMed

    Contractor, Anis; Klyachko, Vitaly A; Portera-Cailliau, Carlos

    2015-08-19

    Fragile X syndrome (FXS) results from a genetic mutation in a single gene yet produces a phenotypically complex disorder with a range of neurological and psychiatric problems. Efforts to decipher how perturbations in signaling pathways lead to the myriad alterations in synaptic and cellular functions have provided insights into the molecular underpinnings of this disorder. From this large body of data, the theme of circuit hyperexcitability has emerged as a potential explanation for many of the neurological and psychiatric symptoms in FXS. The mechanisms for hyperexcitability range from alterations in the expression or activity of ion channels to changes in neurotransmitters and receptors. Contributions of these processes are often brain region and cell type specific, resulting in complex effects on circuit function that manifest as altered excitability. Here, we review the current state of knowledge of the molecular, synaptic, and circuit-level mechanisms underlying hyperexcitability and their contributions to the FXS phenotypes.

  3. Energy imbalance alters Ca(2+) handling and excitability of POMC neurons.

    PubMed

    Paeger, Lars; Pippow, Andreas; Hess, Simon; Paehler, Moritz; Klein, Andreas C; Husch, Andreas; Pouzat, Christophe; Brüning, Jens C; Kloppenburg, Peter

    2017-08-01

    Satiety-signaling, pro-opiomelanocortin (POMC)-expressing neurons in the arcuate nucleus of the hypothalamus play a pivotal role in the regulation of energy homeostasis. Recent studies reported altered mitochondrial dynamics and decreased mitochondria- endoplasmic reticulum contacts in POMC neurons during diet-induced obesity. Since mitochondria play a crucial role in Ca(2+) signaling, we investigated whether obesity alters Ca(2+) handling of these neurons in mice. In diet-induced obesity, cellular Ca(2+) handling properties including mitochondrial Ca(2+) uptake capacity are impaired, and an increased resting level of free intracellular Ca(2+) is accompanied by a marked decrease in neuronal excitability. Experimentally increasing or decreasing intracellular Ca(2+) concentrations reproduced electrophysiological properties observed in diet-induced obesity. Taken together, we provide the first direct evidence for a diet-dependent deterioration of Ca(2+) homeostasis in POMC neurons during obesity development resulting in impaired function of these critical energy homeostasis-regulating neurons.

  4. Intrinsic Neuronal Excitability Is Reversibly Altered by a Single Experience in Fear Conditioning

    PubMed Central

    Matthews, Elizabeth A.; Oliveira, Fernando A.; Disterhoft, John F.

    2009-01-01

    Learning is known to cause alterations in intrinsic cellular excitability but, to date, these changes have been seen only after multiple training trials. A powerful learning task that can be quickly acquired and extinguished with a single trial is fear conditioning. Rats were trained and extinguished on a hippocampus-dependent form of fear conditioning to determine whether learning-related changes in intrinsic excitability could be observed after a few training trials and a single extinction trial. Following fear training, hippocampal slices were made and intrinsic excitability was assayed via whole cell recordings from CA1 neurons. Alterations in intrinsic excitability, assayed by the postburst afterhyperpolarization and firing frequency accommodation, were observed after only three trials of contextual or trace-cued fear conditioning. Animals that had been trained in contextual and trace-cued fear were then extinguished. Context fear-conditioned animals extinguished in a single trial and the changes in intrinsic excitability were reversed. Trace-cue conditioned animals only partially extinguished in a single trial and reductions in excitability remained. Thus a single learning experience is sufficient to alter intrinsic excitability. This dramatically extends observations of learning-specific changes in intrinsic neuronal excitability previously observed in paradigms requiring many training trials, suggesting the excitability changes have a basic role in acquiring new information. PMID:19726729

  5. Spinocerebellar ataxia type 13 mutant potassium channel alters neuronal excitability and causes locomotor deficits in zebrafish.

    PubMed

    Issa, Fadi A; Mazzochi, Christopher; Mock, Allan F; Papazian, Diane M

    2011-05-04

    Whether changes in neuronal excitability can cause neurodegenerative disease in the absence of other factors such as protein aggregation is unknown. Mutations in the Kv3.3 voltage-gated K(+) channel cause spinocerebellar ataxia type 13 (SCA13), a human autosomal-dominant disease characterized by locomotor impairment and the death of cerebellar neurons. Kv3.3 channels facilitate repetitive, high-frequency firing of action potentials, suggesting that pathogenesis in SCA13 is triggered by changes in electrical activity in neurons. To investigate whether SCA13 mutations alter excitability in vivo, we expressed the human dominant-negative R420H mutant subunit in zebrafish. The disease-causing mutation specifically suppressed the excitability of Kv3.3-expressing, fast-spiking motor neurons during evoked firing and fictive swimming and, in parallel, decreased the precision and amplitude of the startle response. The dominant-negative effect of the mutant subunit on K(+) current amplitude was directly responsible for the reduced excitability and locomotor phenotype. Our data provide strong evidence that changes in excitability initiate pathogenesis in SCA13 and establish zebrafish as an excellent model system for investigating how changes in neuronal activity impair locomotor control and cause cell death.

  6. Altered neuronal excitability underlies impaired hippocampal function in an animal model of psychosis

    PubMed Central

    Grüter, Thomas; Wiescholleck, Valentina; Dubovyk, Valentyna; Aliane, Verena; Manahan-Vaughan, Denise

    2015-01-01

    Psychosis is accompanied by severe attentional deficits, and impairments in associational-memory processing and sensory information processing that are ascribed to dysfunctions in prefrontal and hippocampal function. Disruptions of glutamatergic signaling may underlie these alterations: Antagonism of the N-methyl-D-aspartate receptor (NMDAR) results in similar molecular, cellular, cognitive and behavioral changes in rodents and/or humans as those that occur in psychosis, raising the question as to whether changes in glutamatergic transmission may be intrinsic to the pathophysiology of the disease. In an animal model of psychosis that comprises treatment with the irreversible NMDAR-antagonist, MK801, we explored the cellular mechanisms that may underlie hippocampal dysfunction in psychosis. MK801-treatment resulted in a profound loss of hippocampal LTP that was evident 4 weeks after treatment. Whereas neuronal expression of the immediate early gene, Arc, was enhanced in the hippocampus by spatial learning in controls, MK801-treated animals failed to show activity-dependent increases in Arc expression. By contrast, a significant increase in basal Arc expression in the absence of learning was evident compared to controls. Paired-pulse (PP) facilitation was increased at the 40 ms interval indicating that NMDAR and/or fast GABAergic-mediated neurotransmission was disrupted. In line with this, MK801-treatment resulted in a significant decrease in GABA(A), and increase in GABA(B)-receptor-expression in PFC, along with a significant increase of GABA(B)- and NMDAR-GluN2B expression in the dentate gyrus. NMDAR-GluN1 or GluN2A subunit expression was unchanged. These data suggest that in psychosis, deficits in hippocampus-dependent memory may be caused by a loss of hippocampal LTP that arises through enhanced hippocampal neuronal excitability, altered GluN2B and GABA receptor expression and an uncoupling of the hippocampus-prefrontal cortex circuitry. PMID:26042007

  7. Altering neuronal excitability to preserve network connectivity in a computational model of Alzheimer's disease.

    PubMed

    de Haan, Willem; van Straaten, Elisabeth C W; Gouw, Alida A; Stam, Cornelis J

    2017-09-01

    Neuronal hyperactivity and hyperexcitability of the cerebral cortex and hippocampal region is an increasingly observed phenomenon in preclinical Alzheimer's disease (AD). In later stages, oscillatory slowing and loss of functional connectivity are ubiquitous. Recent evidence suggests that neuronal dynamics have a prominent role in AD pathophysiology, making it a potentially interesting therapeutic target. However, although neuronal activity can be manipulated by various (non-)pharmacological means, intervening in a highly integrated system that depends on complex dynamics can produce counterintuitive and adverse effects. Computational dynamic network modeling may serve as a virtual test ground for developing effective interventions. To explore this approach, a previously introduced large-scale neural mass network with human brain topology was used to simulate the temporal evolution of AD-like, activity-dependent network degeneration. In addition, six defense strategies that either enhanced or diminished neuronal excitability were tested against the degeneration process, targeting excitatory and inhibitory neurons combined or separately. Outcome measures described oscillatory, connectivity and topological features of the damaged networks. Over time, the various interventions produced diverse large-scale network effects. Contrary to our hypothesis, the most successful strategy was a selective stimulation of all excitatory neurons in the network; it substantially prolonged the preservation of network integrity. The results of this study imply that functional network damage due to pathological neuronal activity can be opposed by targeted adjustment of neuronal excitability levels. The present approach may help to explore therapeutic effects aimed at preserving or restoring neuronal network integrity and contribute to better-informed intervention choices in future clinical trials in AD.

  8. Actions of adiponectin on the excitability of subfornical organ neurons are altered by food deprivation.

    PubMed

    Alim, Ishraq; Fry, W Mark; Walsh, Michael H; Ferguson, Alastair V

    2010-05-12

    Adiponectin (ADP) is a peptide produced by adipose tissue, which acts as an insulin sensitizing hormone. Recent studies have shown that adiponectin receptors (AdipoR1 and AdipoR2) are present in the CNS, and although adiponectin does appear in both circulation and the cerebrospinal fluid there is still some debate as to whether or not ADP crosses the blood brain barrier (BBB). Circumventricular organs (CVO) are CNS sites which lack normal BBB, and thus represent sites at which circulating adiponectin may act to directly influence the CNS. The subfornical organ (SFO) is a CVO that has been implicated in the regulation of energy balance as a consequence of the ability of SFO neurons to respond to a number of different circulating satiety signals including amylin, CCK, PYY and ghrelin. Our recent microarray analysis suggested the presence of adiponectin receptors in the SFO. We report here that the SFO shows a high density of mRNA for both adiponectin receptors (AdipoR1 and AdipoR2), and that ADP influences the excitability of dissociated SFO neurons. Separate subpopulations of SFO neurons were either depolarized (8.9+/-0.9 mV, 21 of 97 cells), or hyperpolarized (-8.0+/-0.5 mV, 34 of 97 cells), by bath application of 10nM ADP, effects which were concentration dependent and reversible. Our microarray analysis also suggested that 48 h of food deprivation resulted in specific increases in AdipoR2 mRNA expression (no effect on AdipoR1 mRNA), observations which we confirm here using real-time PCR techniques. The effects of food deprivation also resulted in a change in the responsiveness of SFO neurons to adiponectin with 77% (8/11) of cells tested responding to adiponectin with depolarization, while no hyperpolarizations were observed. These observations support the concept that the SFO may be a key player in sensing circulating ADP and transmitting such information to critical CNS sites involved in the regulation of energy balance. (c) 2010. Published by Elsevier B.V. All

  9. Trigeminal ganglion neuron subtype-specific alterations of CaV2.1 calcium current and excitability in a Cacna1a mouse model of migraine

    PubMed Central

    Fioretti, B; Catacuzzeno, L; Sforna, L; Gerke-Duncan, M B; van den Maagdenberg, A M J M; Franciolini, F; Connor, M; Pietrobon, D

    2011-01-01

    Abstract Familial hemiplegic migraine type-1 (FHM1), a monogenic subtype of migraine with aura, is caused by gain-of-function mutations in CaV2.1 (P/Q-type) calcium channels. The consequences of FHM1 mutations on the trigeminovascular pathway that generates migraine headache remain largely unexplored. Here we studied the calcium currents and excitability properties of two subpopulations of small-diameter trigeminal ganglion (TG) neurons from adult wild-type (WT) and R192Q FHM1 knockin (KI) mice: capsaicin-sensitive neurons without T-type calcium currents (CS) and capsaicin-insensitive neurons characterized by the expression of T-type calcium currents (CI-T). Small TG neurons retrogradely labelled from the dura are mostly CS neurons, while CI-T neurons were not present in the labelled population. CS and CI-T neurons express CaV2.1 channels with different activation properties, and the CaV2.1 channels are differently affected by the FHM1 mutation in the two TG neuron subtypes. In CI-T neurons from FHM1 KI mice there was a larger P/Q-type current density following mild depolarizations, a larger action potential (AP)-evoked calcium current and a longer AP duration when compared to CI-T neurons from WT mice. In striking contrast, the P/Q-type current density, voltage dependence and kinetics were not altered by the FHM1 mutation in CS neurons. The excitability properties of mutant CS neurons were also unaltered. Congruently, the FHM1 mutation did not alter depolarization-evoked CGRP release from the dura mater, while CGRP release from the trigeminal ganglion was larger in KI compared to WT mice. Our findings suggest that the facilitation of peripheral mechanisms of CGRP action, such as dural vasodilatation and nociceptor sensitization at the meninges, does not contribute to the generation of headache in FHM1. PMID:22005682

  10. Alterations in CA1 pyramidal neuronal intrinsic excitability mediated by Ih channel currents in a rat model of amyloid beta pathology.

    PubMed

    Eslamizade, M J; Saffarzadeh, F; Mousavi, S M M; Meftahi, G H; Hosseinmardi, N; Mehdizadeh, M; Janahmadi, M

    2015-10-01

    Amyloid beta (Aβ) accumulation plays an important role in the pathogenesis of Alzheimer's disease (AD) by changing the neuronal excitability. However, the cellular mechanisms by which accumulation of Aβ affects intrinsic neuronal properties are not well understood. The effect of bilateral intra-frontal cortex Aβ (1-42) peptide injection on the intrinsic excitability of hippocampal CA1 pyramidal neurons with particular focus on the contribution of hyperpolarization-activated (Ih) channel currents was examined using whole-cell patch-clamp recording. Passive avoidance memory impairment and morphological changes in rats receiving intra-frontal Aβ treatment were observed, which was associated with significant changes both in passive and active intrinsic electrical membrane properties of CA1 pyramidal neurons. Electrophysiological recording showed a significant decrease in neuronal excitability associated with an augmentation in the first spike after-hyperpolarization (AHP) amplitude. In addition, the depolarizing sag voltage was altered in neurons recorded from Aβ-treated group. In voltage-clamp condition, a hyperpolarizing activated inward current sensitive to ZD7288 and capsaicin was significantly increased in neurons from Aβ-treated rats. The Ih current density was increased and the activation curve was shifted toward less negative potential in the Aβ-treated group as compared to control group. The enhancing effect of Aβ treatment on Ih current was confirmed by showing upregulation of the mRNA of HCN1 channel in the CA1 pyramidal layer of hippocampi. These findings suggest the contribution of Ih and possibly TRPV1 channel currents to the changes induced by Aβ treatment in the intrinsic membrane properties, which, in turn, may provide therapeutic targets for treatment of AD. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  11. Alteration of Neuronal Excitability and Short-Term Synaptic Plasticity in the Prefrontal Cortex of a Mouse Model of Mental Illness.

    PubMed

    Crabtree, Gregg W; Sun, Ziyi; Kvajo, Mirna; Broek, Jantine A C; Fénelon, Karine; McKellar, Heather; Xiao, Lan; Xu, Bin; Bahn, Sabine; O'Donnell, James M; Gogos, Joseph A

    2017-04-12

    Using a genetic mouse model that faithfully recapitulates a DISC1 genetic alteration strongly associated with schizophrenia and other psychiatric disorders, we examined the impact of this mutation within the prefrontal cortex. Although cortical layering, cytoarchitecture, and proteome were found to be largely unaffected, electrophysiological examination of the mPFC revealed both neuronal hyperexcitability and alterations in short-term synaptic plasticity consistent with enhanced neurotransmitter release. Increased excitability of layer II/III pyramidal neurons was accompanied by consistent reductions in voltage-activated potassium currents near the action potential threshold as well as by enhanced recruitment of inputs arising from superficial layers to layer V. We further observed reductions in both the paired-pulse ratios and the enhanced short-term depression of layer V synapses arising from superficial layers consistent with enhanced neurotransmitter release at these synapses. Recordings from layer II/III pyramidal neurons revealed action potential widening that could account for enhanced neurotransmitter release. Significantly, we found that reduced functional expression of the voltage-dependent potassium channel subunit Kv1.1 substantially contributes to both the excitability and short-term plasticity alterations that we observed. The underlying dysregulation of Kv1.1 expression was attributable to cAMP elevations in the PFC secondary to reduced phosphodiesterase 4 activity present in Disc1 deficiency and was rescued by pharmacological blockade of adenylate cyclase. Our results demonstrate a potentially devastating impact of Disc1 deficiency on neural circuit function, partly due to Kv1.1 dysregulation that leads to a dual dysfunction consisting of enhanced neuronal excitability and altered short-term synaptic plasticity.SIGNIFICANCE STATEMENT Schizophrenia is a profoundly disabling psychiatric illness with a devastating impact not only upon the afflicted but

  12. Does the Altered Expression of Ion Channels Give Rise to the Enhanced Excitability of Neurons Isolated from Nf1 +/- Mice?

    DTIC Science & Technology

    2011-09-01

    functional profiles of voltage- gated Na(+) channels in injured and non-injured DRG neurons in the SNI model of neuropathic pain. Mol Cell Neurosci 37:196...channels in injured and non-injured DRG neurons in the SNI model of neuropathic pain. Mol Cell Neurosci 37:196–208. evan S, Chiu SY, Gray PT, Ritchie

  13. Deficits in the activity of presynaptic γ-aminobutyric acid type B receptors contribute to altered neuronal excitability in fragile X syndrome.

    PubMed

    Kang, Ji-Yong; Chadchankar, Jayashree; Vien, Thuy N; Mighdoll, Michelle I; Hyde, Thomas M; Mather, Robert J; Deeb, Tarek Z; Pangalos, Menelas N; Brandon, Nicholas J; Dunlop, John; Moss, Stephen J

    2017-04-21

    The behavioral and anatomical deficits seen in fragile X syndrome (FXS) are widely believed to result from imbalances in the relative strengths of excitatory and inhibitory neurotransmission. Although modified neuronal excitability is thought to be of significance, the contribution that alterations in GABAergic inhibition play in the pathophysiology of FXS are ill defined. Slow sustained neuronal inhibition is mediated by γ-aminobutyric acid type B (GABAB) receptors, which are heterodimeric G-protein-coupled receptors constructed from R1a and R2 or R1b and R2 subunits. Via the activation of Gi/o, they limit cAMP accumulation, diminish neurotransmitter release, and induce neuronal hyperpolarization. Here we reveal that selective deficits in R1a subunit expression are seen in Fmr1 knock-out mice (KO) mice, a widely used animal model of FXS, but the levels of the respective mRNAs were unaffected. Similar trends of R1a expression were seen in a subset of FXS patients. GABAB receptors (GABABRs) exert powerful pre- and postsynaptic inhibitory effects on neurotransmission. R1a-containing GABABRs are believed to mediate presynaptic inhibition in principal neurons. In accordance with this result, deficits in the ability of GABABRs to suppress glutamate release were seen in Fmr1-KO mice. In contrast, the ability of GABABRs to suppress GABA release and induce postsynaptic hyperpolarization was unaffected. Significantly, this deficit contributes to the pathophysiology of FXS as the GABABR agonist (R)-baclofen rescued the imbalances between excitatory and inhibitory neurotransmission evident in Fmr1-KO mice. Collectively, our results provided evidence that selective deficits in the activity of presynaptic GABABRs contribute to the pathophysiology of FXS. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  14. Impact of inhibitory constraint of interneurons on neuronal excitability.

    PubMed

    Lee, Vallent; Maguire, Jamie

    2013-12-01

    Tonic inhibition is thought to dampen the excitability of principal neurons; however, little is known about the role of tonic GABAergic inhibition in interneurons and the impact on principal neuron excitability. In many brain regions, tonic GABAergic inhibition is mediated by extrasynaptic, δ-subunit-containing GABAA receptors (GABAARs). In the present study we demonstrate the importance of GABAAR δ-subunit-mediated tonic inhibition in interneurons. Selective elimination of the GABAAR δ-subunit from interneurons was achieved by crossing a novel floxed Gabrd mouse model with GAD65-Cre mice (Gabrd/Gad mice). Deficits in GABAAR δ-subunit expression in GAD65-positive neurons result in a decrease in tonic GABAergic inhibition and increased excitability of both molecular layer (ML) and stratum radiatum (SR) interneurons. Disinhibition of interneurons results in robust alterations in the neuronal excitability of principal neurons and decreased seizure susceptibility. Gabrd/Gad mice have enhanced tonic and phasic GABAergic inhibition in both CA1 pyramidal neurons and dentate gyrus granule cells (DGGCs). Consistent with alterations in hippocampal excitability, CA1 pyramidal neurons and DGGCs from Gabrd/Gad mice exhibit a shift in the input-output relationship toward decreased excitability compared with those from Cre(-/-) littermates. Furthermore, seizure susceptibility, in response to 20 mg/kg kainic acid, is significantly decreased in Gabrd/Gad mice compared with Cre(-/-) controls. These data demonstrate a critical role for GABAAR δ-subunit-mediated tonic GABAergic inhibition of interneurons on principal neuronal excitability and seizure susceptibility.

  15. A neuronal disruption in redox homeostasis elicited by ammonia alters the glycine/glutamate (GABA) cycle and contributes to MMA-induced excitability.

    PubMed

    Royes, Luiz Fernando Freire; Gabbi, Patrícia; Ribeiro, Leandro Rodrigo; Della-Pace, Iuri Domingues; Rodrigues, Fernanda Silva; de Oliveira Ferreira, Ana Paula; da Silveira Junior, Mauro Eduardo Porto; da Silva, Luís Roberto Hart; Grisólia, Alan Barroso Araújo; Braga, Danielle Valente; Dobrachinski, Fernando; da Silva, Anderson Manoel Herculano Oliveira; Soares, Félix Alexandre Antunes; Marchesan, Sara; Furian, Ana Flavia; Oliveira, Mauro Schneider; Fighera, Michele Rechia

    2016-06-01

    Hyperammonemia is a common finding in children with methylmalonic acidemia. However, its contribution to methylmalonate-induced excitotoxicty is poorly understood. The aim of this study was to evaluate the mechanisms by which ammonia influences in the neurotoxicity induced by methylmalonate (MMA) in mice. The effects of ammonium chloride (NH4Cl 3, 6, and 12 mmol/kg; s.c.) on electroencephalographic (EEG) and behavioral convulsions induced by MMA (0.3, 0.66, and 1 µmol/2 µL, i.c.v.) were observed in mice. After, ammonia, TNF-α, IL1β, IL-6, nitrite/nitrate (NOx) levels, mitochondrial potential (ΔΨ), reactive oxygen species (ROS) generation, Methyl-Tetrazolium (MTT) reduction, succinate dehydrogenase (SDH), and Na(+), K(+)-ATPase activity levels were measured in the cerebral cortex. The binding of [(3)H]flunitrazepam, release of glutamate-GABA; glutamate decarboxylase (GAD) and glutamine synthetase (GS) activity and neuronal damage [opening of blood brain barrier (BBB) permeability and cellular death volume] were also measured. EEG recordings showed that an intermediate dose of NH4Cl (6 mmol/kg) increased the duration of convulsive episodes induced by MMA (0.66 μmol/2 μL i.c.v). NH4Cl (6 mmol/kg) administration also induced neuronal ammonia and NOx increase, as well as mitochondrial ROS generation throughout oxidation of 2,7-dichlorofluorescein diacetate (DCFH-DA) to DCF-RS, followed by GS and GAD inhibition. The NH4Cl plus MMA administration did not alter cytokine levels, plasma fluorescein extravasation, or neuronal damage. However, it potentiated DCF-RS levels, decreased the ΔΨ potential, reduced MTT, inhibited SDH activity, and increased Na(+), K(+)-ATPase activity. NH4Cl also altered the GABA cycle characterized by GS and GAD activity inhibition, [(3)H]flunitrazepam binding, and GABA release after MMA injection. On the basis of our findings, the changes in ROS and reactive nitrogen species (RNS) levels elicited by ammonia alter the glycine

  16. A novel phase portrait for neuronal excitability.

    PubMed

    Drion, Guillaume; Franci, Alessio; Seutin, Vincent; Sepulchre, Rodolphe

    2012-01-01

    Fifty years ago, FitzHugh introduced a phase portrait that became famous for a twofold reason: it captured in a physiological way the qualitative behavior of Hodgkin-Huxley model and it revealed the power of simple dynamical models to unfold complex firing patterns. To date, in spite of the enormous progresses in qualitative and quantitative neural modeling, this phase portrait has remained a core picture of neuronal excitability. Yet, a major difference between the neurophysiology of 1961 and of 2011 is the recognition of the prominent role of calcium channels in firing mechanisms. We show that including this extra current in Hodgkin-Huxley dynamics leads to a revision of FitzHugh-Nagumo phase portrait that affects in a fundamental way the reduced modeling of neural excitability. The revisited model considerably enlarges the modeling power of the original one. In particular, it captures essential electrophysiological signatures that otherwise require non-physiological alteration or considerable complexification of the classical model. As a basic illustration, the new model is shown to highlight a core dynamical mechanism by which calcium channels control the two distinct firing modes of thalamocortical neurons.

  17. A Novel Phase Portrait for Neuronal Excitability

    PubMed Central

    Seutin, Vincent; Sepulchre, Rodolphe

    2012-01-01

    Fifty years ago, FitzHugh introduced a phase portrait that became famous for a twofold reason: it captured in a physiological way the qualitative behavior of Hodgkin-Huxley model and it revealed the power of simple dynamical models to unfold complex firing patterns. To date, in spite of the enormous progresses in qualitative and quantitative neural modeling, this phase portrait has remained a core picture of neuronal excitability. Yet, a major difference between the neurophysiology of 1961 and of 2011 is the recognition of the prominent role of calcium channels in firing mechanisms. We show that including this extra current in Hodgkin-Huxley dynamics leads to a revision of FitzHugh-Nagumo phase portrait that affects in a fundamental way the reduced modeling of neural excitability. The revisited model considerably enlarges the modeling power of the original one. In particular, it captures essential electrophysiological signatures that otherwise require non-physiological alteration or considerable complexification of the classical model. As a basic illustration, the new model is shown to highlight a core dynamical mechanism by which calcium channels control the two distinct firing modes of thalamocortical neurons. PMID:22905107

  18. Neuronal chloride and excitability - the big impact of small changes.

    PubMed

    Raimondo, Joseph V; Richards, Blake A; Woodin, Melanie A

    2016-12-16

    Synaptic inhibition is a critical regulator of neuronal excitability, and in the mature brain the majority of synaptic inhibition is mediated by Cl(-)-permeable GABAA receptors. Unlike other physiologically relevant ions, Cl(-) is dynamically regulated, and alterations in the Cl(-) gradient can have significant impact on neuronal excitability. Due to changes in the neuronal Cl(-) concentration, GABAergic transmission can bidirectionally regulate the induction of excitatory synaptic plasticity and gate the closing of the critical period for monocular deprivation in visual cortex. GABAergic circuitry can also provide a powerful restraining mechanism for the spread of excitation, however Cl(-) extrusion mechanisms can become overwhelmed and GABA can paradoxically contribute to pathological excitation such as the propagation of seizure activity.

  19. Learning and Aging Related Changes in Intrinsic Neuronal Excitability

    PubMed Central

    Oh, M. Matthew; Oliveira, Fernando A.; Disterhoft, John F.

    2010-01-01

    A goal of many laboratories that study aging is to find a key cellular change(s) that can be manipulated and restored to a young-like state, and thus, reverse the age-related cognitive deficits. We have chosen to focus our efforts on the alteration of intrinsic excitability (as reflected by the postburst afterhyperpolarization, AHP) during the learning process in hippocampal pyramidal neurons. We have consistently found that the postburst AHP is significantly reduced in hippocampal pyramidal neurons from young adults that have successfully learned a hippocampus-dependent task. In the context of aging, the baseline intrinsic excitability of hippocampal neurons is decreased and therefore cognitive learning is impaired. In aging animals that are able to learn, neuron changes in excitability similar to those seen in young neurons during learning occur. Our challenge, then, is to understand how and why excitability changes occur in neurons from aging brains and cause age-associated learning impairments. After understanding the changes, we should be able to formulate strategies for reversing them, thus making old neurons function more as they did when they were young. Such a reversal should rescue the age-related cognitive deficits. PMID:20552042

  20. Optimal stimulus shapes for neuronal excitation.

    PubMed

    Forger, Daniel B; Paydarfar, David; Clay, John R

    2011-07-01

    An important problem in neuronal computation is to discern how features of stimuli control the timing of action potentials. One aspect of this problem is to determine how an action potential, or spike, can be elicited with the least energy cost, e.g., a minimal amount of applied current. Here we show in the Hodgkin & Huxley model of the action potential and in experiments on squid giant axons that: 1) spike generation in a neuron can be highly discriminatory for stimulus shape and 2) the optimal stimulus shape is dependent upon inputs to the neuron. We show how polarity and time course of post-synaptic currents determine which of these optimal stimulus shapes best excites the neuron. These results are obtained mathematically using the calculus of variations and experimentally using a stochastic search methodology. Our findings reveal a surprising complexity of computation at the single cell level that may be relevant for understanding optimization of signaling in neurons and neuronal networks.

  1. Cholinergic Neurons Excite Cortically Projecting Basal Forebrain GABAergic Neurons

    PubMed Central

    Yang, Chun; McKenna, James T.; Zant, Janneke C.; Winston, Stuart; Basheer, Radhika

    2014-01-01

    The basal forebrain (BF) plays an important role in the control of cortical activation and attention. Understanding the modulation of BF neuronal activity is a prerequisite to treat disorders of cortical activation involving BF dysfunction, such as Alzheimer's disease. Here we reveal the interaction between cholinergic neurons and cortically projecting BF GABAergic neurons using immunohistochemistry and whole-cell recordings in vitro. In GAD67-GFP knock-in mice, BF cholinergic (choline acetyltransferase-positive) neurons were intermingled with GABAergic (GFP+) neurons. Immunohistochemistry for the vesicular acetylcholine transporter showed that cholinergic fibers apposed putative cortically projecting GABAergic neurons containing parvalbumin (PV). In coronal BF slices from GAD67-GFP knock-in or PV-tdTomato mice, pharmacological activation of cholinergic receptors with bath application of carbachol increased the firing rate of large (>20 μm diameter) BF GFP+ and PV (tdTomato+) neurons, which exhibited the intrinsic membrane properties of cortically projecting neurons. The excitatory effect of carbachol was blocked by antagonists of M1 and M3 muscarinic receptors in two subpopulations of BF GABAergic neurons [large hyperpolarization-activated cation current (Ih) and small Ih, respectively]. Ion substitution experiments and reversal potential measurements suggested that the carbachol-induced inward current was mediated mainly by sodium-permeable cation channels. Carbachol also increased the frequency of spontaneous excitatory and inhibitory synaptic currents. Furthermore, optogenetic stimulation of cholinergic neurons/fibers caused a mecamylamine- and atropine-sensitive inward current in putative GABAergic neurons. Thus, cortically projecting, BF GABAergic/PV neurons are excited by neighboring BF and/or brainstem cholinergic neurons. Loss of cholinergic neurons in Alzheimer's disease may impair cortical activation, in part, through disfacilitation of BF cortically

  2. Culturing conditions determine neuronal and glial excitability.

    PubMed

    Stoppelkamp, Sandra; Riedel, Gernot; Platt, Bettina

    2010-12-15

    The cultivation of pure neuronal cultures is considered advantageous for the investigation of cell-type specific responses (such as transmitter release and also pharmacological agents), however, divergent results are a likely consequence of media modifications and culture composition. Using Fura-2 based imaging techniques, we here set out to compare calcium responses of rat hippocampal neurones and glia to excitatory stimulation with l-glutamate in different culture types and media. Neurones in neurone-enriched cultures had increased responses to 10 μM and 100 μM l-glutamate (+43 and 45%, respectively; p's< 0.001) and a slower recovery compared to mixed cultures, indicating heightened excitability. In matured (15-20 days in vitro) mixed cultures, neuronal responder rates were suppressed in a neurone-supportive medium (Neurobasal-A, NB: 65%) compared to a general-purpose medium (supplemented minimal essential medium, MEM: 96%). Glial response size in contrast did not differ greatly in isolated or mixed cultures maintained in MEM, but responder rates were suppressed in both culture types in NB (e.g. 10 μM l-glutamate responders in mixed cultures: 29% in NB, 71% in MEM). This indicates that medium composition is more important for glial excitability than the presence of neurones, whereas the presence of glia has an important impact on neuronal excitability. Therefore, careful consideration of culturing conditions is crucial for interpretation and comparison of experimental results. Especially for investigations of toxicity and neuroprotection mixed cultures may be more physiologically relevant over isolated cultures as they comprise aspects of mutual influences between glia and neurones.

  3. Kisspeptin Excitation of GnRH Neurons

    PubMed Central

    Rønnekleiv, Oline K.; Kelly, Martin J.

    2014-01-01

    Kisspeptin binding to its cognate G protein-coupled receptor (GPR54, aka Kiss1R) in gonadotropin-releasing hormone (GnRH) neurons stimulates peptide release and activation of the reproductive axis in mammals. Kisspeptin has pronounced pre- and postsynaptic effects, with the latter dominating the excitability of GnRH neurons. Presynaptically, kisspeptin increases the excitatory drive (both GABA-A and glutamate) to GnRH neurons and postsynaptically, kisspeptin inhibits an A-type and inwardly rectifying K + (Kir 6.2 and GIRK) currents and activates nonselective cation (TRPC) currents to cause long-lasting depolarization and increased action potential firing. The signaling cascades and the multiple intracellular targets of kisspeptin actions in native GnRH neurons are continuing to be elucidated. This review summarizes our current state of knowledge about kisspeptin signaling in GnRH neurons. PMID:23550004

  4. Perceptual Load Alters Visual Excitability

    ERIC Educational Resources Information Center

    Carmel, David; Thorne, Jeremy D.; Rees, Geraint; Lavie, Nilli

    2011-01-01

    Increasing perceptual load reduces the processing of visual stimuli outside the focus of attention, but the mechanism underlying these effects remains unclear. Here we tested an account attributing the effects of perceptual load to modulations of visual cortex excitability. In contrast to stimulus competition accounts, which propose that load…

  5. Increased excitability and altered action potential waveform in cerebellar granule neurons of the Ts65Dn mouse model of Down syndrome

    PubMed Central

    Usowicz, Maria M.; Garden, Claire L.P.

    2012-01-01

    Down syndrome (DS) is characterized by intellectual disability and impaired motor control. Lack of coordinated movement, poor balance, and unclear speech imply dysfunction of the cerebellum, which is known to be reduced in volume in DS. The principal cause of the smaller cerebellum is a diminished number of granule cells (GCs). These neurons form the ‘input layer’ of the cerebellar cortex, where sensorimotor information carried by incoming mossy fibers is transformed before it is conveyed to Purkinje cells and inhibitory interneurons. However, it is not known how processing of this information is affected in the hypogranular cerebellum that characterizes DS. Here we explore the possibility that the electrical properties of the surviving GCs are changed. We find that in the Ts65Dn mouse model of DS, GCs have a higher input resistance at voltages approaching the threshold for firing, which causes them to be more excitable. In addition, they fire narrower and larger amplitude action potentials. These subtly modified electrical properties may result in atypical transfer of information at the input layer of the cerebellum. PMID:22627164

  6. Optimal Stimulus Shapes for Neuronal Excitation

    PubMed Central

    Forger, Daniel B.; Paydarfar, David; Clay, John R.

    2011-01-01

    An important problem in neuronal computation is to discern how features of stimuli control the timing of action potentials. One aspect of this problem is to determine how an action potential, or spike, can be elicited with the least energy cost, e.g., a minimal amount of applied current. Here we show in the Hodgkin & Huxley model of the action potential and in experiments on squid giant axons that: 1) spike generation in a neuron can be highly discriminatory for stimulus shape and 2) the optimal stimulus shape is dependent upon inputs to the neuron. We show how polarity and time course of post-synaptic currents determine which of these optimal stimulus shapes best excites the neuron. These results are obtained mathematically using the calculus of variations and experimentally using a stochastic search methodology. Our findings reveal a surprising complexity of computation at the single cell level that may be relevant for understanding optimization of signaling in neurons and neuronal networks. PMID:21760759

  7. Excitation of central nervous system neurons by nonuniform electric fields.

    PubMed Central

    McIntyre, C C; Grill, W M

    1999-01-01

    The goal of this study was to determine which neural elements are excited by microstimulation of the central nervous system. A cable model of a neuron including an axon, initial segment, axon hillock, soma, and simplified dendritic tree was used to study excitation with an extracellular point source electrode. The model reproduced a wide range of experimentally documented extracellular excitation patterns. The site of action potential initiation (API) was a function of the electrode position, stimulus duration, and stimulus polarity. The axon or initial segment was always the site of API at threshold. When the electrode was positioned near the cell body, the site of excitation was dependent on the stimulus amplitude. With the electrode in close proximity to the neuron, short-duration cathodic pulses produced lower thresholds with the electrode positioned over the axon than over the cell body, and long-duration stimuli produced opposite relative thresholds. This result was robust to alterations in either the maximum conductances or the intracellular resistivities of the model. The site of maximum depolarization was not always an accurate predictor of the site of API, and the temporal evolution of the changes in membrane potential played a strong role in determining the site of excitation. PMID:9929489

  8. Diverse precerebellar neurons share similar intrinsic excitability

    PubMed Central

    Kolkman, Kristine E.; McElvain, Lauren E.; du Lac, Sascha

    2011-01-01

    The cerebellum dedicates a majority of the brain’s neurons to processing a wide range of sensory, motor, and cognitive signals. Stereotyped circuitry within the cerebellar cortex suggests that similar computations are performed throughout the cerebellum, but little is known about whether diverse precerebellar neurons are specialized for the nature of the information they convey. In vivo recordings indicate that firing responses to sensory or motor stimuli vary dramatically across different precerebellar nuclei, but whether this reflects diverse synaptic inputs or differentially tuned intrinsic excitability has not been determined. We targeted whole-cell patch clamp recordings to neurons in 8 precerebellar nuclei which were retrogradely labeled from different regions of the cerebellum in mice. Intrinsic physiology was compared across neurons in the medial vestibular, external cuneate, lateral reticular, prepositus hypoglossi, supragenual, Roller/intercalatus, reticularis tegmenti pontis (NRTP), and pontine nuclei. Within the firing domain, precerebellar neurons were remarkably similar. Firing faithfully followed temporally modulated inputs, could be sustained at high rates, and was a linear function of input current over a wide range of inputs and firing rates. Pharmacological analyses revealed common expression of Kv3 currents, which were essential for a wide linear firing range, and of SK currents, which were essential for a wide linear input range. In contrast, membrane properties below spike threshold varied considerably within and across precerebellar nuclei, as evidenced by variability in postinhibitory rebound firing. Our findings indicate that diverse precerebellar neurons perfom similar scaling computations on their inputs but may be differentially tuned to synaptic inhibition. PMID:22090493

  9. Changes in Appetitive Associative Strength Modulates Nucleus Accumbens, But Not Orbitofrontal Cortex Neuronal Ensemble Excitability.

    PubMed

    Ziminski, Joseph J; Hessler, Sabine; Margetts-Smith, Gabriella; Sieburg, Meike C; Crombag, Hans S; Koya, Eisuke

    2017-03-22

    Cues that predict the availability of food rewards influence motivational states and elicit food-seeking behaviors. If a cue no longer predicts food availability, then animals may adapt accordingly by inhibiting food-seeking responses. Sparsely activated sets of neurons, coined "neuronal ensembles," have been shown to encode the strength of reward-cue associations. Although alterations in intrinsic excitability have been shown to underlie many learning and memory processes, little is known about these properties specifically on cue-activated neuronal ensembles. We examined the activation patterns of cue-activated orbitofrontal cortex (OFC) and nucleus accumbens (NAc) shell ensembles using wild-type and Fos-GFP mice, which express green fluorescent protein (GFP) in activated neurons, after appetitive conditioning with sucrose and extinction learning. We also investigated the neuronal excitability of recently activated, GFP+ neurons in these brain areas using whole-cell electrophysiology in brain slices. Exposure to a sucrose cue elicited activation of neurons in both the NAc shell and OFC. In the NAc shell, but not the OFC, these activated GFP+ neurons were more excitable than surrounding GFP- neurons. After extinction, the number of neurons activated in both areas was reduced and activated ensembles in neither area exhibited altered excitability. These data suggest that learning-induced alterations in the intrinsic excitability of neuronal ensembles is regulated dynamically across different brain areas. Furthermore, we show that changes in associative strength modulate the excitability profile of activated ensembles in the NAc shell.SIGNIFICANCE STATEMENT Sparsely distributed sets of neurons called "neuronal ensembles" encode learned associations about food and cues predictive of its availability. Widespread changes in neuronal excitability have been observed in limbic brain areas after associative learning, but little is known about the excitability changes that

  10. Estragole blocks neuronal excitability by direct inhibition of Na+ channels

    PubMed Central

    Silva-Alves, K.S.; Ferreira-da-Silva, F.W.; Peixoto-Neves, D.; Viana-Cardoso, K.V.; Moreira-Júnior, L.; Oquendo, M.B.; Oliveira-Abreu, K.; Albuquerque, A.A.C.; Coelho-de-Souza, A.N.; Leal-Cardoso, J.H.

    2013-01-01

    Estragole is a volatile terpenoid, which occurs naturally as a constituent of the essential oils of many plants. It has several pharmacological and biological activities. The objective of the present study was to investigate the mechanism of action of estragole on neuronal excitability. Intact and dissociated dorsal root ganglion neurons of rats were used to record action potential and Na+ currents with intracellular and patch-clamp techniques, respectively. Estragole blocked the generation of action potentials in cells with or without inflexions on their descendant (repolarization) phase (Ninf and N0 neurons, respectively) in a concentration-dependent manner. The resting potentials and input resistances of Ninf and N0 cells were not altered by estragole (2, 4, and 6 mM). Estragole also inhibited total Na+ current and tetrodotoxin-resistant Na+ current in a concentration-dependent manner (IC50 of 3.2 and 3.6 mM, respectively). Kinetic analysis of Na+ current in the presence of 4 mM estragole showed a statistically significant reduction of fast and slow inactivation time constants, indicating an acceleration of the inactivation process. These data demonstrate that estragole blocks neuronal excitability by direct inhibition of Na+ channel conductance activation. This action of estragole is likely to be relevant to the understanding of the mechanisms of several pharmacological effects of this substance. PMID:24345915

  11. Astrocytic modulation of neuronal excitability through K(+) spatial buffering.

    PubMed

    Bellot-Saez, Alba; Kékesi, Orsolya; Morley, John W; Buskila, Yossi

    2017-03-06

    The human brain contains two major cell populations, neurons and glia. While neurons are electrically excitable and capable of discharging short voltage pulses known as action potentials, glial cells are not. However, astrocytes, the prevailing subtype of glia in the cortex, are highly connected and can modulate the excitability of neurons by changing the concentration of potassium ions in the extracellular environment, a process called K(+) clearance. During the past decade, astrocytes have been the focus of much research, mainly due to their close association with synapses and their modulatory impact on neuronal activity. It has been shown that astrocytes play an essential role in normal brain function including: nitrosative regulation of synaptic release in the neocortex, synaptogenesis, synaptic transmission and plasticity. Here, we discuss the role of astrocytes in network modulation through their K(+) clearance capabilities, a theory that was first raised 50 years ago by Orkand and Kuffler. We will discuss the functional alterations in astrocytic activity that leads to aberrant modulation of network oscillations and synchronous activity.

  12. Learning Enhances Intrinsic Excitability in a Subset of Lateral Amygdala Neurons

    ERIC Educational Resources Information Center

    Sehgal, Megha; Ehlers, Vanessa L.; Moyer, James R., Jr.

    2014-01-01

    Learning-induced modulation of neuronal intrinsic excitability is a metaplasticity mechanism that can impact the acquisition of new memories. Although the amygdala is important for emotional learning and other behaviors, including fear and anxiety, whether learning alters intrinsic excitability within the amygdala has received very little…

  13. Learning Enhances Intrinsic Excitability in a Subset of Lateral Amygdala Neurons

    ERIC Educational Resources Information Center

    Sehgal, Megha; Ehlers, Vanessa L.; Moyer, James R., Jr.

    2014-01-01

    Learning-induced modulation of neuronal intrinsic excitability is a metaplasticity mechanism that can impact the acquisition of new memories. Although the amygdala is important for emotional learning and other behaviors, including fear and anxiety, whether learning alters intrinsic excitability within the amygdala has received very little…

  14. Self-organized criticality in single-neuron excitability.

    PubMed

    Gal, Asaf; Marom, Shimon

    2013-12-01

    We present experimental and theoretical arguments, at the single-neuron level, suggesting that neuronal response fluctuations reflect a process that positions the neuron near a transition point that separates excitable and unexcitable phases. This view is supported by the dynamical properties of the system as observed in experiments on isolated cultured cortical neurons, as well as by a theoretical mapping between the constructs of self-organized criticality and membrane excitability biophysics.

  15. Control of hair cell excitability by vestibular primary sensory neurons

    PubMed Central

    Brugeaud, Aurore; Travo, Cécile; Demêmes, Danielle; Lenoir, Marc; Llorens, Jordi; Puel, Jean-Luc; Chabbert, Christian

    2007-01-01

    In the rat utricle, synaptic contacts between hair cells and the nerve fibers arising from the vestibular primary neurons form during the first week after birth. During that period, the sodium-based excitability that characterizes neonate utricle sensory cells is switched off. To investigate whether the establishment of synaptic contacts was responsible for the modulation of the hair cell excitability, we used an organotypic culture of rat utricle in which the setting of synapses was prevented. Under this condition, the voltage-gated sodium current and the underlying action potentials persisted in a large proportion of non-afferented hair cells. We then studied whether impairment of nerve terminals in utricle of adult rats may also affect hair cell excitability. We induced selective and transient damages of afferent terminals using glutamate excitotoxicity in vivo. The efficiency of the excitotoxic injury was attested by selective swellings of the terminals and underlying altered vestibular behavior. Under this condition, the sodium-based excitability transiently recovered in hair cells. These results indicate that the modulation of hair cells excitability depends on the state of the afferent terminals. In adult utricle hair cells this property may be essential to set the conditions required for restoration of the sensory network after damage. This is achieved via re-expression of a biological process that occurs during synaptogenesis. PMID:17392466

  16. Leptin regulation of neuronal excitability and cognitive function.

    PubMed

    Harvey, Jenni

    2007-12-01

    Leptin, a hormone produced by adipocytes, provides signals to specific regions of the hypothalamus to control energy homeostasis. However, the past decade of research has not only revealed that leptin receptors are widely expressed in the CNS, but has also identified numerous additional functions for this hormone in the brain. In particular, there is evidence that leptin influences neuronal excitability via the activation as well as trafficking of specific potassium channels in several brain regions. Leptin-induced alterations in neuronal excitability have been implicated in the regulation of food intake, reward behaviour and anti-convulsant effects. A number of studies have also identified a role for leptin in cognitive processes that involve activation of leptin receptors in limbic structures, such as the hippocampus. Indeed, leptin influences hippocampal-dependent learning and memory, and more recently leptin has been shown to have anti-depressant properties. Characterisation of these novel actions of leptin is providing valuable insights into the role of this hormone in the regulation of diverse neuronal functions in health and disease.

  17. Leptin regulation of neuronal excitability and cognitive function

    PubMed Central

    Harvey, Jenni

    2007-01-01

    Leptin, a hormone produced by adipocytes, provides signals to specific regions of the hypothalamus to control energy homeostasis. However, the past decade of research has not only revealed that leptin receptors are widely expressed in the CNS, but has also identified numerous additional functions for this hormone in the brain. In particular, there is evidence that leptin influences neuronal excitability via the activation as well as trafficking of specific potassium channels in several brain regions. Leptin-induced alterations in neuronal excitability have been implicated in the regulation of food intake, reward behaviour and anti-convulsant effects. A number of studies have also identified a role for leptin in cognitive processes that involve activation of leptin receptors in limbic structures, such as the hippocampus. Indeed, leptin influences hippocampal-dependent learning and memory, and more recently leptin has been shown to have anti-depressant properties. Characterisation of these novel actions of leptin is providing valuable insights into the role of this hormone in the regulation of diverse neuronal functions in health and disease. PMID:18024215

  18. Excitation-Contraction Coupling Alterations in Myopathies

    PubMed Central

    Marty, Isabelle; Fauré, Julien

    2016-01-01

    During the complex series of events leading to muscle contraction, the initial electric signal coming from motor neurons is transformed into an increase in calcium concentration that triggers sliding of myofibrils. This process, referred to as excitation–contraction coupling, is reliant upon the calcium-release complex, which is restricted spatially to a sub-compartment of muscle cells (“the triad”) and regulated precisely. Any dysfunction in the calcium-release complex leads to muscle impairment and myopathy. Various causes can lead to alterations in excitation–contraction coupling and to muscle diseases. The latter are reviewed and classified into four categories: (i) mutation in a protein of the calcium-release complex; (ii) alteration in triad structure; (iii) modification of regulation of channels; (iv) modification in calcium stores within the muscle. Current knowledge of the pathophysiologic mechanisms in each category is described and discussed. PMID:27911331

  19. Arginine Vasopressin Alters Both Spontaneous and Phase-Locked Synaptic Inputs to Airway Vagal Preganglionic Neuron via Activation of V1a Receptor: Insights into Stress-Related Airway Vagal Excitation

    PubMed Central

    Yan, Xianxia; Chen, Xingxin; Guo, Yuhong; He, Ding; Chen, Yonghua; Xia, Chunmei; Wang, Jijiang

    2017-01-01

    The airway vagal preganglionic neurons (AVPNs) in the external formation of the nucleus ambiguus (eNA) play a major role in the vagal control of tracheobronchial smooth muscle tone and maintenance of airway resistance. The eNA receives vasopressinergic projection from the hypothalamic paraventricular nucleus (PVN), the key node for the genesis of psychological stress. Since airway vagal excitation is reportedly to be associated with the psychological stress-induced/exacerbated airway hyperresponsiveness in asthmatics, arginine vasopressin (AVP) might be involved in stress-related airway vagal excitation. However, this possibility has not been validated. This study aimed to test whether and how AVP regulates AVPNs. In rhythmically active medullary slices of newborn rats, retrogradely labeled AVPNs were identified as inspiratory-activated and inspiratory-inhibited AVPNs (IA- and II-AVPNs) using patch-clamp techniques according to their inspiratory-related firing behavior and synaptic activities. The results show that under current clamp, AVP depolarized both IA- and II-AVPNs, and significantly increased their spontaneous firing rate. Under voltage clamp, AVP elicited a slow inward current, and significantly increased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) in both types of AVPNs. In addition, AVP significantly enhanced the phase-locked excitatory inspiratory inward current in inspiratory-activated airway vagal preganglionic neurons (IA-AVPNs), but significantly suppressed the phase-locked inhibitory inspiratory outward current in II-AVPNs. In both types AVPNs, AVP significantly increased the frequency and amplitude of pharmacologically isolated spontaneous GABAergic and glycinergic inhibitory postsynaptic currents (IPSCs). All of the AVP-induced effects were prevented by SR49059, an antagonist of V1a receptors, but unaffected by SSR149415, an antagonist of V1b receptors. AVP did not cause significant changes in the miniature excitatory

  20. Antibiotic Supplements Affect Electrophysiological Properties and Excitability of Rat Hippocampal Pyramidal Neurons in Primary Culture

    PubMed Central

    Bahrami, Farideh; Janahmadi, Mahyar

    2013-01-01

    Introduction: Antibiotic supplements are regularly used in neuronal culture media to control contamination; however, they can interfere with the neuronal excitability and affect electrophysiological properties. Therefore, in this study, the effect of penicillin/streptomycin supplements on the spontaneous electrophysiological activity of hippocampal pyramidal neurons was examined. Methods: Electrophysiological whole-cell patch-clamp recordings from rat hippocampal pyramidal cells in primary culture were performed to investigate the effects of antibiotic supplements on the intrinsic excitability of cultured cells. Results: The present findings indicated that presence of antibiotic supplements (penicillin/streptomycin) in the culture medium altered the intrinsic electrical activity of hippocampal pyramidal neurons in primary culture. These alterations included: 1) depolarized resting membrane potential; 2) a significant enhancement in the after-hyperpolarization amplitude; 3) a significant increase in the area under the action potential and in the decay and rise time of the action potential; 4) a significant broadening of action potential and 5) a significant reduction in the firing frequency. Conclusion: These findings suggest that addition of antibiotic supplements to culture media influences the neuronal excitability and alters the electrophysiological properties of cultured neurons, possibly through changing the ionic conductance underlying neuronal excitability. PMID:23567852

  1. Sleep Interacts with Aβ to Modulate Intrinsic Neuronal Excitability

    PubMed Central

    Tabuchi, Masashi; Lone, Shahnaz R.; Liu, Sha; Liu, Qili; Zhang, Julia; Spira, Adam P.; Wu, Mark N.

    2015-01-01

    SUMMARY Background Emerging data suggest an important relationship between sleep and Alzheimer’s Disease (AD), but how poor sleep promotes the development of AD remains unclear. Results Here, using a Drosophila model of AD, we provide evidence suggesting that changes in neuronal excitability underlie the effects of sleep loss on AD pathogenesis. β-amyloid (Aβ) accumulation leads to reduced and fragmented sleep, while chronic sleep deprivation increases Aβ burden. Moreover, enhancing sleep reduces Aβ deposition. Increasing neuronal excitability phenocopies the effects of reducing sleep on Aβ, and decreasing neuronal activity blocks the elevated Aβ accumulation induced by sleep deprivation. At the single neuron level, we find that chronic sleep deprivation, as well as Aβ expression, enhances intrinsic neuronal excitability. Importantly, these data reveal that sleep loss exacerbates Aβ–induced hyperexcitability and suggest that defects in specific K+ currents underlie the hyperexcitability caused by sleep loss and Aβ expression. Finally, we show that feeding levetiracetam, an anti-epileptic medication, to Aβ-expressing flies suppresses neuronal excitability and significantly prolongs their lifespan. Conclusions Our findings directly link sleep loss to changes in neuronal excitability and Aβ accumulation and further suggest that neuronal hyperexcitability is an important mediator of Aβ toxicity. Taken together, these data provide a mechanistic framework for a positive feedback loop, whereby sleep loss and neuronal excitation accelerate the accumulation of Aβ, a key pathogenic step in the development of AD. PMID:25754641

  2. Learning enhances intrinsic excitability in a subset of lateral amygdala neurons

    PubMed Central

    Sehgal, Megha; Ehlers, Vanessa L.; Moyer, James R.

    2014-01-01

    Learning-induced modulation of neuronal intrinsic excitability is a metaplasticity mechanism that can impact the acquisition of new memories. Although the amygdala is important for emotional learning and other behaviors, including fear and anxiety, whether learning alters intrinsic excitability within the amygdala has received very little attention. Fear conditioning was combined with intracellular recordings to investigate the effects of learning on the intrinsic excitability of lateral amygdala (LA) neurons. To assess time-dependent changes, brain slices were prepared either immediately or 24-h post-conditioning. Fear conditioning significantly enhanced excitability of LA neurons, as evidenced by both decreased afterhyperpolarization (AHP) and increased neuronal firing. These changes were time-dependent such that reduced AHPs were evident at both time points whereas increased neuronal firing was only observed at the later (24-h) time point. Moreover, these changes occurred within a subset (32%) of LA neurons. Previous work also demonstrated that learning-related changes in synaptic plasticity are also evident in less than one-third of amygdala neurons, suggesting that the neurons undergoing intrinsic plasticity may be critical for fear memory. These data may be clinically relevant as enhanced LA excitability following fear learning could influence future amygdala-dependent behaviors. PMID:24554670

  3. Enhanced excitability of guinea pig ileum myenteric AH neurons during and following recovery from chemical colitis.

    PubMed

    Linden, David R

    2013-06-17

    Inflammation of the colon changes motor function of more proximal regions of the gastrointestinal tract. Colitis alters the neurophysiology of enteric neurons within the region of inflammation, which may contribute to altered colonic motor and secretory function. This study seeks to test the hypothesis that colitis alters the neurophysiology of myenteric neurons in the non-inflamed ileum, and that altered neurophysiology coincides with altered small bowel motor function. Trinitrobenzene sulfonic acid (TNBS)-induced colitis was associated with hyperexcitability of AH neurons in the ileum myenteric plexus, demonstrated by depolarized neurons and increased numbers of action potentials, but without changes in the action potential duration or afterhyperpolarization typical of plasticity in these cells. There were no changes in synaptic transmission of either AH neurons or S neurons observed in the current study. The onset of AH neuron hyperexcitability occurred 24 h following administration of TNBS, and persisted to eight weeks, a time point following the resolution of colitis. Small bowel transit was reduced as early as 12 h after TNBS and resolved by 48 h after TNBS. While AH neurons play a central role in coordinating motor function of the ileum, changes in excitability of these neurons did not coincide with changes in small bowel transit. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  4. Interplay between excitability type and distributions of neuronal connectivity determines neuronal network synchronization.

    PubMed

    Mofakham, Sima; Fink, Christian G; Booth, Victoria; Zochowski, Michal R

    2016-10-01

    While the interplay between neuronal excitability properties and global properties of network topology is known to affect network propensity for synchronization, it is not clear how detailed characteristics of these properties affect spatiotemporal pattern formation. Here we study mixed networks, composed of neurons having type I and/or type II phase response curves, with varying distributions of local and random connections and show that not only average network properties, but also the connectivity distribution statistics, significantly affect network synchrony. Namely, we study networks with fixed networkwide properties, but vary the number of random connections that nodes project. We show that varying node excitability (type I vs type II) influences network synchrony most dramatically for systems with long-tailed distributions of the number of random connections per node. This indicates that a cluster of even a few highly rewired cells with a high propensity for synchronization can alter the degree of synchrony in the network as a whole. We show this effect generally on a network of coupled Kuramoto oscillators and investigate the impact of this effect more thoroughly in pulse-coupled networks of biophysical neurons.

  5. Interplay between excitability type and distributions of neuronal connectivity determines neuronal network synchronization

    NASA Astrophysics Data System (ADS)

    Mofakham, Sima; Fink, Christian G.; Booth, Victoria; Zochowski, Michal R.

    2016-10-01

    While the interplay between neuronal excitability properties and global properties of network topology is known to affect network propensity for synchronization, it is not clear how detailed characteristics of these properties affect spatiotemporal pattern formation. Here we study mixed networks, composed of neurons having type I and/or type II phase response curves, with varying distributions of local and random connections and show that not only average network properties, but also the connectivity distribution statistics, significantly affect network synchrony. Namely, we study networks with fixed networkwide properties, but vary the number of random connections that nodes project. We show that varying node excitability (type I vs type II) influences network synchrony most dramatically for systems with long-tailed distributions of the number of random connections per node. This indicates that a cluster of even a few highly rewired cells with a high propensity for synchronization can alter the degree of synchrony in the network as a whole. We show this effect generally on a network of coupled Kuramoto oscillators and investigate the impact of this effect more thoroughly in pulse-coupled networks of biophysical neurons.

  6. Synchronization properties of heterogeneous neuronal networks with mixed excitability type.

    PubMed

    Leone, Michael J; Schurter, Brandon N; Letson, Benjamin; Booth, Victoria; Zochowski, Michal; Fink, Christian G

    2015-03-01

    We study the synchronization of neuronal networks with dynamical heterogeneity, showing that network structures with the same propensity for synchronization (as quantified by master stability function analysis) may develop dramatically different synchronization properties when heterogeneity is introduced with respect to neuronal excitability type. Specifically, we investigate networks composed of neurons with different types of phase response curves (PRCs), which characterize how oscillating neurons respond to excitatory perturbations. Neurons exhibiting type 1 PRC respond exclusively with phase advances, while neurons exhibiting type 2 PRC respond with either phase delays or phase advances, depending on when the perturbation occurs. We find that Watts-Strogatz small world networks transition to synchronization gradually as the proportion of type 2 neurons increases, whereas scale-free networks may transition gradually or rapidly, depending upon local correlations between node degree and excitability type. Random placement of type 2 neurons results in gradual transition to synchronization, whereas placement of type 2 neurons as hubs leads to a much more rapid transition, showing that type 2 hub cells easily "hijack" neuronal networks to synchronization. These results underscore the fact that the degree of synchronization observed in neuronal networks is determined by a complex interplay between network structure and the dynamical properties of individual neurons, indicating that efforts to recover structural connectivity from dynamical correlations must in general take both factors into account.

  7. Diverse impact of acute and long-term extracellular proteolytic activity on plasticity of neuronal excitability.

    PubMed

    Wójtowicz, Tomasz; Brzdąk, Patrycja; Mozrzymas, Jerzy W

    2015-01-01

    Learning and memory require alteration in number and strength of existing synaptic connections. Extracellular proteolysis within the synapses has been shown to play a pivotal role in synaptic plasticity by determining synapse structure, function, and number. Although synaptic plasticity of excitatory synapses is generally acknowledged to play a crucial role in formation of memory traces, some components of neural plasticity are reflected by nonsynaptic changes. Since information in neural networks is ultimately conveyed with action potentials, scaling of neuronal excitability could significantly enhance or dampen the outcome of dendritic integration, boost neuronal information storage capacity and ultimately learning. However, the underlying mechanism is poorly understood. With this regard, several lines of evidence and our most recent study support a view that activity of extracellular proteases might affect information processing in neuronal networks by affecting targets beyond synapses. Here, we review the most recent studies addressing the impact of extracellular proteolysis on plasticity of neuronal excitability and discuss how enzymatic activity may alter input-output/transfer function of neurons, supporting cognitive processes. Interestingly, extracellular proteolysis may alter intrinsic neuronal excitability and excitation/inhibition balance both rapidly (time of minutes to hours) and in long-term window. Moreover, it appears that by cleavage of extracellular matrix (ECM) constituents, proteases may modulate function of ion channels or alter inhibitory drive and hence facilitate active participation of dendrites and axon initial segments (AISs) in adjusting neuronal input/output function. Altogether, a picture emerges whereby both rapid and long-term extracellular proteolysis may influence some aspects of information processing in neurons, such as initiation of action potential, spike frequency adaptation, properties of action potential and dendritic

  8. Diverse impact of acute and long-term extracellular proteolytic activity on plasticity of neuronal excitability

    PubMed Central

    Wójtowicz, Tomasz; Brzdąk, Patrycja; Mozrzymas, Jerzy W.

    2015-01-01

    Learning and memory require alteration in number and strength of existing synaptic connections. Extracellular proteolysis within the synapses has been shown to play a pivotal role in synaptic plasticity by determining synapse structure, function, and number. Although synaptic plasticity of excitatory synapses is generally acknowledged to play a crucial role in formation of memory traces, some components of neural plasticity are reflected by nonsynaptic changes. Since information in neural networks is ultimately conveyed with action potentials, scaling of neuronal excitability could significantly enhance or dampen the outcome of dendritic integration, boost neuronal information storage capacity and ultimately learning. However, the underlying mechanism is poorly understood. With this regard, several lines of evidence and our most recent study support a view that activity of extracellular proteases might affect information processing in neuronal networks by affecting targets beyond synapses. Here, we review the most recent studies addressing the impact of extracellular proteolysis on plasticity of neuronal excitability and discuss how enzymatic activity may alter input-output/transfer function of neurons, supporting cognitive processes. Interestingly, extracellular proteolysis may alter intrinsic neuronal excitability and excitation/inhibition balance both rapidly (time of minutes to hours) and in long-term window. Moreover, it appears that by cleavage of extracellular matrix (ECM) constituents, proteases may modulate function of ion channels or alter inhibitory drive and hence facilitate active participation of dendrites and axon initial segments (AISs) in adjusting neuronal input/output function. Altogether, a picture emerges whereby both rapid and long-term extracellular proteolysis may influence some aspects of information processing in neurons, such as initiation of action potential, spike frequency adaptation, properties of action potential and dendritic

  9. Bidirectional Modulation of Intrinsic Excitability in Rat Prelimbic Cortex Neuronal Ensembles and Non-Ensembles after Operant Learning.

    PubMed

    Whitaker, Leslie R; Warren, Brandon L; Venniro, Marco; Harte, Tyler C; McPherson, Kylie B; Beidel, Jennifer; Bossert, Jennifer M; Shaham, Yavin; Bonci, Antonello; Hope, Bruce T

    2017-09-06

    Learned associations between environmental stimuli and rewards drive goal-directed learning and motivated behavior. These memories are thought to be encoded by alterations within specific patterns of sparsely distributed neurons called neuronal ensembles that are activated selectively by reward-predictive stimuli. Here, we use the Fos promoter to identify strongly activated neuronal ensembles in rat prelimbic cortex (PLC) and assess altered intrinsic excitability after 10 d of operant food self-administration training (1 h/d). First, we used the Daun02 inactivation procedure in male FosLacZ-transgenic rats to ablate selectively Fos-expressing PLC neurons that were active during operant food self-administration. Selective ablation of these neurons decreased food seeking. We then used male FosGFP-transgenic rats to assess selective alterations of intrinsic excitability in Fos-expressing neuronal ensembles (FosGFP(+)) that were activated during food self-administration and compared these with alterations in less activated non-ensemble neurons (FosGFP(-)). Using whole-cell recordings of layer V pyramidal neurons in an ex vivo brain slice preparation, we found that operant self-administration increased excitability of FosGFP(+) neurons and decreased excitability of FosGFP(-) neurons. Increased excitability of FosGFP(+) neurons was driven by increased steady-state input resistance. Decreased excitability of FosGFP(-) neurons was driven by increased contribution of small-conductance calcium-activated potassium (SK) channels. Injections of the specific SK channel antagonist apamin into PLC increased Fos expression but had no effect on food seeking. Overall, operant learning increased intrinsic excitability of PLC Fos-expressing neuronal ensembles that play a role in food seeking but decreased intrinsic excitability of Fos(-) non-ensembles.SIGNIFICANCE STATEMENT Prefrontal cortex activity plays a critical role in operant learning, but the underlying cellular mechanisms are

  10. Kisspeptin and GnRH Neuronal Excitability: Molecular Mechanisms Driven by 17β-Estradiol

    PubMed Central

    Rønnekleiv, Oline K.; Zhang, Chunguang; Bosch, Martha A.; Kelly, Martin J.

    2014-01-01

    Kisspeptin is a neuropeptide that signals via a Gαq-coupled receptor, GPR54, in gonadotropin-releasing hormone (GnRH) neurons and is essential for pubertal maturation and fertility. Kisspeptin depolarizes and excites GnRH neurons primarily through the activation of canonical transient receptor potential (TRPC) channels and inhibition of K+ channels. The gonadal steroid 17β-estradiol (E2) up-regulates not only kisspeptin (Kiss1) mRNA, but also increases the excitability of the rostral forebrain Kiss1 neurons. In addition, a primary postsynaptic action of E2 on GnRH neurons is to up-regulate the expression of channel transcripts that orchestrate the downstream signaling of kisspeptin in GnRH neurons. These include not only TRPC4 channels, but also low voltage-activated T-type calcium channels and high voltage-activated L-, N- and R-type calcium channel transcripts. Moreover, E2 has direct membrane-initiated actions to alter the excitability of GnRH neurons by enhancing ATP-sensitive potassium (KATP) channel activity, which is critical for maintaining GnRH neurons in a hyperpolarized state for recruitment of T-type calcium channels that are important for burst firing. Therefore, E2 modulates the excitability of GnRH neurons as well as Kiss1 neurons by altering the expression and/or function of ion channels; and kisspeptin provides critical excitatory input to GnRH neurons to facilitate burst firing activity and peptide release. PMID:25612870

  11. Neuronal excitability level transition induced by electrical stimulation

    NASA Astrophysics Data System (ADS)

    Florence, G.; Kurths, J.; Machado, B. S.; Fonoff, E. T.; Cerdeira, H. A.; Teixeira, M. J.; Sameshima, K.

    2014-12-01

    In experimental studies, electrical stimulation (ES) has been applied to induce neuronal activity or to disrupt pathological patterns. Nevertheless, the underlying mechanisms of these activity pattern transitions are not clear. To study these phenomena, we simulated a model of the hippocampal region CA1. The computational simulations using different amplitude levels and duration of ES revealed three states of neuronal excitability: burst-firing mode, depolarization block and spreading depression wave. We used the bifurcation theory to analyse the interference of ES in the cellular excitability and the neuronal dynamics. Understanding this process would help to improve the ES techniques to control some neurological disorders.

  12. Which Neurons Will Be the Engram - Activated Neurons and/or More Excitable Neurons?

    PubMed Central

    Kim, Ji-il; Cho, Hye-Yeon; Han, Jin-Hee

    2016-01-01

    During past decades, the formation and storage principle of memory have received much attention in the neuroscience field. Although some studies have attempted to demonstrate the nature of the engram, elucidating the memory engram allocation mechanism was not possible because of the limitations of existing methods, which cannot specifically modulate the candidate neuronal population. Recently, the development of new techniques, which offer ways to mark and control specific populations of neurons, may accelerate solving this issue. Here, we review the recent advances, which have provided substantial evidence showing that both candidates (neuronal population that is activated by learning, and that has increased CREB level/excitability at learning) satisfy the criteria of the engram, which are necessary and sufficient for memory expression. PMID:27122991

  13. Change in types of neuronal excitability via bifurcation control.

    PubMed

    Xie, Yong; Aihara, Kazuyuki; Kang, Yan Mei

    2008-02-01

    This paper proposes an approach to changing the types of neuronal excitability via bifurcation control. A washout filter-aided dynamic feedback controller is introduced to bifurcation dynamics of a two-dimensional Hindmarsh-Rose type model neuron, which shows a saddle-node on invariant circle (SNIC) bifurcation from quiescence to periodic spiking and then exhibits type-I excitability. At first, a Hopf bifurcation is created at a desired parameter value before the SNIC bifurcation occurs, and then the criticality of the created Hopf bifurcation is regulated by choosing appropriate values of the controller parameters. In this manner, the model neuron starts to show type-II excitability. Therefore the type of neuronal excitability is transformed from type-I excitability to type-II excitability for the model neuron via the washout filter-aided dynamic feedback controller. In such a controller, the linear control gain is determined by the two basic critical conditions for the Hopf bifurcation, i.e., the eigenvalue assignment and the transversality condition. We apply the center manifold and normal form theory to deduce a closed-form analytic expression for the bifurcation stability coefficient, which is a function with respect to the nonlinear control gain. A suitable nonlinear control gain is chosen to make the bifurcation stability coefficient negative, and thus the criticality of the created Hopf bifurcation can be changed from subcritical to supercritical. In addition, the amplitude of the corresponding periodic solution can be also regulated by the nonlinear control gain.

  14. The Effects of Hydrazines of Neuronal Excitability

    DTIC Science & Technology

    1992-01-10

    resulting in a broadening of the action potential from 3-4 msec duration to about 10 msec (Figure 5A). HZ also affected responses of spinal neurons to...these experiments. These neurons were usually spontaneously active, firing action potentials on a underlying background synaptic barrage. These action ... action potentials , often followed by prolonged, 10-20 mV depolarizing plateau potentials . Some bursts were followed by extremely prolonged large (30

  15. The Effects of Hydrazines of Neuronal Excitability.

    DTIC Science & Technology

    1991-12-31

    these experiments. These neurons were usually spontaneously active, firing action potentials on a underlying background synaptic barrage. These action ...of action potentials , often followed by prolonged, 10-20 mV depolarizing plateau potentials . Some bursts were followed by extremely prolonged large (30... action potential from 3-4 msec duration to about 10 msec (Figure 5A). HZ also affected responses of spinal neurons to sustained stimuli. Under control

  16. Matrix Metalloproteinase-9 Regulates Neuronal Circuit Development and Excitability.

    PubMed

    Murase, Sachiko; Lantz, Crystal L; Kim, Eunyoung; Gupta, Nitin; Higgins, Richard; Stopfer, Mark; Hoffman, Dax A; Quinlan, Elizabeth M

    2016-07-01

    In early postnatal development, naturally occurring cell death, dendritic outgrowth, and synaptogenesis sculpt neuronal ensembles into functional neuronal circuits. Here, we demonstrate that deletion of the extracellular proteinase matrix metalloproteinase-9 (MMP-9) affects each of these processes, resulting in maladapted neuronal circuitry. MMP-9 deletion increases the number of CA1 pyramidal neurons but decreases dendritic length and complexity. Parallel changes in neuronal morphology are observed in primary visual cortex and persist into adulthood. Individual CA1 neurons in MMP-9(-/-) mice have enhanced input resistance and a significant increase in the frequency, but not amplitude, of miniature excitatory postsynaptic currents (mEPSCs). Additionally, deletion of MMP-9 significantly increases spontaneous neuronal activity in awake MMP-9(-/-) mice and enhances response to acute challenge by the excitotoxin kainate. Our data document a novel role for MMP-9-dependent proteolysis: the regulation of several aspects of circuit maturation to constrain excitability throughout life.

  17. Block of voltage-gated potassium channels by Pacific ciguatoxin-1 contributes to increased neuronal excitability in rat sensory neurons

    SciTech Connect

    Birinyi-Strachan, Liesl C.; Gunning, Simon J.; Lewis, Richard J.; Nicholson, Graham M. . E-mail: Graham.Nicholson@uts.edu.au

    2005-04-15

    The present study investigated the actions of the polyether marine toxin Pacific ciguatoxin-1 (P-CTX-1) on neuronal excitability in rat dorsal root ganglion (DRG) neurons using patch-clamp recording techniques. Under current-clamp conditions, bath application of 2-20 nM P-CTX-1 caused a rapid, concentration-dependent depolarization of the resting membrane potential in neurons expressing tetrodotoxin (TTX)-sensitive voltage-gated sodium (Na{sub v}) channels. This action was completely suppressed by the addition of 200 nM TTX to the external solution, indicating that this effect was mediated through TTX-sensitive Na{sub v} channels. In addition, P-CTX-1 also prolonged action potential and afterhyperpolarization (AHP) duration. In a subpopulation of neurons, P-CTX-1 also produced tonic action potential firing, an effect that was not accompanied by significant oscillation of the resting membrane potential. Conversely, in neurons expressing TTX-resistant Na{sub v} currents, P-CTX-1 failed to alter any parameter of neuronal excitability examined in this study. Under voltage-clamp conditions in rat DRG neurons, P-CTX-1 inhibited both delayed-rectifier and 'A-type' potassium currents in a dose-dependent manner, actions that occurred in the absence of alterations to the voltage dependence of activation. These actions appear to underlie the prolongation of the action potential and AHP, and contribute to repetitive firing. These data indicate that a block of potassium channels contributes to the increase in neuronal excitability, associated with a modulation of Na{sub v} channel gating, observed clinically in response to ciguatera poisoning.

  18. Sodium Leak Channels in Neuronal Excitability and Rhythmic Behaviors

    PubMed Central

    Ren, Dejian

    2011-01-01

    Extracellular K+, Na+, and Ca2+ ions all influence the resting membrane potential of the neuron. However, the mechanisms by which extracellular Na+ and Ca2+ regulate basal neuronal excitability are not well understood. Recent findings suggest that NALCN, in association with UNC79 and UNC80, contributes a basal Na+ leak conductance in neurons. Mutations in Nalcn, Unc79, or Unc80 lead to severe phenotypes that include neonatal lethality and disruption in rhythmic behaviors. This review discusses the properties of the NALCN complex, its regulation, and its contribution to neuronal function and animal behavior. PMID:22196327

  19. Pharmacological upregulation of h-channels reduces the excitability of pyramidal neuron dendrites.

    PubMed

    Poolos, Nicholas P; Migliore, Michele; Johnston, Daniel

    2002-08-01

    The dendrites of pyramidal neurons have markedly different electrical properties from those of the soma, owing to the non-uniform distribution of voltage-gated ion channels in dendrites. It is thus possible that drugs acting on ion channels might preferentially alter dendritic, but not somatic, excitability. Using dendritic and somatic whole-cell and cell-attached recordings in rat hippocampal slices, we found that the anticonvulsant lamotrigine selectively reduced action potential firing from dendritic depolarization, while minimally affecting firing at the soma. This regional and input-specific effect resulted from an increase in the hyperpolarization-activated cation current (I(h)), a voltage-gated current present predominantly in dendrites. These results demonstrate that neuronal excitability can be altered by drugs acting selectively on dendrites, and suggest an important role for I(h) in controlling dendritic excitability and epileptogenesis.

  20. The splicing regulator Rbfox1 (A2BP1) controls neuronal excitation in the mammalian brain

    PubMed Central

    Gehman, Lauren T.; Stoilov, Peter; Maguire, Jamie; Damianov, Andrey; Lin, Chia-Ho; Shiue, Lily; Ares, Manuel; Mody, Istvan; Black, Douglas L.

    2011-01-01

    The Rbfox family of RNA binding proteins regulates alternative splicing of many important neuronal transcripts but their role in neuronal physiology is not clear1. We show here that central nervous system (CNS)-specific deletion of the Rbfox1 gene results in heightened susceptibility to spontaneous and kainic acid-induced seizures. Electrophysiological recording reveals a corresponding increase in neuronal excitability in the dentate gyrus of the knockout mice. Whole transcriptome analyses identify multiple splicing changes in the Rbfox1−/− brain with few changes in overall transcript abundance. These splicing changes alter proteins that mediate synaptic transmission and membrane excitation, some of which are implicated in human epilepsy. Thus, Rbfox1 directs a genetic program required in the prevention of neuronal hyperexcitation and seizures. The Rbfox1 knockout mice provide a new model to study the post-transcriptional regulation of synaptic function. PMID:21623373

  1. Dopamine Neurons Change the Type of Excitability in Response to Stimuli

    PubMed Central

    Gutkin, Boris S.; Lapish, Christopher C.; Kuznetsov, Alexey

    2016-01-01

    The dynamics of neuronal excitability determine the neuron’s response to stimuli, its synchronization and resonance properties and, ultimately, the computations it performs in the brain. We investigated the dynamical mechanisms underlying the excitability type of dopamine (DA) neurons, using a conductance-based biophysical model, and its regulation by intrinsic and synaptic currents. Calibrating the model to reproduce low frequency tonic firing results in N-methyl-D-aspartate (NMDA) excitation balanced by γ-Aminobutyric acid (GABA)-mediated inhibition and leads to type I excitable behavior characterized by a continuous decrease in firing frequency in response to hyperpolarizing currents. Furthermore, we analyzed how excitability type of the DA neuron model is influenced by changes in the intrinsic current composition. A subthreshold sodium current is necessary for a continuous frequency decrease during application of a negative current, and the low-frequency “balanced” state during simultaneous activation of NMDA and GABA receptors. Blocking this current switches the neuron to type II characterized by the abrupt onset of repetitive firing. Enhancing the anomalous rectifier Ih current also switches the excitability to type II. Key characteristics of synaptic conductances that may be observed in vivo also change the type of excitability: a depolarized γ-Aminobutyric acid receptor (GABAR) reversal potential or co-activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) leads to an abrupt frequency drop to zero, which is typical for type II excitability. Coactivation of N-methyl-D-aspartate receptors (NMDARs) together with AMPARs and GABARs shifts the type I/II boundary toward more hyperpolarized GABAR reversal potentials. To better understand how altering each of the aforementioned currents leads to changes in excitability profile of DA neuron, we provide a thorough dynamical analysis. Collectively, these results imply that type I

  2. Moderate hypoxia influences excitability and blocks dendrotoxin sensitive K+ currents in rat primary sensory neurones

    PubMed Central

    Gruss, Marco; Ettorre, Giovanni; Stehr, Annette Jana; Henrich, Michael; Hempelmann, Gunter; Scholz, Andreas

    2006-01-01

    Hypoxia alters neuronal function and can lead to neuronal injury or death especially in the central nervous system. But little is known about the effects of hypoxia in neurones of the peripheral nervous system (PNS), which survive longer hypoxic periods. Additionally, people have experienced unpleasant sensations during ischemia which are dedicated to changes in conduction properties or changes in excitability in the PNS. However, the underlying ionic conductances in dorsal root ganglion (DRG) neurones have not been investigated in detail. Therefore we investigated the influence of moderate hypoxia (27.0 ± 1.5 mmHg) on action potentials, excitability and ionic conductances of small neurones in a slice preparation of DRGs of young rats. The neurones responded within a few minutes non-uniformly to moderate hypoxia: changes of excitability could be assigned to decreased outward currents in most of the neurones (77%) whereas a smaller group (23%) displayed increased outward currents in Ringer solution. We were able to attribute most of the reduction in outward-current to a voltage-gated K+ current which activated at potentials positive to -50 mV and was sensitive to 50 nM α-dendrotoxin (DTX). Other toxins that inhibit subtypes of voltage gated K+ channels, such as margatoxin (MgTX), dendrotoxin-K (DTX-K), r-tityustoxin Kα (TsTX-K) and r-agitoxin (AgTX-2) failed to prevent the hypoxia induced reduction. Therefore we could not assign the hypoxia sensitive K+ current to one homomeric KV channel type in sensory neurones. Functionally this K+ current blockade might underlie the increased action potential (AP) duration in these neurones. Altogether these results, might explain the functional impairment of peripheral neurones under moderate hypoxia. PMID:16579848

  3. Cingulate seizure-like activity reveals neuronal avalanche regulated by network excitability and thalamic inputs

    PubMed Central

    2014-01-01

    Background Cortical neurons display network-level dynamics with unique spatiotemporal patterns that construct the backbone of processing information signals and contribute to higher functions. Recent years have seen a wealth of research on the characteristics of neuronal networks that are sufficient conditions to activate or cease network functions. Local field potentials (LFPs) exhibit a scale-free and unique event size distribution (i.e., a neuronal avalanche) that has been proven in the cortex across species, including mice, rats, and humans, and may be used as an index of cortical excitability. In the present study, we induced seizure activity in the anterior cingulate cortex (ACC) with medial thalamic inputs and evaluated the impact of cortical excitability and thalamic inputs on network-level dynamics. We measured LFPs from multi-electrode recordings in mouse cortical slices and isoflurane-anesthetized rats. Results The ACC activity exhibited a neuronal avalanche with regard to avalanche size distribution, and the slope of the power-law distribution of the neuronal avalanche reflected network excitability in vitro and in vivo. We found that the slope of the neuronal avalanche in seizure-like activity significantly correlated with cortical excitability induced by γ-aminobutyric acid system manipulation. The thalamic inputs desynchronized cingulate seizures and affected the level of cortical excitability, the modulation of which could be determined by the slope of the avalanche size. Conclusions We propose that the neuronal avalanche may be a tool for analyzing cortical activity through LFPs to determine alterations in network dynamics. PMID:24387299

  4. Activity-dependent relocation of the axon initial segment fine-tunes neuronal excitability.

    PubMed

    Grubb, Matthew S; Burrone, Juan

    2010-06-24

    In neurons, the axon initial segment (AIS) is a specialized region near the start of the axon that is the site of action potential initiation. The precise location of the AIS varies across and within different neuronal types, and has been linked to cells' information-processing capabilities; however, the factors determining AIS position in individual neurons remain unknown. Here we show that changes in electrical activity can alter the location of the AIS. In dissociated hippocampal cultures, chronic depolarization with high extracellular potassium moves multiple components of the AIS, including voltage-gated sodium channels, up to 17 mum away from the soma of excitatory neurons. This movement reverses when neurons are returned to non-depolarized conditions, and depends on the activation of T- and/or L-type voltage-gated calcium channels. The AIS also moved distally when we combined long-term LED (light-emitting diode) photostimulation with sparse neuronal expression of the light-activated cation channel channelrhodopsin-2; here, burst patterning of activity was successful where regular stimulation at the same frequency failed. Furthermore, changes in AIS position correlate with alterations in current thresholds for action potential spiking. Our results show that neurons can regulate the position of an entire subcellular structure according to their ongoing levels and patterns of electrical activity. This novel form of activity-dependent plasticity may fine-tune neuronal excitability during development.

  5. Altered cortical excitability in anorexia nervosa.

    PubMed

    Khedr, E M; El Fetoh, N A; El Bieh, E; Ali, A M; Karim, A A

    2014-09-01

    Recent EEG and positron emission tomography (PET) studies have reported hyperactivation of the right hemisphere in anorexia nervosa (AN). The aim of the present study was to test this notion by examining cortical excitability in subjects with AN using transcranial magnetic stimulation (TMS). We investigated thirteen patients meeting the DSM IV diagnostic criteria for AN and 14 controls age and sex matched. Each subject was assessed clinically using the Eating Disorder Inventory (EDI), the Eating Attitude Test (EAT) and Beck's Depression Inventory (BDI-II). TMS measures involved resting and active motor thresholds (RMT, AMT) as well as motor evoked potentials (MEP), cortical silent period duration (CSP), transcallosal inhibition (TCI), and short latency intracortical inhibition (SICI) of the first dorsal interosseous muscle (FDI) were assessed. Cortical esophageal MEP latencies (CL) were also recorded. The RMT and MEP onset latency of the FDI and the esophagus as well as duration of the TCI were significantly reduced in anorexic patients compared to the control group. There were no significant differences neither in AMT nor CSP between patients and controls. Moreover, we found significant negative correlations between the EAT scores and RMT, and TCI duration. Although anorexic patients had significantly higher BDI score, there was no correlation between it and cortical excitability. Anorexic individuals are characterized by pathologically increased motor and esophageal cortical excitability that significantly correlates with clinical symptoms of anorexia nervosa. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  6. Chronic CXCL10 Alters Neuronal Properties in Rat Hippocampal Culture

    PubMed Central

    Cho, Jungsook; Nelson, Thomas E.; Bajova, Hilda; Gruol, Donna L.

    2009-01-01

    The chemokine CXCL10 is expressed in the central nervous system (CNS) during neuroinflammatory conditions. Neurons express CXCR3, the receptor for CXCL10, and neuronal function has been shown to be altered by acute exposure to CXCL10. Little is known about the effects of chronic exposure to CXCL10 on neuronal function. Results from our studies show that chronic exposure of cultured rat hippocampal neurons to CXCL10 results in altered levels of protein for GABA and glutamate receptors and altered synaptic network activity. These effects of CXCL10 may contribute to altered CNS function that occurs in some chronic neuroinflammatory conditions. PMID:19167097

  7. Oxytocin excites nucleus accumbens shell neurons in vivo.

    PubMed

    Moaddab, Mahsa; Hyland, Brian I; Brown, Colin H

    2015-09-01

    Oxytocin modulates reward-related behaviors. The nucleus accumbens shell (NAcSh) is a major relay in the brain reward pathway and expresses oxytocin receptors, but the effects of oxytocin on the activity of NAcSh neurons in vivo are unknown. Hence, we used in vivo extracellular recording to show that intracerebroventricular (ICV) oxytocin administration (0.2μg) robustly increased medial NAcSh neuron mean firing rate; this increase was almost exclusively evident in slow-firing neurons and was not associated with any change in firing pattern. To determine whether oxytocin excitation of medial NAcSh neurons is modulated by drugs that impact the brain reward pathway, we next tested the effects of ICV oxytocin following repeated morphine treatment. In morphine-treated rats, ICV oxytocin did not affect the mean firing rate of medial NAcSh neurons. Taken together, these results show that oxytocin excites medial NAcSh neurons but does not do so after repeated morphine. This could be an important factor in oxytocin modulation of reward-related behaviors, such as drug addiction.

  8. Heterogeneous intrinsic excitability of murine spiral ganglion neurons is determined by Kv1 and HCN channels.

    PubMed

    Liu, Q; Lee, E; Davis, R L

    2014-01-17

    The spiral ganglion conveys afferent auditory information predominantly through a single class of type I neurons that receive signals from inner hair cell sensory receptors. These auditory primary afferents, like in other systems (Puopolo and Belluzzi, 1998; Gascon and Moqrich, 2010; Leao et al., 2012) possess a marked diversity in their electrophysiological features (Taberner and Liberman, 2005). Consistent with these observations, when the auditory primary afferents were assessed in neuronal explants separated from their peripheral and central targets it was found that individual neurons were markedly heterogeneous in their endogenous electrophysiological features. One aspect of this heterogeneity, obvious throughout the ganglion, was their wide range of excitability as assessed by voltage threshold measurements (Liu and Davis, 2007). Thus, while neurons in the base differed significantly from apical and middle neurons in their voltage thresholds, each region showed distinctly wide ranges of values. To determine whether the resting membrane potentials (RMPs) of these neurons correlate with the threshold distribution and to identify the ion channel regulatory elements underlying heterogeneous neuronal excitability in the ganglion, patch-clamp recordings were made from postnatal day (P5-8) murine spiral ganglion neurons in vitro. We found that RMP mirrored the tonotopic threshold distribution, and contributed an additional level of heterogeneity in each cochlear location. Pharmacological experiments further indicated that threshold and RMP was coupled through the Kv1 current, which had a dual impact on both electrophysiological parameters. Whereas, hyperpolarization-activated cationic channels decoupled these two processes by primarily affecting RMP without altering threshold level. Thus, beyond mechanical and synaptic specializations, ion channel regulation of intrinsic membrane properties imbues spiral ganglion neurons with different excitability levels, a

  9. Enhanced excitability of guinea pig inferior mesenteric ganglion neurons during and following recovery from chemical colitis.

    PubMed

    Linden, David R

    2012-11-01

    Postganglionic sympathetic neurons in the prevertebral ganglia (PVG) provide ongoing inhibitory tone to the gastrointestinal tract and receive innervation from mechanosensory intestinofugal afferent neurons primarily located in the colon and rectum. This study tests the hypothesis that colitis alters the excitability of PVG neurons. Intracellular recording techniques were used to evaluate changes in the electrical properties of inferior mesenteric ganglion (IMG) neurons in the trinitrobenzene sulfonic acid (TNBS) and acetic acid models of guinea pig colitis. Visceromotor IMG neurons were hyperexcitable 12 and 24 h, but not 6 h, post-TNBS during "acute" inflammation. Hyperexcitability persisted at 6 days post-TNBS during "chronic" inflammation, as well as at 56 days post-TNBS when colitis had resolved. In contrast, there was only a modest decrease in the current required to elicit an action potential at 24 h after acetic acid administration. Vasomotor neurons from inflamed preparations exhibited normal excitability. The excitatory effects of XE-991, a blocker of the channel that contributes to the M-type potassium current, and heteropodatoxin-2, a blocker of the channel that contributes to the A-type potassium current, were unchanged in TNBS-inflamed preparations, suggesting that these currents did not contribute to hyperexcitability. Riluzole, an inhibitor of persistent sodium currents, caused tonic visceromotor neurons to accommodate to sustained current pulses, regardless of the inflammatory state of the preparation, and restored a normal rheobase in neurons from TNBS-inflamed preparations but did not alter the rheobase of control preparations, suggesting that enhanced activity of voltage-gated sodium channels may contribute to colitis-induced hyperexcitability. Collectively, these data indicate that enhanced sympathetic drive as a result of hyperexcitable visceromotor neurons may contribute to small bowel dysfunction during colitis.

  10. Nonlinear Dynamics of Neuronal Excitability, Oscillations, and Coincidence Detection

    PubMed Central

    RINZEL, JOHN; HUGUET, GEMMA

    2014-01-01

    We review some widely studied models and firing dynamics for neuronal systems, both at the single cell and network level, and dynamical systems techniques to study them. In particular, we focus on two topics in mathematical neuroscience that have attracted the attention of mathematicians for decades: single-cell excitability and bursting. We review the mathematical framework for three types of excitability and onset of repetitive firing behavior in single-neuron models and their relation with Hodgkin’s classification in 1948 of repetitive firing properties. We discuss the mathematical dissection of bursting oscillations using fast/slow analysis and demonstrate the approach using single-cell and mean-field network models. Finally, we illustrate the properties of Type III excitability in which case repetitive firing for constant or slow inputs is absent. Rather, firing is in response only to rapid enough changes in the stimulus. Our case study involves neuronal computations for sound localization for which neurons in the auditory brain stem perform extraordinarily precise coincidence detection with submillisecond temporal resolution. PMID:25392560

  11. Histamine excites noradrenergic neurons in locus coeruleus in rats.

    PubMed

    Korotkova, Tatiana M; Sergeeva, Olga A; Ponomarenko, Alexei A; Haas, Helmut L

    2005-07-01

    Histamine is implicated in the control of many brain functions, in particular the control of arousal. Histaminergic neurons send dense projections through the entire brain, including the locus coeruleus (LC)--the main noradrenergic (NAergic) nucleus. In this study, we have examined the effect of bath-applied histamine on cells in the LC by single-unit recordings in slices and the expression of histamine receptors in this area by single-cell RT-PCR. Histamine (10 microM) increased the firing of NAergic cells to 130+/-9% of control, 100 microM to 256+/-58% of control. This excitation was unaffected by blocking synaptic transmission. Histamine-mediated excitation was blocked by an H1 receptor antagonist, mepyramine, in 78% of cells and by cimetidine, an H2 receptor antagonist, in 42% of cells, but not by the H3 receptor antagonist, thioperamide. RT-PCR revealed that mRNA for the H1 receptor was expressed in 77% of isolated LC neurons, mRNA for the H2 receptor in 41% of LC neurons and H3 receptors in 29%. These findings underline the coordination between aminergic systems and suggest that the arousal induced by the histamine system could involve excitation of noradrenergic neurons in the locus coeruleus.

  12. Cannabinoids excite dopamine neurons in the ventral tegmentum and substantia nigra.

    PubMed

    French, E D; Dillon, K; Wu, X

    1997-02-10

    Extracellular recordings were used to determine the effects of cannabinoids on the activity of dopamine neurons within the ventral tegmental area (VTA) and substantia nigra pars compacta (SNC). Systemic administration of the natural psychoactive cannabinoid delta 9-tetrahydrocannabinol (delta 9-THC) and the synthetic cannabimimetic aminoalkylindole WIN 55,212-2 produced dose-dependent increases in firing rate and burst firing in both neuronal populations. These effects appear to be specific as the non-psychoactive cannabidiol and the inactive enantiomer WIN 55,212-3 failed to alter either parameter of neuronal excitability. Furthermore, dopamine neurons in the VTA were more sensitive than those in the SNC to the stimulatory actions of delta 9-THC. These results may provide a mechanism by which psychoactive cannabinoids increase extracellular dopamine levels in mesolimbic and striatal tissues, and thereby contribute to the reinforcing effects of marijuana.

  13. Angiotensin II attenuates synaptic GABA release and excites paraventricular-rostral ventrolateral medulla output neurons.

    PubMed

    Li, De-Pei; Pan, Hui-Lin

    2005-06-01

    The hypothalamic paraventricular nucleus (PVN) neurons regulate sympathetic outflow through projections to the spinal cord and rostral ventrolateral medulla (RVLM). Although the PVN-RVLM pathway is important for the action of brain angiotensin II (Ang II) on autonomic control, the cellular mechanisms involved are not fully known. In this study, we examined the effect of Ang II on the excitability and synaptic inputs to RVLM-projecting PVN neurons. PVN neurons were retrogradely labeled by FluoSpheres injected into the RVLM of rats. Whole-cell patch-clamp recordings were performed on labeled PVN neurons in brain slices. Ang II significantly increased the firing rate of PVN neurons from 3.63 +/- 0.65 to 6.10 +/- 0.75 Hz (P < 0.05, n = 9), and such an effect was eliminated by an AT(1) receptor antagonist, losartan. Furthermore, inclusion of a G protein inhibitor, guanosine 5'-O-(2-thiodiphosphate, in the pipette internal solution did not alter the excitatory effect of Ang II on labeled PVN neurons. Application of 0.5 to 5 microM Ang II significantly decreased the amplitude of evoked GABAergic inhibitory postsynaptic currents (IPSCs) in a dose-dependent manner. Also, 2 microM Ang II significantly decreased the frequency of miniature IPSCs (mIPSCs) from 3.89 +/- 0.84 to 2.06 +/- 0.45 Hz (P < 0.05, n = 11), but did not change the amplitude and decay time constant of mIPSCs. By contrast, Ang II had no significant effect on glutamatergic excitatory postsynaptic currents at the concentrations that inhibited IPSCs. In addition, Ang II failed to excite PVN neurons in the presence of bicuculline. Collectively, this study provides important new information that Ang II excites RVLM-projecting PVN neurons through attenuation of GABAergic synaptic inputs.

  14. Increased excitability of lateral habenula neurons in adolescent rats following cocaine self-administration.

    PubMed

    Neumann, Peter A; Ishikawa, Masago; Otaka, Mami; Huang, Yanhua H; Schlüter, Oliver M; Dong, Yan

    2014-12-28

    The lateral habenula is a brain region that has been critically implicated in modulating negative emotional states and responses to aversive stimuli. Exposure to addictive drugs such as cocaine negatively impacts affective states, an effect persisting longer than acute drug effects. However, the mechanisms of this effect are poorly understood. We hypothesized that drugs of abuse, such as cocaine, may contribute to drug-induced negative affective states by altering the firing properties of lateral habenula neurons, thus changing the signaling patterns from the lateral habenula to downstream circuits. Using whole-cell current-clamp recording of acutely prepared brain slices of rats after various periods of withdrawal from cocaine self-administration, we characterized an important heterogeneous subregion of the lateral habenula based on membrane properties. We found two major relevant neuronal subtypes: burst firing neurons and regular spiking neurons. We also found that lateral habenula regular spiking neurons had higher membrane excitability for at least 7 days following cocaine self-administration, likely due to a greater membrane resistance. Both the increase in lateral habenula excitability and membrane resistance returned to baseline when tested after a more prolonged period of 45 days of withdrawal. This is the first study to look at intrinsic lateral habenula neuron properties following cocaine exposure beyond acute drug effects. These results may help to explain how cocaine and other drugs negatively impact affect states. © The Author 2015. Published by Oxford University Press on behalf of CINP.

  15. Morphine disinhibits glutamatergic input to VTA dopamine neurons and promotes dopamine neuron excitation.

    PubMed

    Chen, Ming; Zhao, Yanfang; Yang, Hualan; Luan, Wenjie; Song, Jiaojiao; Cui, Dongyang; Dong, Yi; Lai, Bin; Ma, Lan; Zheng, Ping

    2015-07-24

    One reported mechanism for morphine activation of dopamine (DA) neurons of the ventral tegmental area (VTA) is the disinhibition model of VTA-DA neurons. Morphine inhibits GABA inhibitory neurons, which shifts the balance between inhibitory and excitatory input to VTA-DA neurons in favor of excitation and then leads to VTA-DA neuron excitation. However, it is not known whether morphine has an additional strengthening effect on excitatory input. Our results suggest that glutamatergic input to VTA-DA neurons is inhibited by GABAergic interneurons via GABAB receptors and that morphine promotes presynaptic glutamate release by removing this inhibition. We also studied the contribution of the morphine-induced disinhibitory effect on the presynaptic glutamate release to the overall excitatory effect of morphine on VTA-DA neurons and related behavior. Our results suggest that the disinhibitory action of morphine on presynaptic glutamate release might be the main mechanism for morphine-induced increase in VTA-DA neuron firing and related behaviors.

  16. Morphine disinhibits glutamatergic input to VTA dopamine neurons and promotes dopamine neuron excitation

    PubMed Central

    Chen, Ming; Zhao, Yanfang; Yang, Hualan; Luan, Wenjie; Song, Jiaojiao; Cui, Dongyang; Dong, Yi; Lai, Bin; Ma, Lan; Zheng, Ping

    2015-01-01

    One reported mechanism for morphine activation of dopamine (DA) neurons of the ventral tegmental area (VTA) is the disinhibition model of VTA-DA neurons. Morphine inhibits GABA inhibitory neurons, which shifts the balance between inhibitory and excitatory input to VTA-DA neurons in favor of excitation and then leads to VTA-DA neuron excitation. However, it is not known whether morphine has an additional strengthening effect on excitatory input. Our results suggest that glutamatergic input to VTA-DA neurons is inhibited by GABAergic interneurons via GABAB receptors and that morphine promotes presynaptic glutamate release by removing this inhibition. We also studied the contribution of the morphine-induced disinhibitory effect on the presynaptic glutamate release to the overall excitatory effect of morphine on VTA-DA neurons and related behavior. Our results suggest that the disinhibitory action of morphine on presynaptic glutamate release might be the main mechanism for morphine-induced increase in VTA-DA neuron firing and related behaviors. DOI: http://dx.doi.org/10.7554/eLife.09275.001 PMID:26208338

  17. Exon Silencing by UAGG Motifs in Response to Neuronal Excitation

    PubMed Central

    An, Ping; Grabowski, Paula J

    2007-01-01

    Alternative pre-mRNA splicing plays fundamental roles in neurons by generating functional diversity in proteins associated with the communication and connectivity of the synapse. The CI cassette of the NMDA R1 receptor is one of a variety of exons that show an increase in exon skipping in response to cell excitation, but the molecular nature of this splicing responsiveness is not yet understood. Here we investigate the molecular basis for the induced changes in splicing of the CI cassette exon in primary rat cortical cultures in response to KCl-induced depolarization using an expression assay with a tight neuron-specific readout. In this system, exon silencing in response to neuronal excitation was mediated by multiple UAGG-type silencing motifs, and transfer of the motifs to a constitutive exon conferred a similar responsiveness by gain of function. Biochemical analysis of protein binding to UAGG motifs in extracts prepared from treated and mock-treated cortical cultures showed an increase in nuclear hnRNP A1-RNA binding activity in parallel with excitation. Evidence for the role of the NMDA receptor and calcium signaling in the induced splicing response was shown by the use of specific antagonists, as well as cell-permeable inhibitors of signaling pathways. Finally, a wider role for exon-skipping responsiveness is shown to involve additional exons with UAGG-related silencing motifs, and transcripts involved in synaptic functions. These results suggest that, at the post-transcriptional level, excitable exons such as the CI cassette may be involved in strategies by which neurons mount adaptive responses to hyperstimulation. PMID:17298175

  18. Perineuronal Nets Enhance the Excitability of Fast-Spiking Neurons

    PubMed Central

    2016-01-01

    Perineuronal nets (PNNs) are specialized complexes of extracellular matrix molecules that surround the somata of fast-spiking neurons throughout the vertebrate brain. PNNs are particularly prevalent throughout the auditory brainstem, which transmits signals with high speed and precision. It is unknown whether PNNs contribute to the fast-spiking ability of the neurons they surround. Whole-cell recordings were made from medial nucleus of the trapezoid body (MNTB) principal neurons in acute brain slices from postnatal day 21 (P21) to P27 mice. PNNs were degraded by incubating slices in chondroitinase ABC (ChABC) and were compared to slices that were treated with a control enzyme (penicillinase). ChABC treatment did not affect the ability of MNTB neurons to fire at up to 1000 Hz when driven by current pulses. However, f–I (frequency–intensity) curves constructed by injecting Gaussian white noise currents superimposed on DC current steps showed that ChABC treatment reduced the gain of spike output. An increase in spike threshold may have contributed to this effect, which is consistent with the observation that spikes in ChABC-treated cells were delayed relative to control-treated cells. In addition, parvalbumin-expressing fast-spiking cortical neurons in >P70 slices that were treated with ChABC also had reduced excitability and gain. The development of PNNs around somata of fast-spiking neurons may be essential for fast and precise sensory transmission and synaptic inhibition in the brain. PMID:27570824

  19. FGF14 regulates the intrinsic excitability of cerebellar Purkinje neurons.

    PubMed

    Shakkottai, Vikram G; Xiao, Maolei; Xu, Lin; Wong, Michael; Nerbonne, Jeanne M; Ornitz, David M; Yamada, Kelvin A

    2009-01-01

    A missense mutation in the fibroblast growth factor 14 (FGF14) gene underlies SCA27, an autosomal dominant spinocerebellar ataxia in humans. Mice with a targeted disruption of the Fgf14 locus (Fgf14(-/-)) develop ataxia resembling human SCA27. We tested the hypothesis that loss of FGF14 affects the firing properties of Purkinje neurons, which play an important role in motor control and coordination. Current clamp recordings from Purkinje neurons in cerebellar slices revealed attenuated spontaneous firing in Fgf14(-/-) neurons. Unlike in the wild type animals, more than 80% of Fgf14(-/-) Purkinje neurons were quiescent and failed to fire repetitively in response to depolarizing current injections. Immunohistochemical examination revealed reduced expression of Nav1.6 protein in Fgf14(-/-) Purkinje neurons. Together, these observations suggest that FGF14 is required for normal Nav1.6 expression in Purkinje neurons, and that the loss of FGF14 impairs spontaneous and repetitive firing in Purkinje neurons by altering the expression of Nav1.6 channels.

  20. Changes in the Excitability of Neocortical Neurons in a Mouse Model of Amyotrophic Lateral Sclerosis Are Not Specific to Corticospinal Neurons and Are Modulated by Advancing Disease.

    PubMed

    Kim, Juhyun; Hughes, Ethan G; Shetty, Ashwin S; Arlotta, Paola; Goff, Loyal A; Bergles, Dwight E; Brown, Solange P

    2017-09-13

    Cell type-specific changes in neuronal excitability have been proposed to contribute to the selective degeneration of corticospinal neurons in amyotrophic lateral sclerosis (ALS) and to neocortical hyperexcitability, a prominent feature of both inherited and sporadic variants of the disease, but the mechanisms underlying selective loss of specific cell types in ALS are not known. We analyzed the physiological properties of distinct classes of cortical neurons in the motor cortex of hSOD1(G93A) mice of both sexes and found that they all exhibit increases in intrinsic excitability that depend on disease stage. Targeted recordings and in vivo calcium imaging further revealed that neurons adapt their functional properties to normalize cortical excitability as the disease progresses. Although different neuron classes all exhibited increases in intrinsic excitability, transcriptional profiling indicated that the molecular mechanisms underlying these changes are cell type specific. The increases in excitability in both excitatory and inhibitory cortical neurons show that selective dysfunction of neuronal cell types cannot account for the specific vulnerability of corticospinal motor neurons in ALS. Furthermore, the stage-dependent alterations in neuronal function highlight the ability of cortical circuits to adapt as disease progresses. These findings show that both disease stage and cell type must be considered when developing therapeutic strategies for treating ALS.SIGNIFICANCE STATEMENT It is not known why certain classes of neurons preferentially die in different neurodegenerative diseases. It has been proposed that the enhanced excitability of affected neurons is a major contributor to their selective loss. We show using a mouse model of amyotrophic lateral sclerosis (ALS), a disease in which corticospinal neurons exhibit selective vulnerability, that changes in excitability are not restricted to this neuronal class and that excitability does not increase

  1. Purines and neuronal excitability: links to the ketogenic diet.

    PubMed

    Masino, S A; Kawamura, M; Ruskin, D N; Geiger, J D; Boison, D

    2012-07-01

    ATP and adenosine are purines that play dual roles in cell metabolism and neuronal signaling. Acting at the A(1) receptor (A(1)R) subtype, adenosine acts directly on neurons to inhibit excitability and is a powerful endogenous neuroprotective and anticonvulsant molecule. Previous research showed an increase in ATP and other cell energy parameters when an animal is administered a ketogenic diet, an established metabolic therapy to reduce epileptic seizures, but the relationship among purines, neuronal excitability and the ketogenic diet was unclear. Recent work in vivo and in vitro tested the specific hypothesis that adenosine acting at A(1)Rs is a key mechanism underlying the success of ketogenic diet therapy and yielded direct evidence linking A(1)Rs to the antiepileptic effects of a ketogenic diet. Specifically, an in vitro mimic of a ketogenic diet revealed an A(1)R-dependent metabolic autocrine hyperpolarization of hippocampal neurons. In parallel, applying the ketogenic diet in vivo to transgenic mouse models with spontaneous electrographic seizures revealed that intact A(1)Rs are necessary for the seizure-suppressing effects of the diet. This is the first direct in vivo evidence linking A(1)Rs to the antiepileptic effects of a ketogenic diet. Other predictions of the relationship between purines and the ketogenic diet are discussed. Taken together, recent research on the role of purines may offer new opportunities for metabolic therapy and insight into its underlying mechanisms.

  2. Purines and Neuronal Excitability: Links to the Ketogenic Diet

    PubMed Central

    Masino, SA; Kawamura, M; Ruskin, DN; Geiger, JD; Boison, D

    2011-01-01

    ATP and adenosine are purines that play dual roles in cell metabolism and neuronal signaling. Acting at the A1 receptor (A1R) subtype, adenosine acts directly on neurons to inhibit excitability and is a powerful endogenous neuroprotective and anticonvulsant molecule. Previous research showed an increase in ATP and other cell energy parameters when an animal is administered a ketogenic diet, an established metabolic therapy to reduce epileptic seizures, but the relationship among purines, neuronal excitability and the ketogenic diet was unclear. Recent work in vivo and in vitro tested the specific hypothesis that adenosine acting at A1Rs is a key mechanism underlying the success of ketogenic diet therapy and yielded direct evidence linking A1Rs to the antiepileptic effects of a ketogenic diet. Specifically, an in vitro mimic of a ketogenic diet revealed an A1R-dependent metabolic autocrine hyperpolarization of hippocampal neurons. In parallel, applying the ketogenic diet in vivo to transgenic mouse models with spontaneous electrographic seizures revealed that intact A1Rs are necessary for the seizure-suppressing effects of the diet. This is the first direct in vivo evidence linking A1Rs to the antiepileptic effects of a ketogenic diet. Other predictions of the relationship between purines and the ketogenic diet are discussed. Taken together, recent research on the role of purines may offer new opportunities for metabolic therapy and insight into its underlying mechanisms. PMID:21880467

  3. Leptin influences the excitability of area postrema neurons.

    PubMed

    Smith, Pauline M; Brzezinska, Paulina; Hubert, Fabien; Mimee, Andrea; Maurice, Donald H; Ferguson, Alastair V

    2016-03-01

    The area postrema (AP) is a circumventricular organ with important roles in central autonomic regulation. This medullary structure has been shown to express the leptin receptor and has been suggested to have a role in modulating peripheral signals, indicating energy status. Using RT-PCR, we have confirmed the presence of mRNA for the leptin receptor, ObRb, in AP, and whole cell current-clamp recordings from dissociated AP neurons demonstrated that leptin influenced the excitability of 51% (42/82) of AP neurons. The majority of responsive neurons (62%) exhibited a depolarization (5.3 ± 0.7 mV), while the remaining affected cells (16/42) demonstrated hyperpolarizing effects (-5.96 ± 0.95 mV). Amylin was found to influence the same population of AP neurons. To elucidate the mechanism(s) of leptin and amylin actions in the AP, we used fluorescence resonance energy transfer (FRET) to determine the effect of these peptides on cAMP levels in single AP neurons. Leptin and amylin were found to elevate cAMP levels in the same dissociated AP neurons (leptin: % total FRET response 25.3 ± 4.9, n = 14; amylin: % total FRET response 21.7 ± 3.1, n = 13). When leptin and amylin were coapplied, % total FRET response rose to 53.0 ± 8.3 (n = 6). The demonstration that leptin and amylin influence a subpopulation of AP neurons and that these two signaling molecules have additive effects on single AP neurons to increase cAMP, supports a role for the AP as a central nervous system location at which these circulating signals may act through common intracellular signaling pathways to influence central control of energy balance.

  4. Profilin2 contributes to synaptic vesicle exocytosis, neuronal excitability, and novelty-seeking behavior

    PubMed Central

    Pilo Boyl, Pietro; Di Nardo, Alessia; Mulle, Christophe; Sassoè-Pognetto, Marco; Panzanelli, Patrizia; Mele, Andrea; Kneussel, Matthias; Costantini, Vivian; Perlas, Emerald; Massimi, Marzia; Vara, Hugo; Giustetto, Maurizio; Witke, Walter

    2007-01-01

    Profilins are actin binding proteins essential for regulating cytoskeletal dynamics, however, their function in the mammalian nervous system is unknown. Here, we provide evidence that in mouse brain profilin1 and profilin2 have distinct roles in regulating synaptic actin polymerization with profilin2 preferring a WAVE-complex-mediated pathway. Mice lacking profilin2 show a block in synaptic actin polymerization in response to depolarization, which is accompanied by increased synaptic excitability of glutamatergic neurons due to higher vesicle exocytosis. These alterations in neurotransmitter release correlate with a hyperactivation of the striatum and enhanced novelty-seeking behavior in profilin2 mutant mice. Our results highlight a novel, profilin2-dependent pathway, regulating synaptic physiology, neuronal excitability, and complex behavior. PMID:17541406

  5. Heat pulse excitability of vestibular hair cells and afferent neurons

    PubMed Central

    Brichta, Alan M.; Tabatabaee, Hessam; Boutros, Peter J.; Ahn, JoongHo; Della Santina, Charles C.; Poppi, Lauren A.; Lim, Rebecca

    2016-01-01

    In the present study we combined electrophysiology with optical heat pulse stimuli to examine thermodynamics of membrane electrical excitability in mammalian vestibular hair cells and afferent neurons. We recorded whole cell currents in mammalian type II vestibular hair cells using an excised preparation (mouse) and action potentials (APs) in afferent neurons in vivo (chinchilla) in response to optical heat pulses applied to the crista (ΔT ≈ 0.25°C per pulse). Afferent spike trains evoked by heat pulse stimuli were diverse and included asynchronous inhibition, asynchronous excitation, and/or phase-locked APs synchronized to each infrared heat pulse. Thermal responses of membrane currents responsible for APs in ganglion neurons were strictly excitatory, with Q10 ≈ 2. In contrast, hair cells responded with a mix of excitatory and inhibitory currents. Excitatory hair cell membrane currents included a thermoelectric capacitive current proportional to the rate of temperature rise (dT/dt) and an inward conduction current driven by ΔT. An iberiotoxin-sensitive inhibitory conduction current was also evoked by ΔT, rising in <3 ms and decaying with a time constant of ∼24 ms. The inhibitory component dominated whole cell currents in 50% of hair cells at −68 mV and in 67% of hair cells at −60 mV. Responses were quantified and described on the basis of first principles of thermodynamics. Results identify key molecular targets underlying heat pulse excitability in vestibular sensory organs and provide quantitative methods for rational application of optical heat pulses to examine protein biophysics and manipulate cellular excitability. PMID:27226448

  6. Time and dose dependent effects of oxidative stress induced by cumene hydroperoxide in neuronal excitability of rat motor cortex neurons.

    PubMed

    Pardillo-Díaz, R; Carrascal, L; Muñoz, M F; Ayala, A; Nunez-Abades, P

    2016-03-01

    It has been claimed that oxidative stress and the production of reactive oxygen radicals can contribute to neuron degeneration and might be one factor in the development of different neurological diseases. In our study, we have attempted to clarify how oxidative damage induces dose dependent changes in functional membrane properties of neurons by means of whole cell patch clamp techniques in brain slices from young adult rats. Our research demonstrates physiological changes in membrane properties of pyramidal motor cortex neurons exposed to 3 concentrations of cumene hydroperoxide (CH; 1, 10 and 100μM) during 30min. Results show that oxidative stress induced by CH evokes important changes, in a concentration and time dependent manner, in the neuronal excitability of motor cortex neurons of the rat: (i) Low concentration of the drug (1μM) already blocks inward rectifications (sag) and decreases action potential amplitude and gain, a drug concentration which has no effects on other neuronal populations, (ii) 10μM of CH depresses the excitability of pyramidal motor cortex neurons by decreasing input resistance, amplitude of the action potential, and gain and maximum frequency of the repetitive firing discharge, and (iii) 100μM completely blocks the capability to produce repetitive discharge of action potentials in all cells. Both larger drug concentrations and/or longer times of exposure to CH narrow the current working range. This happens because of the increase in the rheobase, and the reduction of the cancelation current. The effects caused by oxidative stress, including those produced by the level of lipid peroxidation, are practically irreversible and, this, therefore, indicates that neuroprotective agents should be administered at the first symptoms of alterations to membrane properties. In fact, the pre-treatment with melatonin, acting as an antioxidant, prevented the lipid peroxidation and the physiological changes induced by CH. Larger cells (as estimated

  7. Metabotropic suppression of excitation in murine autaptic hippocampal neurons.

    PubMed

    Straiker, Alex; Mackie, Ken

    2007-02-01

    Depolarization-induced suppression of excitation (DSE) and inhibition (DSI) are forms of short-term neuronal plasticity involving postsynaptic release of an endocannabinoid and the activation of presynaptic cannabinoid CB1 receptors. We have recently reported that CB1-dependent DSE can be elicited in autaptic cultures of excitatory hippocampal neurons of the mouse. We now report that the same preparation exhibits a parallel G(q)-coupled receptor-dependent production of endocannabinoids causing retrograde inhibition, also via CB1 receptors, which we will refer to as metabotropic suppression of excitation (MSE). We tested a spectrum of G(q)-coupled receptor agonists and found that both muscarinic and metabotropic glutamate receptors (group I) mediate retrograde inhibition via CB1 receptors in autaptic hippocampal neurons. Thus these neurons possess not only the pre- and postsynaptic machinery necessary for DSE but also that for MSE. This permitted a closer examination of MSE and its interaction with other aspects of the endocannabinoid retrograde signalling machinery: MSE mimics and occludes DSE and is itself occluded by the endocannabinoid 2-arachidonoyl glycerol (2-AG), consistent with 2-AG as a likely mediator of MSE. In contrast to DSE, MSE undergoes heterologous desensitization over the time course of minutes. In keeping with data reported for metabotropic suppression of inhibition (MSI) and DSI in the hippocampus, subthreshold MSE and DSE act synergistically. We additionally found that Delta9-tetrahydrocannabinol, which has been shown to attenuate DSE, antagonizes MSE. Finally, we have distinguished a neuronal subpopulation that exhibits DSE and a differential complement of MSE-mediating Gq-coupled receptors, making possible contrasting studies of MSE. Autaptic endocannabinoid signalling is rich, robust and complex in a deceptively simple package, including a previously unreported postsynaptic mechanism of adaptation in addition to known presynaptic CB1

  8. Oxidative stress induced by cumene hydroperoxide evokes changes in neuronal excitability of rat motor cortex neurons.

    PubMed

    Pardillo-Díaz, R; Carrascal, L; Ayala, A; Nunez-Abades, P

    2015-03-19

    Oxidative stress and the production of reactive oxygen radicals play a key role in neuronal cell damage. This paper describes an in vitro study that explores the neuronal responses to oxidative stress focusing on changes in neuronal excitability and functional membrane properties. This study was carried out in pyramidal cells of the motor cortex by applying whole-cell patch-clamp techniques on brain slices from young adult rats. Oxygen-derived free radical formation was induced by bath application of 10μM cumene hydroperoxide (CH) for 30min. CH produced marked changes in the electrophysiological properties of neurons (n=30). Resting membrane potential became progressively depolarized, as well as depolarization voltage, with no variations in voltage threshold. Membrane resistance showed a biphasic behavior, increasing after 5min of drug exposure and then it started to decrease, even under control values, after 15 and 30min. At the same time, changes in membrane resistance produced compensatory variations in the rheobase. The amplitude of the action potentials diminished and the duration increased progressively over time. Some of the neurons under study also lost their ability to discharge action potentials in a repetitive way. Most of the neurons, however, kept their repetitive discharge even though their maximum frequency and gain decreased. Furthermore, cancelation of the repetitive firing discharge took place at intensities that decreased with time of exposure to CH, which resulted in a narrower working range. We can conclude that oxidative stress compromises both neuronal excitability and the capability of generating action potentials, and so this type of neuronal functional failure could precede the neuronal death characteristics of many neurodegenerative diseases.

  9. Neonatal tissue injury reduces the intrinsic excitability of adult mouse superficial dorsal horn neurons.

    PubMed

    Li, J; Baccei, M L

    2014-01-03

    Tissue damage during the neonatal period evokes long-lasting changes in nociceptive processing within the adult spinal cord which contribute to persistent alterations in pain sensitivity. However, it remains unclear if the observed modifications in neuronal activity within the mature superficial dorsal horn (SDH) following early injury reflect shifts in the intrinsic membrane properties of these cells. Therefore, the present study was undertaken to identify the effects of neonatal surgical injury on the intrinsic excitability of both GABAergic and presumed glutamatergic neurons within lamina II of the adult SDH using in vitro patch clamp recordings from spinal cord slices prepared from glutamic acid decarboxylase-green fluorescent protein (Gad-GFP) mice. The results demonstrate that hindpaw surgical incision at postnatal day (P) 3 altered the passive membrane properties of both Gad-GFP and adjacent, non-GFP neurons in the mature SDH, as evidenced by decreased membrane resistance and more negative resting potentials in comparison to naïve littermate controls. This was accompanied by a reduction in the prevalence of spontaneous activity within the GABAergic population. Both Gad-GFP and non-GFP neurons displayed a significant elevation in rheobase and decreased instantaneous firing frequency after incision, suggesting that early tissue damage lowers the intrinsic membrane excitability of adult SDH neurons. Isolation of inward-rectifying K(+) (K(ir)) currents revealed that neonatal incision significantly increased K(ir) conductance near physiological membrane potentials in GABAergic, but not glutamatergic, lamina II neurons. Overall, these findings suggest that neonatal tissue injury causes a long-term dampening of intrinsic firing across the general population of lamina II interneurons, but the underlying ionic mechanisms may be cell-type specific. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

  10. Intracellular gold nanoparticles increase neuronal excitability and aggravate seizure activity in the mouse brain.

    PubMed

    Jung, Seungmoon; Bang, Minji; Kim, Byung Sun; Lee, Sungmun; Kotov, Nicholas A; Kim, Bongsoo; Jeon, Daejong

    2014-01-01

    Due to their inert property, gold nanoparticles (AuNPs) have drawn considerable attention; their biological application has recently expanded to include nanomedicine and neuroscience. However, the effect of AuNPs on the bioelectrical properties of a single neuron remains unknown. Here we present the effect of AuNPs on a single neuron under physiological and pathological conditions in vitro. AuNPs were intracellularly applied to hippocampal CA1 neurons from the mouse brain. The electrophysiological property of CA1 neurons treated with 5- or 40-nm AuNPs was assessed using the whole-cell patch-clamp technique. Intracellular application of AuNPs increased both the number of action potentials (APs) and input resistance. The threshold and duration of APs and the after hyperpolarization (AHP) were decreased by the intracellular AuNPs. In addition, intracellular AuNPs elicited paroxysmal depolarizing shift-like firing patterns during sustained repetitive firings (SRF) induced by prolonged depolarization (10 sec). Furthermore, low Mg2+-induced epileptiform activity was aggravated by the intracellular AuNPs. In this study, we demonstrated that intracellular AuNPs alter the intrinsic properties of neurons toward increasing their excitability, and may have deleterious effects on neurons under pathological conditions, such as seizure. These results provide some considerable direction on application of AuNPs into central nervous system (CNS).

  11. Increased excitability of both principle neurons and interneurons during associative learning

    PubMed Central

    Oh, M. Matthew; Disterhoft, John F.

    2015-01-01

    In this review, we highlight several studies indicating that modulation of intrinsic neuronal excitability is a key for successful memory formation. Specifically, we will focus our discussion on our hypothesis that the postburst afterhyperpolarization (AHP: a key regulator of intrinsic excitability) is an essential cellular mechanism used by both principle and inhibitory neurons to change their neuronal activity as memory is formed. In addition, we propose that these intrinsic excitability changes occur first in principle neurons, followed by changes in inhibitory neurons; thus maintaining the balance of network activity among neurons for successful encoding and read-out of memory. PMID:24946769

  12. Connectivity, excitability and activity patterns in neuronal networks

    NASA Astrophysics Data System (ADS)

    le Feber, Joost; Stoyanova, Irina I.; Chiappalone, Michela

    2014-06-01

    Extremely synchronized firing patterns such as those observed in brain diseases like epilepsy may result from excessive network excitability. Although network excitability is closely related to (excitatory) connectivity, a direct measure for network excitability remains unavailable. Several methods currently exist for estimating network connectivity, most of which are related to cross-correlation. An example is the conditional firing probability (CFP) analysis which calculates the pairwise probability (CFPi,j) that electrode j records an action potential at time t = τ, given that electrode i recorded a spike at t = 0. However, electrode i often records multiple spikes within the analysis interval, and CFP values are biased by the on-going dynamic state of the network. Here we show that in a linear approximation this bias may be removed by deconvoluting CFPi,j with the autocorrelation of i (i.e. CFPi,i), to obtain the single pulse response (SPRi,j)—the average response at electrode j to a single spike at electrode i. Thus, in a linear system SPRs would be independent of the dynamic network state. Nonlinear components of synaptic transmission, such as facilitation and short term depression, will however still affect SPRs. Therefore SPRs provide a clean measure of network excitability. We used carbachol and ghrelin to moderately activate cultured cortical networks to affect their dynamic state. Both neuromodulators transformed the bursting firing patterns of the isolated networks into more dispersed firing. We show that the influence of the dynamic state on SPRs is much smaller than the effect on CFPs, but not zero. The remaining difference reflects the alteration in network excitability. We conclude that SPRs are less contaminated by the dynamic network state and that mild excitation may decrease network excitability, possibly through short term synaptic depression.

  13. Efavirenz Induces Neuronal Autophagy and Mitochondrial Alterations

    PubMed Central

    Purnell, Phillip R.

    2014-01-01

    Efavirenz (EFV) is a non-nucleoside reverse-transcriptase inhibitor in wide use for the treatment of human immunodeficiency virus infection. Although EFV is generally well tolerated, neuropsychiatric toxicity has been well documented. The toxic effects of EFV in hepatocytes and keratinocytes have been linked to mitochondrial perturbations and changes in autophagy. Here, we studied the effect of EFV on mitochondria and autophagy in neuronal cell lines and primary neurons. In SH-SY5Y cells, EFV induced a drop in ATP production, which coincided with increased autophagy, mitochondrial fragmentation, and mitochondrial depolarization. EFV-induced mitophagy was also detected by colocalization of mitochondria and autophagosomes and use of an outer mitochondrial membrane tandem fluorescent vector. Pharmacologic inhibition of autophagy with 3-methyladenine increased the cytotoxic effect of EFV, suggesting that autophagy promotes cell survival. EFV also reduces ATP production in primary neurons, induces autophagy, and changes mitochondrial morphology. Overall, EFV is able to acutely induce autophagy and mitochondrial changes in neurons. These changes may be involved in the mechanism leading to central nervous system toxicity observed in clinical EFV use. PMID:25161171

  14. Nicotinic receptor-mediated biphasic effect on neuronal excitability in chick lateral spiriform neurons.

    PubMed

    Liu, Y-B; Guo, J-Z; Chiappinelli, V A

    2007-09-21

    Local neuronal circuits integrate synaptic information with different excitatory or inhibitory time windows. Here we report that activation of nicotinic acetylcholine receptors (nAChRs) leads to biphasic effects on excitability in chick lateral spiriform (SPL) neurons during whole cell recordings in brain slices. Carbachol (100 microM in the presence of 1 microM atropine) produced an initial short-term increase in the firing rates of SPL neurons (125+/-14% of control) that was mediated by postsynaptic nAChRs. However, after 3 min exposure to nicotinic agonists, the firing rate measured during an 800 ms depolarizing pulse declined to 19+/-7% (100 microM carbachol) or 26+/-8% (10 microM nicotine) of the control rate and remained decreased for 10-20 min after washout of the agonists. Similarly, after 60 s of electrically-stimulated release of endogenous acetylcholine (ACh) from cholinergic afferent fibers, there was a marked reduction (45+/-5% of control) in firing rates in SPL neurons. All of these effects were blocked by the nAChR antagonist dihydro-beta-erythroidine (30 microM). The inhibitory effect was not observed in Ca(2+)-free buffer. The nAChR-mediated inhibition depended on active G-proteins in SPL neurons and was prevented by the GABA(B) receptor antagonist phaclofen (200 microM), while the GABA(B) receptor agonist baclofen (10 microM) decreased firing rate in SPL neurons to 13+/-1% of control. The inhibitory response thus appears to be due to a nAChR-mediated enhancement of presynaptic GABA release, which then activates postsynaptic GABA(B) receptors. In conclusion, activation of nAChRs in the SPL initiates a limited time window for an excitatory period, after which a prolonged inhibitory effect turns off this window. The prolonged inhibitory effect may serve to protect SPL neurons from excessive excitation.

  15. Genetic activation of BK currents in vivo generates bidirectional effects on neuronal excitability

    PubMed Central

    Montgomery, Jenna R.; Meredith, Andrea L.

    2012-01-01

    Large-conductance calcium-activated potassium channels (BK) are potent negative regulators of excitability in neurons and muscle, and increasing BK current is a novel therapeutic strategy for neuro- and cardioprotection, disorders of smooth muscle hyperactivity, and several psychiatric diseases. However, in some neurons, enhanced BK current is linked with seizures and paradoxical increases in excitability, potentially complicating the clinical use of agonists. The mechanisms that switch BK influence from inhibitory to excitatory are not well defined. Here we investigate this dichotomy using a gain-of-function subunit (BKR207Q) to enhance BK currents. Heterologous expression of BKR207Q generated currents that activated at physiologically relevant voltages in lower intracellular Ca2+, activated faster, and deactivated slower than wild-type currents. We then used BKR207Q expression to broadly augment endogenous BK currents in vivo, generating a transgenic mouse from a circadian clock-controlled Period1 gene fragment (Tg-BKR207Q). The specific impact on excitability was assessed in neurons of the suprachiasmatic nucleus (SCN) in the hypothalamus, a cell type where BK currents regulate spontaneous firing under distinct day and night conditions that are defined by different complements of ionic currents. In the SCN, Tg-BKR207Q expression converted the endogenous BK current to fast-activating, while maintaining similar current-voltage properties between day and night. Alteration of BK currents in Tg-BKR207Q SCN neurons increased firing at night but decreased firing during the day, demonstrating that BK currents generate bidirectional effects on neuronal firing under distinct conditions. PMID:23112153

  16. Quasimodo mediates daily and acute light effects on Drosophila clock neuron excitability.

    PubMed

    Buhl, Edgar; Bradlaugh, Adam; Ogueta, Maite; Chen, Ko-Fan; Stanewsky, Ralf; Hodge, James J L

    2016-11-22

    We have characterized a light-input pathway regulating Drosophila clock neuron excitability. The molecular clock drives rhythmic electrical excitability of clock neurons, and we show that the recently discovered light-input factor Quasimodo (Qsm) regulates this variation, presumably via an Na(+), K(+), Cl(-) cotransporter (NKCC) and the Shaw K(+) channel (dKV3.1). Because of light-dependent degradation of the clock protein Timeless (Tim), constant illumination (LL) leads to a breakdown of molecular and behavioral rhythms. Both overexpression ((OX)) and knockdown ((RNAi)) of qsm, NKCC, or Shaw led to robust LL rhythmicity. Whole-cell recordings of the large ventral lateral neurons (l-LNv) showed that altering Qsm levels reduced the daily variation in neuronal activity: qsm(OX) led to a constitutive less active, night-like state, and qsm(RNAi) led to a more active, day-like state. Qsm also affected daily changes in K(+) currents and the GABA reversal potential, suggesting a role in modifying membrane currents and GABA responses in a daily fashion, potentially modulating light arousal and input to the clock. When directly challenged with blue light, wild-type l-LNvs responded with increased firing at night and no net response during the day, whereas altering Qsm, NKKC, or Shaw levels abolished these day/night differences. Finally, coexpression of Shaw(OX) and NKCC(RNAi) in a qsm mutant background restored LL-induced behavioral arrhythmicity and wild-type neuronal activity patterns, suggesting that the three genes operate in the same pathway. We propose that Qsm affects both daily and acute light effects in l-LNvs probably acting on Shaw and NKCC.

  17. Glutamate alteration of glutamic acid decarboxylase (GAD) in GABAergic neurons: the role of cysteine proteases.

    PubMed

    Monnerie, Hubert; Le Roux, Peter D

    2008-09-01

    Brain cell vulnerability to neurologic insults varies greatly, depending on their neuronal subpopulation. Among cells that survive a pathological insult such as ischemia or brain trauma, some may undergo morphological and/or biochemical changes that could compromise brain function. We previously reported that surviving cortical GABAergic neurons exposed to glutamate in vitro displayed an NMDA receptor (NMDAR)-mediated alteration in the levels of the GABA synthesizing enzyme glutamic acid decarboxylase (GAD65/67) [Monnerie, H., Le Roux, P., 2007. Reduced dendrite growth and altered glutamic acid decarboxylase (GAD) 65- and 67-kDa isoform protein expression from mouse cortical GABAergic neurons following excitotoxic injury in vitro. Exp. Neurol. 205, 367-382]. In this study, we examined the mechanisms by which glutamate excitotoxicity caused a change in cortical GABAergic neurons' GAD protein levels. Removing extracellular calcium prevented the NMDAR-mediated decrease in GAD protein levels, measured using Western blot techniques, whereas inhibiting calcium entry through voltage-gated calcium channels had no effect. Glutamate's effect on GAD protein isoforms was significantly attenuated by preincubation with the cysteine protease inhibitor N-Acetyl-L-Leucyl-L-Leucyl-L-norleucinal (ALLN). Using class-specific protease inhibitors, we observed that ALLN's effect resulted from the blockade of calpain and cathepsin protease activities. Cell-free proteolysis assay confirmed that both proteases were involved in glutamate-induced alteration in GAD protein levels. Together these results suggest that glutamate-induced excitotoxic stimulation of NMDAR in cultured cortical neurons leads to altered GAD protein levels from GABAergic neurons through intracellular calcium increase and protease activation including calpain and cathepsin. Biochemical alterations in surviving cortical GABAergic neurons in various disease states may contribute to the altered balance between excitation

  18. Noise-induced transition in excitable neuron models.

    PubMed

    Tanabe, S; Pakdaman, K

    2001-10-01

    We studied the influence of noisy stimulation on the Hodgkin-Huxley neuron model. Rather than examining the noise-related variability of the discharge times of the model--as has been done previously--our study focused on the effect of noise on the stationary distributions of the membrane potential and gating variables of the model. We observed that a gradual increase in the noise intensity did not result in a gradual change of the distributions. Instead, we could identify a critical intermediate noise range in which the shapes of the distributions underwent a drastic qualitative change. Namely, they moved from narrow unimodal Gaussian-like shapes associated with low noise intensities to ones that spread widely at large noise intensities. In particular, for the membrane potential and the sodium activation variable, the distributions changed from unimodal to bimodal. Thus, our investigation revealed a noise-induced transition in the Hodgkin-Huxley model. In order to further characterize this phenomenon, we considered a reduced one-dimensional model of an excitable system, namely the active rotator. For this model, our analysis indicated that the noise-induced transition is associated with a deterministic bifurcation of approximate equations governing the dynamics of the mean and variance of the state variable. Finally, we shed light on the possible functional importance of this noise-induced transition in neuronal coding by determining its effect on the spike timing precision in models of neuronal ensembles.

  19. An FPGA-Based Silicon Neuronal Network with Selectable Excitability Silicon Neurons.

    PubMed

    Li, Jing; Katori, Yuichi; Kohno, Takashi

    2012-01-01

    This paper presents a digital silicon neuronal network which simulates the nerve system in creatures and has the ability to execute intelligent tasks, such as associative memory. Two essential elements, the mathematical-structure-based digital spiking silicon neuron (DSSN) and the transmitter release based silicon synapse, allow us to tune the excitability of silicon neurons and are computationally efficient for hardware implementation. We adopt mixed pipeline and parallel structure and shift operations to design a sufficient large and complex network without excessive hardware resource cost. The network with 256 full-connected neurons is built on a Digilent Atlys board equipped with a Xilinx Spartan-6 LX45 FPGA. Besides, a memory control block and USB control block are designed to accomplish the task of data communication between the network and the host PC. This paper also describes the mechanism of associative memory performed in the silicon neuronal network. The network is capable of retrieving stored patterns if the inputs contain enough information of them. The retrieving probability increases with the similarity between the input and the stored pattern increasing. Synchronization of neurons is observed when the successful stored pattern retrieval occurs.

  20. An FPGA-Based Silicon Neuronal Network with Selectable Excitability Silicon Neurons

    PubMed Central

    Li, Jing; Katori, Yuichi; Kohno, Takashi

    2012-01-01

    This paper presents a digital silicon neuronal network which simulates the nerve system in creatures and has the ability to execute intelligent tasks, such as associative memory. Two essential elements, the mathematical-structure-based digital spiking silicon neuron (DSSN) and the transmitter release based silicon synapse, allow us to tune the excitability of silicon neurons and are computationally efficient for hardware implementation. We adopt mixed pipeline and parallel structure and shift operations to design a sufficient large and complex network without excessive hardware resource cost. The network with 256 full-connected neurons is built on a Digilent Atlys board equipped with a Xilinx Spartan-6 LX45 FPGA. Besides, a memory control block and USB control block are designed to accomplish the task of data communication between the network and the host PC. This paper also describes the mechanism of associative memory performed in the silicon neuronal network. The network is capable of retrieving stored patterns if the inputs contain enough information of them. The retrieving probability increases with the similarity between the input and the stored pattern increasing. Synchronization of neurons is observed when the successful stored pattern retrieval occurs. PMID:23269911

  1. Regulation of neuronal excitability by interaction of fragile X mental retardation protein with slack potassium channels.

    PubMed

    Zhang, Yalan; Brown, Maile R; Hyland, Callen; Chen, Yi; Kronengold, Jack; Fleming, Matthew R; Kohn, Andrea B; Moroz, Leonid L; Kaczmarek, Leonard K

    2012-10-31

    Loss of the RNA-binding protein fragile X mental retardation protein (FMRP) represents the most common form of inherited intellectual disability. Studies with heterologous expression systems indicate that FMRP interacts directly with Slack Na(+)-activated K(+) channels (K(Na)), producing an enhancement of channel activity. We have now used Aplysia bag cell (BC) neurons, which regulate reproductive behaviors, to examine the effects of Slack and FMRP on excitability. FMRP and Slack immunoreactivity were colocalized at the periphery of isolated BC neurons, and the two proteins could be reciprocally coimmunoprecipitated. Intracellular injection of FMRP lacking its mRNA binding domain rapidly induced a biphasic outward current, with an early transient tetrodotoxin-sensitive component followed by a slowly activating sustained component. The properties of this current matched that of the native Slack potassium current, which was identified using an siRNA approach. Addition of FMRP to inside-out patches containing native Aplysia Slack channels increased channel opening and, in current-clamp recordings, produced narrowing of action potentials. Suppression of Slack expression did not alter the ability of BC neurons to undergo a characteristic prolonged discharge in response to synaptic stimulation, but prevented recovery from a prolonged inhibitory period that normally follows the discharge. Recovery from the inhibited period was also inhibited by the protein synthesis inhibitor anisomycin. Our studies indicate that, in BC neurons, Slack channels are required for prolonged changes in neuronal excitability that require new protein synthesis, and raise the possibility that channel-FMRP interactions may link changes in neuronal firing to changes in protein translation.

  2. Increased Cell-Intrinsic Excitability Induces Synaptic Changes in New Neurons in the Adult Dentate Gyrus That Require Npas4

    PubMed Central

    Sim, Shuyin; Antolin, Salome; Lin, Chia-Wei; Lin, Ying-Xi

    2013-01-01

    Electrical activity regulates the manner in which neurons mature and form connections to each other. However, it remains unclear whether increased single-cell activity is sufficient to alter the development of synaptic connectivity of that neuron or whether a global increase in circuit activity is necessary. To address this question, we genetically increased neuronal excitability of in vivo individual adult-born neurons in the mouse dentate gyrus via expression of a voltage-gated bacterial sodium channel. We observed that increasing the excitability of new neurons in an otherwise unperturbed circuit leads to changes in both their input and axonal synapses. Furthermore, the activity-dependent transcription factor Npas4 is necessary for the changes in the input synapses of these neurons, but it is not involved in changes to their axonal synapses. Our results reveal that an increase in cell-intrinsic activity during maturation is sufficient to alter the synaptic connectivity of a neuron with the hippocampal circuit and that Npas4 is required for activity-dependent changes in input synapses. PMID:23637184

  3. Low excitatory innervation balances high intrinsic excitability of immature dentate neurons

    SciTech Connect

    Dieni, Cristina V.; Panichi, Roberto; Aimone, James B.; Kuo, Chay T.; Wadiche, Jacques I.; Overstreet-Wadiche, Linda

    2016-04-20

    Persistent neurogenesis in the dentate gyrus produces immature neurons with high intrinsic excitability and low levels of inhibition that are predicted to be more broadly responsive to afferent activity than mature neurons. Mounting evidence suggests that these immature neurons are necessary for generating distinct neural representations of similar contexts, but it is unclear how broadly responsive neurons help distinguish between similar patterns of afferent activity. Here we show that stimulation of the entorhinal cortex in mouse brain slices paradoxically generates spiking of mature neurons in the absence of immature neuron spiking. Immature neurons with high intrinsic excitability fail to spike due to insufficient excitatory drive that results from low innervation rather than silent synapses or low release probability. Here, our results suggest that low synaptic connectivity prevents immature neurons from responding broadly to cortical activity, potentially enabling excitable immature neurons to contribute to sparse and orthogonal dentate representations.

  4. Low excitatory innervation balances high intrinsic excitability of immature dentate neurons

    DOE PAGES

    Dieni, Cristina V.; Panichi, Roberto; Aimone, James B.; ...

    2016-04-20

    Persistent neurogenesis in the dentate gyrus produces immature neurons with high intrinsic excitability and low levels of inhibition that are predicted to be more broadly responsive to afferent activity than mature neurons. Mounting evidence suggests that these immature neurons are necessary for generating distinct neural representations of similar contexts, but it is unclear how broadly responsive neurons help distinguish between similar patterns of afferent activity. Here we show that stimulation of the entorhinal cortex in mouse brain slices paradoxically generates spiking of mature neurons in the absence of immature neuron spiking. Immature neurons with high intrinsic excitability fail to spikemore » due to insufficient excitatory drive that results from low innervation rather than silent synapses or low release probability. Here, our results suggest that low synaptic connectivity prevents immature neurons from responding broadly to cortical activity, potentially enabling excitable immature neurons to contribute to sparse and orthogonal dentate representations.« less

  5. Low excitatory innervation balances high intrinsic excitability of immature dentate neurons

    PubMed Central

    Dieni, Cristina V.; Panichi, Roberto; Aimone, James B.; Kuo, Chay T.; Wadiche, Jacques I.; Overstreet-Wadiche, Linda

    2016-01-01

    Persistent neurogenesis in the dentate gyrus produces immature neurons with high intrinsic excitability and low levels of inhibition that are predicted to be more broadly responsive to afferent activity than mature neurons. Mounting evidence suggests that these immature neurons are necessary for generating distinct neural representations of similar contexts, but it is unclear how broadly responsive neurons help distinguish between similar patterns of afferent activity. Here we show that stimulation of the entorhinal cortex in mouse brain slices paradoxically generates spiking of mature neurons in the absence of immature neuron spiking. Immature neurons with high intrinsic excitability fail to spike due to insufficient excitatory drive that results from low innervation rather than silent synapses or low release probability. Our results suggest that low synaptic connectivity prevents immature neurons from responding broadly to cortical activity, potentially enabling excitable immature neurons to contribute to sparse and orthogonal dentate representations. PMID:27095423

  6. Low excitatory innervation balances high intrinsic excitability of immature dentate neurons.

    PubMed

    Dieni, Cristina V; Panichi, Roberto; Aimone, James B; Kuo, Chay T; Wadiche, Jacques I; Overstreet-Wadiche, Linda

    2016-04-20

    Persistent neurogenesis in the dentate gyrus produces immature neurons with high intrinsic excitability and low levels of inhibition that are predicted to be more broadly responsive to afferent activity than mature neurons. Mounting evidence suggests that these immature neurons are necessary for generating distinct neural representations of similar contexts, but it is unclear how broadly responsive neurons help distinguish between similar patterns of afferent activity. Here we show that stimulation of the entorhinal cortex in mouse brain slices paradoxically generates spiking of mature neurons in the absence of immature neuron spiking. Immature neurons with high intrinsic excitability fail to spike due to insufficient excitatory drive that results from low innervation rather than silent synapses or low release probability. Our results suggest that low synaptic connectivity prevents immature neurons from responding broadly to cortical activity, potentially enabling excitable immature neurons to contribute to sparse and orthogonal dentate representations.

  7. Pulsed infrared radiation excites cultured neonatal spiral and vestibular ganglion neurons by modulating mitochondrial calcium cycling

    PubMed Central

    Lumbreras, Vicente; Bas, Esperanza; Gupta, Chhavi

    2014-01-01

    Cochlear implants are currently the most effective solution for profound sensorineural hearing loss, and vestibular prostheses are under development to treat bilateral vestibulopathies. Electrical current spread in these neuroprostheses limits channel independence and, in some cases, may impair their performance. In comparison, optical stimuli that are spatially confined may result in a significant functional improvement. Pulsed infrared radiation (IR) has previously been shown to elicit responses in neurons. This study analyzes the response of neonatal rat spiral and vestibular ganglion neurons in vitro to IR (wavelength = 1,863 nm) using Ca2+ imaging. Both types of neurons responded consistently with robust intracellular Ca2+ ([Ca2+]i) transients that matched the low-frequency IR pulses applied (4 ms, 0.25–1 pps). Radiant exposures of ∼637 mJ/cm2 resulted in continual neuronal activation. Temperature or [Ca2+] variations in the media did not alter the IR-evoked transients, ruling out extracellular Ca2+ involvement or primary mediation by thermal effects on the plasma membrane. While blockage of Na+, K+, and Ca2+ plasma membrane channels did not alter the IR-evoked response, blocking of mitochondrial Ca2+ cycling with CGP-37157 or ruthenium red reversibly inhibited the IR-evoked [Ca2+]i transients. Additionally, the magnitude of the IR-evoked transients was dependent on ryanodine and cyclopiazonic acid-dependent Ca2+ release. These results suggest that IR modulation of intracellular calcium cycling contributes to stimulation of spiral and vestibular ganglion neurons. As a whole, the results suggest selective excitation of neurons in the IR beam path and the potential of IR stimulation in future auditory and vestibular prostheses. PMID:24920028

  8. Pulsed infrared radiation excites cultured neonatal spiral and vestibular ganglion neurons by modulating mitochondrial calcium cycling.

    PubMed

    Lumbreras, Vicente; Bas, Esperanza; Gupta, Chhavi; Rajguru, Suhrud M

    2014-09-15

    Cochlear implants are currently the most effective solution for profound sensorineural hearing loss, and vestibular prostheses are under development to treat bilateral vestibulopathies. Electrical current spread in these neuroprostheses limits channel independence and, in some cases, may impair their performance. In comparison, optical stimuli that are spatially confined may result in a significant functional improvement. Pulsed infrared radiation (IR) has previously been shown to elicit responses in neurons. This study analyzes the response of neonatal rat spiral and vestibular ganglion neurons in vitro to IR (wavelength = 1,863 nm) using Ca(2+) imaging. Both types of neurons responded consistently with robust intracellular Ca(2+) ([Ca(2+)]i) transients that matched the low-frequency IR pulses applied (4 ms, 0.25-1 pps). Radiant exposures of ∼637 mJ/cm(2) resulted in continual neuronal activation. Temperature or [Ca(2+)] variations in the media did not alter the IR-evoked transients, ruling out extracellular Ca(2+) involvement or primary mediation by thermal effects on the plasma membrane. While blockage of Na(+), K(+), and Ca(2+) plasma membrane channels did not alter the IR-evoked response, blocking of mitochondrial Ca(2+) cycling with CGP-37157 or ruthenium red reversibly inhibited the IR-evoked [Ca(2+)]i transients. Additionally, the magnitude of the IR-evoked transients was dependent on ryanodine and cyclopiazonic acid-dependent Ca(2+) release. These results suggest that IR modulation of intracellular calcium cycling contributes to stimulation of spiral and vestibular ganglion neurons. As a whole, the results suggest selective excitation of neurons in the IR beam path and the potential of IR stimulation in future auditory and vestibular prostheses.

  9. Altered elemental profiles in neuronal ceroid lipofuscinosis.

    PubMed

    Johansson, E; Lindh, U; Westermarck, T; Heiskala, H; Santavuori, P

    1990-09-01

    The elemental profiles of thrombocytes and mononuclear cells were investigated in five patients with Infantile and eight with Juvenile Neuronal Ceroid Lipofuscinosis. The patients with the infantile form had suffered from the disease for a year and those with the juvenile form for some six years. The thrombocytes exhibited increased concentrations of calcium and magnesium, but the same concentrations of iron and zinc as found in healthy subjects. The mononuclear cells exhibited an increased concentration of iron and a reduced concentration of zinc. The elevated concentrations of magnesium, calcium and iron in the thrombocytes and mononuclear cells may represent the end products of ceroid pigmentation. Five patients with Juvenile and one with Infantile Neuronal Ceroid Lipofuscinosis were treated with antioxidants along with vitamins E, B2 and B6, but this treatment did not affect significantly the concentration of iron in the mononuclear cells. However, selenium was detected in some mononuclear cells in all the patients so treated. This was unexpected since iron (III), being antagonistic to selenium in the form of selenite--which was the antioxidant given--forms a stable complex which cannot be broken down biologically.

  10. Hyperexcitable neurons and altered non-neuronal cells in the compressed spinal ganglion

    PubMed Central

    LaMotte, Robert H.; Chao, MA

    2009-01-01

    The cell body or soma in the dosal root ganglion (DRG) is normally excitable and this excitability can increase and persist after an injury of peripheral sensory neurons. In a rat model of radicular pain, an intraforaminal implantation of a rod that chronically compressed the lumbar DRG (“CCD” model) resulted in neuronal somal hyperexcitability and spontaneous activity that was accompanied by hyperalgesia in the ipsilateral hind paw. By the 5th day after onset of CCD, there was a novel upregulation in neuronal expression of the chemokine, monocyte chemoattractant protein-1 (MCP-1 or CCL2) and also its receptor, CCR2. The neurons developed, in response to topically applied MCP-1, an excitatory response that they normally do not have. CCD also activated non-neuronal cells including, for example, the endothelial cells as evidenced by angiogenesis in the form of an increased number of capillaries in the DRG after 7 days. A working hypothesis is that the CCD induced changes in neurons and non-neuronal cells that may act together to promote the survival of the injured tissue. The release of ligands such as CCL2, in addition to possibly activating nociceptive neurons (maintaining the pain), may also act to preserve injured cells in the face of ischemia and hypoxia, for example, by promoting angiogenesis. Thus, somal hyperexcitability, as often said of inflammation, may represent a double edged sword. PMID:18958366

  11. Hyperexcitable neurons and altered non-neuronal cells in the compressed spinal ganglion.

    PubMed

    LaMotte, Robert H; Ma, Chao

    2008-10-25

    The cell body or soma in the dosal root ganglion (DRG) is normally excitable and this excitability can increase and persist after an injury of peripheral sensory neurons. In a rat model of radicular pain, an intraforaminal implantation of a rod that chronically compressed the lumbar DRG ("CCD" model) resulted in neuronal somal hyperexcitability and spontaneous activity that was accompanied by hyperalgesia in the ipsilateral hind paw. By the 5th day after onset of CCD, there was a novel upregulation in neuronal expression of the chemokine, monocyte chemoattractant protein-1 (MCP-1 or CCL2) and also its receptor, CCR2. The neurons developed, in response to topically applied MCP-1, an excitatory response that they normally do not have. CCD also activated non-neuronal cells including, for example, the endothelial cells as evidenced by angiogenesis in the form of an increased number of capillaries in the DRG after 7 days. A working hypothesis is that the CCD induced changes in neurons and non-neuronal cells that may act together to promote the survival of the injured tissue. The release of ligands such as CCL2, in addition to possibly activating nociceptive neurons (maintaining the pain), may also act to preserve injured cells in the face of ischemia and hypoxia, for example, by promoting angiogenesis. Thus, somal hyperexcitability, as often said of inflammation, may represent a double edged sword.

  12. Altered Nociceptive Neuronal Circuits After Neonatal Peripheral Inflammation

    NASA Astrophysics Data System (ADS)

    Ruda, M. A.; Ling, Qing-Dong; Hohmann, Andrea G.; Peng, Yuan Bo; Tachibana, Toshiya

    2000-07-01

    Nociceptive neuronal circuits are formed during embryonic and postnatal times when painful stimuli are normally absent or limited. Today, medical procedures for neonates with health risks can involve tissue injury and pain for which the long-term effects are unknown. To investigate the impact of neonatal tissue injury and pain on development of nociceptive neuronal circuitry, we used an animal model of persistent hind paw peripheral inflammation. We found that, as adults, these animals exhibited spinal neuronal circuits with increased input and segmental changes in nociceptive primary afferent axons and altered responses to sensory stimulation.

  13. Homeostasis of intrinsic excitability in hippocampal neurones: dynamics and mechanism of the response to chronic depolarization.

    PubMed

    O'Leary, Timothy; van Rossum, Mark C W; Wyllie, David J A

    2010-01-01

    In order to maintain stable functionality in the face of continually changing input, neurones in the CNS must dynamically modulate their electrical characteristics. It has been hypothesized that in order to retain stable network function, neurones possess homeostatic mechanisms which integrate activity levels and alter network and cellular properties in such a way as to counter long-term perturbations. Here we describe a simple model system where we investigate the effects of sustained neuronal depolarization, lasting up to several days, by exposing cultures of primary hippocampal pyramidal neurones to elevated concentrations (10-30 mm) of KCl. Following exposure to KCl, neurones exhibit lower input resistances and resting potentials, and require more current to be injected to evoke action potentials. This results in a rightward shift in the frequency-input current (FI) curve which is explained by a simple linear model of the subthreshold I-V relationship. No changes are observed in action potential profiles, nor in the membrane potential at which action potentials are evoked. Furthermore, following depolarization, an increase in subthreshold potassium conductance is observed which is accounted for within a biophysical model of the subthreshold I-V characteristics of neuronal membranes. The FI curve shift was blocked by the presence of the L-type Ca(2+) channel blocker nifedipine, whilst antagonism of NMDA receptors did not interfere with the effect. Finally, changes in the intrinsic properties of neurones are reversible following removal of the depolarizing stimulus. We suggest that this experimental system provides a convenient model of homeostatic regulation of intrinsic excitability, and permits the study of temporal characteristics of homeostasis and its dependence on stimulus magnitude.

  14. Functional Effects of Schizophrenia-Linked Genetic Variants on Intrinsic Single-Neuron Excitability: A Modeling Study

    PubMed Central

    Mäki-Marttunen, Tuomo; Halnes, Geir; Devor, Anna; Witoelar, Aree; Bettella, Francesco; Djurovic, Srdjan; Wang, Yunpeng; Einevoll, Gaute T.; Andreassen, Ole A.; Dale, Anders M.

    2015-01-01

    Background Recent genome-wide association studies have identified a large number of genetic risk factors for schizophrenia (SCZ) featuring ion channels and calcium transporters. For some of these risk factors, independent prior investigations have examined the effects of genetic alterations on the cellular electrical excitability and calcium homeostasis. In the present proof-of-concept study, we harnessed these experimental results for modeling of computational properties on layer V cortical pyramidal cells and identified possible common alterations in behavior across SCZ-related genes. Methods We applied a biophysically detailed multicompartmental model to study the excitability of a layer V pyramidal cell. We reviewed the literature on functional genomics for variants of genes associated with SCZ and used changes in neuron model parameters to represent the effects of these variants. Results We present and apply a framework for examining the effects of subtle single nucleotide polymorphisms in ion channel and calcium transporter-encoding genes on neuron excitability. Our analysis indicates that most of the considered SCZ-related genetic variants affect the spiking behavior and intracellular calcium dynamics resulting from summation of inputs across the dendritic tree. Conclusions Our results suggest that alteration in the ability of a single neuron to integrate the inputs and scale its excitability may constitute a fundamental mechanistic contributor to mental disease, alongside the previously proposed deficits in synaptic communication and network behavior. PMID:26949748

  15. Muscarinic receptor-mediated excitation of rat intracardiac ganglion neurons.

    PubMed

    Hirayama, Michiko; Ogata, Masanori; Kawamata, Tomoyuki; Ishibashi, Hitoshi

    2015-08-01

    Modulation of the membrane excitability of rat parasympathetic intracardiac ganglion neurons by muscarinic receptors was studied using an amphotericin B-perforated patch-clamp recording configuration. Activation of muscarinic receptors by oxotremorine-M (OxoM) depolarized the membrane, accompanied by repetitive action potentials. OxoM evoked inward currents under voltage-clamp conditions at a holding potential of -60 mV. Removal of extracellular Ca(2+) markedly increased the OxoM-induced current (IOxoM). The inward IOxoM in the absence of extracellular Ca(2+) was fully inhibited by removal of extracellular Na(+), indicating the involvement of non-selective cation channels. The IOxoM was inhibited by organic cation channel antagonists including SKF-96365 and ML-204. The IOxoM was antagonized by muscarinic receptor antagonists with the following potency: 4-DAMP > pirenzepine = darifenacin > methoctramine. Muscarinic toxin 7 (MT-7), a highly selective inhibitor for M1 receptor, produced partial inhibition of the IOxoM. In the presence of MT-7, concentration-inhibition curve of the M3-preferring antagonist darifenacin was shifted to the left. These results suggest the contribution of M1 and M3 receptors to the OxoM response. The IOxoM was inhibited by U-73122, a phospholipase C inhibitor. The membrane-permeable IP3 receptor blocker xestospongin C also inhibited the IOxoM. Furthermore, pretreatment with thapsigargin and BAPTA-AM inhibited the IOxoM, while KN-62, a blocker of Ca(2+)/calmodulin-dependent protein kinase II, had no effect. These results suggest that the activation mechanism involves a PLC pathway, release of Ca(2+) from intracellular Ca(2+) stores and calmodulin. The cation channels activated by muscarinic receptors may play an important role in neuronal membrane depolarization in rat intracardiac ganglion neurons.

  16. Alterations in hippocampal excitability, synaptic transmission and synaptic plasticity in a neurodevelopmental model of schizophrenia.

    PubMed

    Sanderson, Thomas M; Cotel, Marie-Caroline; O'Neill, Michael J; Tricklebank, Mark D; Collingridge, Graham L; Sher, Emanuele

    2012-03-01

    The risk of developing schizophrenia has been linked to perturbations in embryonic development, but the physiological alterations that result from such insults are incompletely understood. Here, we have investigated aspects of hippocampal physiology in a proposed neurodevelopmental model of schizophrenia, induced during gestation in rats by injection of the antimitotic agent methylazoxymethanol acetate (MAM) at embryonic day 17 (MAM(E17)). We observed a reduction in synaptic innervation and synaptic transmission in the dorsal hippocampus of MAM(E17) treated rats, accompanied by a pronounced increase in CA1 pyramidal neuron excitability. Pharmacological investigations suggested that a deficit in GABAergic inhibition could account for the increase in excitability; furthermore, some aspects of the hyper-excitability could be normalised by the GABA(A) receptor (GABA(A)R) potentiator diazepam. Despite these alterations, two major forms of synaptic plasticity, long-term potentiation (LTP) and long-term depression (LTD) could be readily induced. In contrast, there was a substantial deficit in the reversal of LTP, depotentiation. These findings suggest that delivering neurodevelopmental insults at E17 may offer insights into some of the physiological alterations that underlie behavioural and cognitive symptoms observed in schizophrenia.

  17. Cardiopulmonary sympathetic afferent excitation of lower thoracic spinoreticular and spinothalamic neurons.

    PubMed

    Ammons, W S

    1990-12-01

    1. Responses of spinoreticular (SRT) and spinothalamic (STT) neurons located in the T7-T9 segments to cardiopulmonary sympathetic afferent (CPS) stimuli were studied in 27 cats that were anesthetized with alpha-chloralose. 2. CPS stimulation excited 32 SRT and 10 STT neurons. Each neuron was also excited by stimulation of the left greater splanchnic nerve (SPL) and had a somatic receptive field that was most commonly located on the upper abdomen and over the lower rib cage. An additional 12 SRT and 3 STT neurons received input from SPL and somatic structures but failed to respond to CPS stimulation. 3. CPS stimulation evoked early responses (23 cells) or both early and late responses (19 cells) that had average latencies of 12.7 +/- 1.8 and 88.2 +/- 13.1 (SE) ms, respectively. Latencies of responses to SPL stimulation were significantly shorter and averaged 8.1 +/- 0.9 and 46.1 +/- 7.1 ms. Magnitudes of early responses to SPL stimulation were significantly greater than responses to CPS stimulation; however, late responses were not different. 4. Responses to CPS stimulation were inhibited by a prior conditioning stimulus applied to SPL. Greatest inhibition occurred at a conditioning-test interval of 40 ms, and inhibition lasted for at least 300 ms. Inhibition of responses to SPL stimulation could be evoked by conditioning stimuli applied to CPS; however, the inhibition was significantly less than that evoked by SPL stimulation on responses to CPS stimulation. 5. Thirty-eight neurons were tested for responses to injection of bradykinin (4 micrograms/kg) into the left atrium. Discharge rate of 17 cells increased from 5 +/- 2 to 12 +/- 4 Hz. Four cells were tachyphylactic to repeated injections. Injections of bradykinin into the thoracic aorta did not significantly alter cell activity. Bilateral cervical vagotomy had no effect on responses to intracardiac bradykinin. 6. The results indicate that lower thoracic SRT and STT neurons are excited by CPS stimuli including

  18. Altered intrinsic and synaptic properties of lumbosacral dorsal horn neurons in a mouse model of colitis.

    PubMed

    Farrell, Kristen E; Keely, Simon; Walker, Marjorie M; Brichta, Alan M; Graham, Brett A; Callister, Robert J

    2017-08-23

    Visceral pain in inflammatory and functional gastrointestinal conditions is a major clinical problem. The exact mechanisms underlying the development of pain, during and after visceral inflammation, are unknown clinical and pre-clinical evidence that suggests plasticity within the spinal cord dorsal horn is a contributing factor. Here we use an in vivo preparation and patch-clamp electrophysiology to test whether the synaptic and intrinsic properties of superficial dorsal horn (SDH) neurons are altered 5days after the induction of mild colitis in adult male mice (i.e. during acute inflammation of the colon). Whole-cell recordings were made from lumbosacral (L6-S1) superficial dorsal horn neurons (SDH), in animals under isoflurane anesthesia. Noxious colorectal distension (CRD) was used to identify SDH neurons with colonic inputs, while stimulation of the hind paw and tail was employed to assess convergent cutaneous input. Following inflammation, a significantly increased proportion of SDH neurons received both colonic and cutaneous inputs, compared to neurons in naïve animals. In addition, the nature and magnitude of responses to CRD and cutaneous stimulation differed in inflamed animals, as was spontaneous excitatory synaptic drive. Conversely, several measures of intrinsic excitability were altered in a manner that would decrease SDH network excitability following colitis. We propose that during inflammation, sensitization of colonic afferents results in increased signaling to the SDH. This is accompanied by plasticity in SDH neurons whereby their intrinsic properties are changed to compensate for altered afferent activity. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

  19. Control of CNS Neuronal Excitability by Estrogens via Membrane Initiated Signaling

    PubMed Central

    Kelly, Martin J.; Rønnekleiv, Oline K.

    2009-01-01

    It is well known that many of the actions of 17β-estradiol (E2) in the central nervous system (CNS) are mediated via intracellular receptor/transcription factors that interact with steroid response elements on target genes. However, there is compelling evidence for membrane-associated steroid receptors for E2 in hypothalamic and other brain neurons. Indeed, we are just beginning to understand how E2 signals via membrane receptors, and how these signals impact not only membrane excitability but also gene transcription in neurons. We know that E2 can rapidly alter neuronal activity within seconds, indicating that some cellular effects can occur via membrane delimited events. In addition, E2 can affect second messenger systems including calcium mobilization and a plethora of kinases to alter cell signaling. This review will concentrate on rapid membrane-initiated and intracellular signaling by E2 in the hypothalamus and hippocampus, the nature of receptors involved and how they contribute to CNS functions. PMID:19549588

  20. Structural basis of neuron-to-neuron cross-excitation in dorsal root ganglia.

    PubMed

    Shinder, V; Devor, M

    1994-09-01

    Lanthanum was used as a tracer substance to determine whether small molecules in the bulk extracellular space in dorsal root ganglia have access to the narrow cleft that separates sensory neurons from their surrounding satellite cell sheath. Results showed that lanthanum is able to diffuse into this cleft, especially when the tissue is incubated with the tracer before fixation. Lanthanum gained access to the cleft at the seam where adjacent satellite cell processes meet. There appears to be preferential access in the axon hillock-initial segment region. Large diameter light neurons, which generally support fast conducting myelinated axons and carry information about non-nociceptive sensory events, proved more likely to admit lanthanum than small diameter dark neurons, which tend to have thin myelinated and unmyelinated axons and typically carry nociceptive information. Peripheral axotomy triggered a reduction in the access of lanthanum to the neuron-satellite cell cleft. These data bear on the mechanism of non-synaptic cell-to-cell cross-excitation within dorsal root ganglia, and in particular, lend support to the hypothesis that this interaction is mediated chemically rather than electrically.

  1. Balance of excitation and inhibition determines 1/f power spectrum in neuronal networks

    NASA Astrophysics Data System (ADS)

    Lombardi, F.; Herrmann, H. J.; de Arcangelis, L.

    2017-04-01

    The 1/f-like decay observed in the power spectrum of electro-physiological signals, along with scale-free statistics of the so-called neuronal avalanches, constitutes evidence of criticality in neuronal systems. Recent in vitro studies have shown that avalanche dynamics at criticality corresponds to some specific balance of excitation and inhibition, thus suggesting that this is a basic feature of the critical state of neuronal networks. In particular, a lack of inhibition significantly alters the temporal structure of the spontaneous avalanche activity and leads to an anomalous abundance of large avalanches. Here, we study the relationship between network inhibition and the scaling exponent β of the power spectral density (PSD) of avalanche activity in a neuronal network model inspired in Self-Organized Criticality. We find that this scaling exponent depends on the percentage of inhibitory synapses and tends to the value β = 1 for a percentage of about 30%. More specifically, β is close to 2, namely, Brownian noise, for purely excitatory networks and decreases towards values in the interval [1, 1.4] as the percentage of inhibitory synapses ranges between 20% and 30%, in agreement with experimental findings. These results indicate that the level of inhibition affects the frequency spectrum of resting brain activity and suggest the analysis of the PSD scaling behavior as a possible tool to study pathological conditions.

  2. Bistable Dynamics Underlying Excitability of Ion Homeostasis in Neuron Models

    PubMed Central

    Hübel, Niklas; Schöll, Eckehard; Dahlem, Markus A.

    2014-01-01

    When neurons fire action potentials, dissipation of free energy is usually not directly considered, because the change in free energy is often negligible compared to the immense reservoir stored in neural transmembrane ion gradients and the long–term energy requirements are met through chemical energy, i.e., metabolism. However, these gradients can temporarily nearly vanish in neurological diseases, such as migraine and stroke, and in traumatic brain injury from concussions to severe injuries. We study biophysical neuron models based on the Hodgkin–Huxley (HH) formalism extended to include time–dependent ion concentrations inside and outside the cell and metabolic energy–driven pumps. We reveal the basic mechanism of a state of free energy–starvation (FES) with bifurcation analyses showing that ion dynamics is for a large range of pump rates bistable without contact to an ion bath. This is interpreted as a threshold reduction of a new fundamental mechanism of ionic excitability that causes a long–lasting but transient FES as observed in pathological states. We can in particular conclude that a coupling of extracellular ion concentrations to a large glial–vascular bath can take a role as an inhibitory mechanism crucial in ion homeostasis, while the pumps alone are insufficient to recover from FES. Our results provide the missing link between the HH formalism and activator–inhibitor models that have been successfully used for modeling migraine phenotypes, and therefore will allow us to validate the hypothesis that migraine symptoms are explained by disturbed function in ion channel subunits, pumps, and other proteins that regulate ion homeostasis. PMID:24784149

  3. Non-associative Potentiation of Perisomatic Inhibition Alters the Temporal Coding of Neocortical Layer 5 Pyramidal Neurons

    PubMed Central

    Lourenço, Joana; Pacioni, Simone; Rebola, Nelson; van Woerden, Geeske M.; Marinelli, Silvia; DiGregorio, David; Bacci, Alberto

    2014-01-01

    In the neocortex, the coexistence of temporally locked excitation and inhibition governs complex network activity underlying cognitive functions, and is believed to be altered in several brain diseases. Here we show that this equilibrium can be unlocked by increased activity of layer 5 pyramidal neurons of the mouse neocortex. Somatic depolarization or short bursts of action potentials of layer 5 pyramidal neurons induced a selective long-term potentiation of GABAergic synapses (LTPi) without affecting glutamatergic inputs. Remarkably, LTPi was selective for perisomatic inhibition from parvalbumin basket cells, leaving dendritic inhibition intact. It relied on retrograde signaling of nitric oxide, which persistently altered presynaptic GABA release and diffused to inhibitory synapses impinging on adjacent pyramidal neurons. LTPi reduced the time window of synaptic summation and increased the temporal precision of spike generation. Thus, increases in single cortical pyramidal neuron activity can induce an interneuron-selective GABAergic plasticity effectively altering the computation of temporally coded information. PMID:25003184

  4. Maternal immune activation produces neonatal excitability defects in offspring hippocampal neurons from pregnant rats treated with poly I:C

    PubMed Central

    Patrich, Eti; Piontkewitz, Yael; Peretz, Asher; Weiner, Ina; Attali, Bernard

    2016-01-01

    Maternal immune activation (MIA) resulting from prenatal exposure to infectious pathogens or inflammatory stimuli is increasingly recognized to play an important etiological role in neuropsychiatric disorders with neurodevelopmental features. MIA in pregnant rodents induced by injection of the synthetic double-stranded RNA, Poly I:C, a mimic of viral infection, leads to a wide spectrum of behavioral abnormalities as well as structural and functional defects in the brain. Previous MIA studies using poly I:C prenatal treatment suggested that neurophysiological alterations occur in the hippocampus. However, these investigations used only juvenile or adult animals. We postulated that MIA-induced alterations could occur earlier at neonatal/early postnatal stages. Here we examined the neurophysiological properties of cultured pyramidal-like hippocampal neurons prepared from neonatal (P0-P2) offspring of pregnant rats injected with poly I:C. Offspring neurons from poly I:C-treated mothers exhibited significantly lower intrinsic excitability and stronger spike frequency adaptation, compared to saline. A similar lower intrinsic excitability was observed in CA1 pyramidal neurons from hippocampal slices of two weeks-old poly I:C offspring. Cultured hippocampal neurons also displayed lower frequency of spontaneous firing, higher charge transfer of IPSCs and larger amplitude of miniature IPSCs. Thus, maternal immune activation leads to strikingly early neurophysiological abnormalities in hippocampal neurons. PMID:26742695

  5. Maternal immune activation produces neonatal excitability defects in offspring hippocampal neurons from pregnant rats treated with poly I:C.

    PubMed

    Patrich, Eti; Piontkewitz, Yael; Peretz, Asher; Weiner, Ina; Attali, Bernard

    2016-01-08

    Maternal immune activation (MIA) resulting from prenatal exposure to infectious pathogens or inflammatory stimuli is increasingly recognized to play an important etiological role in neuropsychiatric disorders with neurodevelopmental features. MIA in pregnant rodents induced by injection of the synthetic double-stranded RNA, Poly I:C, a mimic of viral infection, leads to a wide spectrum of behavioral abnormalities as well as structural and functional defects in the brain. Previous MIA studies using poly I:C prenatal treatment suggested that neurophysiological alterations occur in the hippocampus. However, these investigations used only juvenile or adult animals. We postulated that MIA-induced alterations could occur earlier at neonatal/early postnatal stages. Here we examined the neurophysiological properties of cultured pyramidal-like hippocampal neurons prepared from neonatal (P0-P2) offspring of pregnant rats injected with poly I:C. Offspring neurons from poly I:C-treated mothers exhibited significantly lower intrinsic excitability and stronger spike frequency adaptation, compared to saline. A similar lower intrinsic excitability was observed in CA1 pyramidal neurons from hippocampal slices of two weeks-old poly I:C offspring. Cultured hippocampal neurons also displayed lower frequency of spontaneous firing, higher charge transfer of IPSCs and larger amplitude of miniature IPSCs. Thus, maternal immune activation leads to strikingly early neurophysiological abnormalities in hippocampal neurons.

  6. Temporal Lobe Epilepsy Induces Intrinsic Alterations in Na Channel Gating in Layer II Medial Entorhinal Cortex Neurons

    PubMed Central

    Hargus, Nicholas J.; Merrick, Ellen C.; Nigam, Aradhya; Kalmar, Christopher L.; Baheti, Aparna R.; Bertram, Edward H.; Patel, Manoj K.

    2010-01-01

    Temporal lobe epilepsy (TLE) is the most common form of adult epilepsy involving the limbic structures of the temporal lobe. Layer II neurons of the entorhinal cortex (EC) form the major excitatory input into the hippocampus via the perforant path and consist of non-stellate and stellate neurons. These neurons are spared and hyper-excitable in TLE. The basis for the hyper-excitability is likely multifactorial and may include alterations in intrinsic properties. In a rat model of TLE, medial EC (mEC) non-stellate and stellate neurons had significantly higher action potential (AP) firing frequencies than in control. The increase remained in the presence of synaptic blockers, suggesting intrinsic mechanisms. Since sodium (Na) channels play a critical role in AP generation and conduction we sought to determine if Na channel gating parameters and expression levels were altered in TLE. Na channel currents recorded from isolated mEC TLE neurons revealed increased Na channel conductances, depolarizing shifts in inactivation parameters and larger persistent (INaP) and resurgent (INaR) Na currents. Immunofluorescence experiments revealed increased staining of Nav1.6 within the axon initial segment and Nav1.2 within the cell bodies of mEC TLE neurons. These studies provide support for additional intrinsic alterations within mEC layer II neurons in TLE and implicate alterations in Na channel activity and expression, in part, for establishing the profound increase in intrinsic membrane excitability of mEC layer II neurons in TLE. These intrinsic changes, together with changes in the synaptic network, could support seizure activity in TLE. PMID:20946956

  7. Ventral tegmental area neurons are either excited or inhibited by cocaine’s actions in the peripheral nervous system

    PubMed Central

    Mejías-Aponte, Carlos A.; Kiyatkin, Eugene A.

    2012-01-01

    Cocaine’s multiple pharmacological substrates are ubiquitously present in the peripheral and central nervous system. Thus, upon its administration, cocaine acts in the periphery before directly acting in the brain. We determined whether cocaine alters ventral tegmental area (VTA) neuronal activity via peripheral actions, and whether this precedes its central actions. In urethane-anesthetized rats, we recorded VTA neurons responses to intravenous injections of two cocaine analogs: cocaine-hydrochloride (HCl, 0.25 mg/kg) that readily cross the blood-brain barrier (BBB) and cocaine-methiodide (MI, 0.33 mg/kg) that does not cross the BBB. Both cocaine analogs produced sustained changes in discharge rates that began 5s after the initiation of a 10s drug infusion. Within the first 90s post-injection the magnitudes of neuronal responsive of both cocaine analogs were comparable, but later in time the effects of cocaine-HCl were stronger and persisted longer than those of cocaine-MI. The proportion of neurons responsive to cocaine-HCl was twice to that of cocaine-MI (74% and 35% respectively). Both analogs also differed in the response onsets. Cocaine-MI rarely evoked responses after 1 min whereas cocaine-HCl continued to evoke responses within 3 min post-injection. VTA neurons were either excited or inhibited by both cocaine analogs. Most units responsive to cocaine-MI, regardless of excitation or inhibition, had electrophysiological characteristics of putative DA neurons. Units inhibited by cocaine-HCl also had characteristic of DA neurons whereas excited neurons had widely varying action potential durations and discharge rates. Cocaine-MI and cocaine-HCl each produced changes in VTA neuron activity under full DA receptor blockade. However, the duration of inhibition was shortened, the number of excitations increased, and they occurred with an earlier onset during DA receptor blockade. These findings indicate that cocaine acts peripherally with a short latency and

  8. Exposure to a high fat diet during the perinatal period alters vagal motoneurone excitability, even in the absence of obesity.

    PubMed

    Bhagat, Ruchi; Fortna, Samuel R; Browning, Kirsteen N

    2015-01-01

    Obesity is recognized as being multifactorial in origin, involving both genetic and environmental factors. The perinatal period is known to be critically important in the development of neural circuits responsible for energy homeostasis and the integration of autonomic reflexes. Diet-induced obesity alters the biophysical, pharmacological and morphological properties of vagal neurocircuits regulating upper gastrointestinal tract functions, including satiety. Less information is available, however, regarding the effects of a high fat diet (HFD) itself on the properties of vagal neurocircuits. The present study was designed to test the hypothesis that exposure to a HFD during the perinatal period alters the electrophysiological, pharmacological and morphological properties of vagal efferent motoneurones innervating the stomach. Our data indicate that perinatal HFD decreases the excitability of gastric-projecting dorsal motor nucleus neurones and dysregulates neurotransmitter release from synaptic inputs and that these alterations occur prior to the development of obesity. These findings represent the first direct evidence that exposure to a HFD modulates the processing of central vagal neurocircuits even in the absence of obesity. The perinatal period is critically important to the development of autonomic neural circuits responsible for energy homeostasis. Vagal neurocircuits are vital to the regulation of upper gastrointestinal functions, including satiety. Diet-induced obesity modulates the excitability and responsiveness of both peripheral vagal afferents and central vagal efferents but less information is available regarding the effects of diet per se on vagal neurocircuit functions. The aims of this study were to investigate whether perinatal exposure to a high fat diet (HFD) dysregulated dorsal motor nucleus of the vagus (DMV) neurones, prior to the development of obesity. Whole cell patch clamp recordings were made from gastric-projecting DMV neurones in thin

  9. All optical experimental design for neuron excitation, inhibition, and action potential detection

    NASA Astrophysics Data System (ADS)

    Walsh, Alex J.; Tolstykh, Gleb; Martens, Stacey; Sedelnikova, Anna; Ibey, Bennett L.; Beier, Hope T.

    2016-03-01

    Recently, infrared light has been shown to both stimulate and inhibit excitatory cells. However, studies of infrared light for excitatory cell inhibition have been constrained by the use of invasive and cumbersome electrodes for cell excitation and action potential recording. Here, we present an all optical experimental design for neuronal excitation, inhibition, and action potential detection. Primary rat neurons were transfected with plasmids containing the light sensitive ion channel CheRiff. CheRiff has a peak excitation around 450 nm, allowing excitation of transfected neurons with pulsed blue light. Additionally, primary neurons were transfected with QuasAr2, a fast and sensitive fluorescent voltage indicator. QuasAr2 is excited with yellow or red light and therefore does not spectrally overlap CheRiff, enabling imaging and action potential activation, simultaneously. Using an optic fiber, neurons were exposed to blue light sequentially to generate controlled action potentials. A second optic fiber delivered a single pulse of 1869nm light to the neuron causing inhibition of the evoked action potentials (by the blue light). When used in concert, these optical techniques enable electrode free neuron excitation, inhibition, and action potential recording, allowing research into neuronal behaviors with high spatial fidelity.

  10. Computational modeling of optogenetic neuronal excitation under complex illumination conditions using a Matlab-Neuron interface (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Yona, Guy; Weissler, Yonatan; Meitav, Nizan; Guzi, Eliran; Rifold, Dafna D.; Kahn, Itamar; Shoham, Shy

    2016-03-01

    Optogenetics has in recent years become a central tool in neuroscience research. Creating a realistic model of optogenetic neuronal excitation is of crucial importance for controlling the activation levels of various neuronal populations in different depths, predicting experimental results and designing the optical systems. However, current approaches to modeling light propagation through rodents' brain tissue suffer from major shortcomings and comprehensive modeling of local illumination levels together with other important factors governing excitation (i.e., cellular morphology, channel dynamics and expression), are still lacking. To address this challenge we introduce a new simulation tool for optogenetic neuronal excitation under complex and realistic illumination conditions that implements a detailed physical model for light scattering (in MATLAB) together with neuron morphology and channelrhodopsin-2 model (in NEURON). These two disparate simulation environments were interconnected using a newly developed generic interface termed 'NeuroLab'. Applying this method, we show that in a layer-V cortical neuron, the relative contribution of the apical dendrites to neuronal excitation is considerably greater than that of the soma or basal dendrites, when illuminated from the surface.

  11. Optical control of neuronal excitation and inhibition using a single opsin protein, ChR2

    NASA Astrophysics Data System (ADS)

    Liske, Holly; Qian, Xiang; Anikeeva, Polina; Deisseroth, Karl; Delp, Scott

    2013-10-01

    The effect of electrical stimulation on neuronal membrane potential is frequency dependent. Low frequency electrical stimulation can evoke action potentials, whereas high frequency stimulation can inhibit action potential transmission. Optical stimulation of channelrhodopsin-2 (ChR2) expressed in neuronal membranes can also excite action potentials. However, it is unknown whether optical stimulation of ChR2-expressing neurons produces a transition from excitation to inhibition with increasing light pulse frequencies. Here we report optical inhibition of motor neuron and muscle activity in vivo in the cooled sciatic nerves of Thy1-ChR2-EYFP mice. We also demonstrate all-optical single-wavelength control of neuronal excitation and inhibition without co-expression of inhibitory and excitatory opsins. This all-optical system is free from stimulation-induced electrical artifacts and thus provides a new approach to investigate mechanisms of high frequency inhibition in neuronal circuits in vivo and in vitro.

  12. Excitatory amino acid-mediated chemoreflex excitation of respiratory neurones in rostral ventrolateral medulla in rats.

    PubMed Central

    Sun, M K; Reis, D J

    1996-01-01

    1. In anaesthetized rats, extracellular and intracellular recordings were made from 119 respiratory neurones in the rostroventrolateral reticular nucleus (RVL) of the medulla oblongata. 2. Two types of active respiratory neurones were detected in RVL: expiratory (E) and pre-inspiratory (Pre-I), based on the relationship between their discharge and that of the phrenic nerve. Some Pre-I but none of the E neurones could be antidromically excited from the C(3)-C(4) level of the spinal cord. 3. E and Pre-I neurones of RVL were excited by stimulation of the arterial chemoreceptors by a close arterial injection of sodium cyanide. The reflex excitation of RVL E neurones was preceded by increased phrenic nerve activity, while the excitation of RVL Pre-I neurones preceded the increases in phrenic nerve activity. 4. The chemoreflex excitation of the two types of RVL respiratory neurones as well as their resting discharge was abolished or significantly depressed by microionophoresis of kynurenate, a wide-spectrum antagonist of excitatory amino acid receptors, while xanthurenate, an inactive analogue of kynurenate, was without effect. 5. In ventilated rats, bilateral microinjection into RVL of kynurenate, but not xanthurenate, abolished resting activity and chemoreflex excitation of phrenic nerve activity, whilst in spontaneously breathing rats, kynurenate microinjection into RVL produced apnea and silenced phrenic nerves. 6. We conclude: (a) chemoreflex excitation of the phrenic nerves is mediated by stimulating Pre-I neurones of RVL by excitatory amino acidergic inputs and (b) RVL Pre-I neurones may directly and/or indirectly excite spinal phrenic motor neurones and hence are involved in inspiratory rhythmogenesis. PMID:9019550

  13. Neurally released pituitary adenylate cyclase-activating polypeptide enhances guinea pig intrinsic cardiac neurone excitability.

    PubMed

    Tompkins, John D; Ardell, Jeffrey L; Hoover, Donald B; Parsons, Rodney L

    2007-07-01

    Intracellular recordings were made in vitro from guinea-pig cardiac ganglia to determine whether endogenous neuropeptides such as pituitary adenylate cyclase-activating polypeptide (PACAP) or substance P released during tetanic neural stimulation modulate cardiac neurone excitability and/or contribute to slow excitatory postsynaptic potentials (sEPSPs). When nicotinic and muscarinic receptors were blocked by hexamethonium and atropine, 20 Hz stimulation for 10 s initiated a sEPSP in all innervated neurones. In 40% of the cells, excitability was enhanced after termination of the sEPSP. This suggested that non-cholinergic receptor-mediated mechanisms contributed to the sEPSP and modulated neuronal excitability. Exogenous PACAP and substance P initiated a slow depolarization in the neurones whereas neuronal excitability was only increased by PACAP. When ganglia were treated with the PAC1 antagonist PACAP6-38 (500 nM), the sEPSP evoked by 20 Hz stimulation was reduced by approximately 50% and an enhanced excitability occurred in only 10% of the cells. These observations suggested that PACAP released from preganglionic nerve terminals during tetanic stimulation enhanced neuronal excitability and evoked sEPSPs. After addition of 1 nM PACAP to the bath, 7 of 9 neurones exhibited a tonic firing pattern whereas in untreated preparations, the neurons had a phasic firing pattern. PACAP6-38 (500 nM) diminished the increase in excitability caused by 1 nM PACAP so that only 4 of 13 neurones exhibited a tonic firing pattern and the other 9 cells retained a phasic firing pattern. These findings indicate that PACAP can be released by tetanic neural stimulation in vitro and increase the excitability of intrinsic cardiac neurones. We hypothesize that in vivo PACAP released during preganglionic firing may modulate neurotransmission within the intrinsic cardiac ganglia.

  14. Simplified system to investigate alteration of retinal neurons in diabetes.

    PubMed

    Dong, Shuqian; Liu, Yan; Zhu, Meili; Xu, Xueliang; Le, Yun-Zheng

    2014-01-01

    Diabetic retinopathy (DR) is traditionally considered as a microvascular complication in diabetic retinas. Emerging evidences suggest that the alteration of neuronal function and the death of retinal neurons are part of DR pathology. However, surprisingly little is known about how retinal neurons behave in DR. As diabetic animals are chronicle models that are difficult and expensive to maintain, we used a chemical hypoxia model that mimics the later stage of diabetes and investigated its potential in predicting retinal cell behaviors in diabetes in an efficient manner. In this chapter, we discuss the similarities and differences between diabetic and hypoxic models and the usefulness and limitation of the cobalt-chloride-generated hypoxia system in mice for studying retinal neurobiology in diabetes.

  15. Mice Deficient for Prion Protein Exhibit Normal Neuronal Excitability and Synaptic Transmission in the Hippocampus

    NASA Astrophysics Data System (ADS)

    Lledo, Pierre-Marie; Tremblay, Patrick; Dearmond, Stephen J.; Prusiner, Stanley B.; Nicoll, Roger A.

    1996-03-01

    We recorded in the CA1 region from hippocampal slices of prion protein (PrP) gene knockout mice to investigate whether the loss of the normal form of prion protein (PrPC) affects neuronal excitability as well as synaptic transmission in the central nervous system. No deficit in synaptic inhibition was found using field potential recordings because (i) responses induced by stimulation in stratum radiatum consisted of a single population spike in PrP gene knockout mice similar to that recorded from control mice and (ii) the plot of field excitatory postsynaptic potential slope versus the population spike amplitude showed no difference between the two groups of mice. Intracellular recordings also failed to detect any difference in cell excitability and the reversal potential for inhibitory postsynaptic potentials. Analysis of the kinetics of inhibitory postsynaptic current revealed no modification. Finally, we examined whether synaptic plasticity was altered and found no difference in long-term potentiation between control and PrP gene knockout mice. On the basis of our findings, we propose that the loss of the normal form of prion protein does not alter the physiology of the CA1 region of the hippocampus.

  16. Glia as a source of cytokines: implications for neuronal excitability and survival.

    PubMed

    Vezzani, Annamaria; Ravizza, Teresa; Balosso, Silvia; Aronica, Eleonora

    2008-01-01

    In the last decade, preclinical studies have provided a better characterization of the homeostatic and maladaptive mechanisms occurring either during the process of epileptogenesis or after the permanent epileptic state has emerged. Experimental evidence supported by clinical observations highlighted the possibility that brain inflammation is a common factor contributing, or predisposing, to the occurrence of seizures and cell death, in various forms of epilepsy of different etiologies. Expression of proinflammatory cytokines, as a hallmark of brain inflammation, has been demonstrated in glia in various experimental models of seizures and in human epilepsies. Experimental studies in rodents with perturbed cytokine systems indicate that these inflammatory mediators can alter neuronal excitability and affect cell survival by activating transcriptional and posttranslational intracellular pathways. This paper will provide an overview on the current knowledge in this field to discuss mechanistic hypotheses into the study of pathogenesis of epilepsy and recognize new potential therapeutic options.

  17. Hydrogen peroxide modulates neuronal excitability and membrane properties in ventral horn neurons of the rat spinal cord.

    PubMed

    Ohashi, Masayuki; Hirano, Toru; Watanabe, Kei; Shoji, Hirokazu; Ohashi, Nobuko; Baba, Hiroshi; Endo, Naoto; Kohno, Tatsuro

    2016-09-07

    Hydrogen peroxide (H2O2), a reactive oxygen species, is an important signaling molecule for synaptic and neuronal activity in the central nervous system; it is produced excessively in brain ischemia and spinal cord injury. Although H2O2-mediated modulations of synaptic transmission have been reported in ventral horn (VH) neurons of the rat spinal cord, the effects of H2O2 on neuronal excitability and membrane properties remain poorly understood. Accordingly, the present study investigated such effects using a whole-cell patch-clamp technique. The bath-application of H2O2 decreased neuronal excitability accompanied by decreased input resistance, firing frequency, and action potential amplitude and by increased rheobase. These H2O2-mediated changes were induced by activation of extrasynaptic, but not synaptic, GABAA receptors. Indeed, GABAergic tonic currents were enhanced by H2O2. On the other hand, the amplitude of medium and slow afterhyperpolarization (mAHP and sAHP), which plays important roles in controlling neuronal excitability and is mediated by small-conductance calcium-activated potassium (SK) channels, was significantly decreased by H2O2. When extrasynaptic GABAA receptors were completely blocked, these decreases of mAHP and sAHP persisted, and H2O2 increased excitability, suggesting that H2O2 per se might have the potential to increase neuronal excitability via decreased SK channel conductance. These findings indicate that activating extrasynaptic GABAA receptors or SK channels may attenuate acute neuronal damage caused by H2O2-induced hyperexcitability and therefore represent a novel therapeutic target for the prevention and treatment of H2O2-induced motor neuron disorders. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  18. Clarithromycin increases neuronal excitability in CA3 pyramidal neurons through a reduction in GABAergic signaling.

    PubMed

    Bichler, Edyta K; Elder, Courtney C; García, Paul S

    2017-01-01

    Antibiotics are used in the treatment and prevention of bacterial infections, but effects on neuron excitability have been documented. A recent study demonstrated that clarithromycin alleviates daytime sleepiness in hypersomnia patients (Trotti LM, Saini P, Freeman AA, Bliwise DL, García PS, Jenkins A, Rye DB. J Psychopharmacol 28: 697-702, 2014). To explore the potential application of clarithromycin as a stimulant, we performed whole cell patch-clamp recordings in rat pyramidal cells from the CA3 region of hippocampus. In the presence of the antibiotic, rheobase current was reduced by 50%, F-I relationship (number of action potentials as a function of injected current) was shifted to the left, and the resting membrane potential was more depolarized. Clarithromycin-induced hyperexcitability was dose dependent; doses of 30 and 300 μM clarithromycin significantly increased the firing frequency and membrane potential compared with controls (P = 0.003, P < 0.0001). We hypothesized that clarithromycin enhanced excitability by reducing GABAA receptor activation. Clarithromycin at 30 μM significantly reduced (P = 0.001) the amplitude of spontaneous miniature inhibitory GABAergic currents and at 300 μM had a minor effect on action potential width. Additionally, we tested the effect of clarithromycin in an ex vivo seizure model by evaluating its effect on spontaneous local field potentials. Bath application of 300 μM clarithromycin enhanced burst frequency twofold compared with controls (P = 0.0006). Taken together, these results suggest that blocking GABAergic signaling with clarithromycin increases cellular excitability and potentially serves as a stimulant, facilitating emergence from anesthesia or normalizing vigilance in hypersomnia and narcolepsy. However, the administration of clarithromycin should be carefully considered in patients with seizure disorders.

  19. AGE-RELATED ALTERATIONS IN NEURONS OF THE MOUSE RETINA

    PubMed Central

    Samuel, Melanie A.; Zhang, Yifeng; Meister, Markus; Sanes, Joshua R.

    2011-01-01

    The behavioral consequences of age-related alterations in neural function are well documented, but less is known about their cellular bases. To characterize such changes, we analyzed 14 molecularly identified subsets of mouse retinal projection neurons [retinal ganglion cells or (RGCs)] and interneurons (amacrine, bipolar, and horizontal cells). The retina thinned but expanded with age, maintaining its volume. There was minimal decline in the number of RGCs, interneurons or photoreceptors, but the diameter of RGC dendritic arbors decreased with age. Together, the increased retinal area and decreased dendritic area may lead to gaps in RGC coverage of the visual field. Axonal arbors of RGCs in the superior colliculus also atrophied with age, suggesting that the relay of visual information to central targets may decline over time. On the other hand, the laminar restriction of RGC dendrites and the interneuronal processes that synapse on them were not detectably disturbed, and RGC subtypes exhibited distinct electrophysiological responses to complex visual stimuli. Other neuronal types aged in different ways: amacrine cell arbors did not remodel detectably, whereas horizontal cell processes sprouted into the photoreceptor layer. Bipolar cells showed arbor-specific alterations: their dendrites sprouted but their axons remained stable. In summary, retinal neurons exhibited numerous age-related quantitative alterations (decreased areas of dendritic and axonal arbors and decreased density of cells and synapses) whereas their qualitative features (molecular identity, laminar specificity, and feature detection) were largely preserved. Together, these data reveal selective age-related alterations in neural circuitry, some of which could underlie declines in visual acuity. PMID:22049445

  20. Enhanced endocannabinoid signaling elevates neuronal excitability in fragile X syndrome.

    PubMed

    Zhang, Longhua; Alger, Bradley E

    2010-04-21

    Fragile X syndrome (FXS) results from deficiency of fragile X mental retardation protein (FMRP). FXS is the most common heritable form of mental retardation, and is associated with the occurrence of seizures. Factors responsible for initiating FXS-related hyperexcitability are poorly understood. Many protein-synthesis-dependent functions of group I metabotropic glutamate receptors (Gp1 mGluRs) are exaggerated in FXS. Gp1 mGluR activation can mobilize endocannabinoids (eCBs) in the hippocampus and thereby increase excitability, but whether FMRP affects eCBs is unknown. We studied Fmr1 knock-out (KO) mice lacking FMRP to test the hypothesis that eCB function is altered in FXS. Whole-cell evoked IPSCs (eIPSCs) and field potentials were recorded in the CA1 region of acute hippocampal slices. Three eCB-mediated responses were examined: depolarization-induced suppression of inhibition (DSI), mGluR-initiated eCB-dependent inhibitory short-term depression (eCB-iSTD), and eCB-dependent inhibitory long-term depression (eCB-iLTD). Low concentrations of a Gp1 mGluR agonist produced larger eCB-mediated responses in Fmr1 KO mice than in wild-type (WT) mice, without affecting DSI. Western blots revealed that levels of mGluR1, mGluR5, or cannabinoid receptor (CB1R) were unchanged in Fmr1 KO animals, suggesting that the coupling between mGluR activation and eCB mobilization was enhanced by FMRP deletion. The increased susceptibility of Fmr1 KO slices to eCB-iLTD was physiologically relevant, since long-term potentiation of EPSP-spike (E-S) coupling induced by the mGluR agonist was markedly larger in Fmr1 KO mice than in WT animals. Alterations in eCB signaling could contribute to the cognitive dysfunction associated with FXS.

  1. Pet-1 Switches Transcriptional Targets Postnatally to Regulate Maturation of Serotonin Neuron Excitability

    PubMed Central

    Wyler, Steven C.; Spencer, W. Clay; Green, Noah H.; Rood, Benjamin D.; Crawford, LaTasha; Craige, Caryne; Gresch, Paul; McMahon, Douglas G.; Beck, Sheryl G.

    2016-01-01

    Newborn neurons enter an extended maturation stage, during which they acquire excitability characteristics crucial for development of presynaptic and postsynaptic connectivity. In contrast to earlier specification programs, little is known about the regulatory mechanisms that control neuronal maturation. The Pet-1 ETS (E26 transformation-specific) factor is continuously expressed in serotonin (5-HT) neurons and initially acts in postmitotic precursors to control acquisition of 5-HT transmitter identity. Using a combination of RNA sequencing, electrophysiology, and conditional targeting approaches, we determined gene expression patterns in maturing flow-sorted 5-HT neurons and the temporal requirements for Pet-1 in shaping these patterns for functional maturation of mouse 5-HT neurons. We report a profound disruption of postmitotic expression trajectories in Pet-1−/− neurons, which prevented postnatal maturation of 5-HT neuron passive and active intrinsic membrane properties, G-protein signaling, and synaptic responses to glutamatergic, lysophosphatidic, and adrenergic agonists. Unexpectedly, conditional targeting revealed a postnatal stage-specific switch in Pet-1 targets from 5-HT synthesis genes to transmitter receptor genes required for afferent modulation of 5-HT neuron excitability. 5-HT1a autoreceptor expression depended transiently on Pet-1, thus revealing an early postnatal sensitive period for control of 5-HT excitability genes. Chromatin immunoprecipitation followed by sequencing revealed that Pet-1 regulates 5-HT neuron maturation through direct gene activation and repression. Moreover, Pet-1 directly regulates the 5-HT neuron maturation factor Engrailed 1, which suggests Pet-1 orchestrates maturation through secondary postmitotic regulatory factors. The early postnatal switch in Pet-1 targets uncovers a distinct neonatal stage-specific function for Pet-1, during which it promotes maturation of 5-HT neuron excitability. SIGNIFICANCE STATEMENT The

  2. MicroRNA-128 governs neuronal excitability and motor behavior in mice.

    PubMed

    Tan, Chan Lek; Plotkin, Joshua L; Venø, Morten T; von Schimmelmann, Melanie; Feinberg, Philip; Mann, Silas; Handler, Annie; Kjems, Jørgen; Surmeier, D James; O'Carroll, Dónal; Greengard, Paul; Schaefer, Anne

    2013-12-06

    The control of motor behavior in animals and humans requires constant adaptation of neuronal networks to signals of various types and strengths. We found that microRNA-128 (miR-128), which is expressed in adult neurons, regulates motor behavior by modulating neuronal signaling networks and excitability. miR-128 governs motor activity by suppressing the expression of various ion channels and signaling components of the extracellular signal-regulated kinase ERK2 network that regulate neuronal excitability. In mice, a reduction of miR-128 expression in postnatal neurons causes increased motor activity and fatal epilepsy. Overexpression of miR-128 attenuates neuronal responsiveness, suppresses motor activity, and alleviates motor abnormalities associated with Parkinson's-like disease and seizures in mice. These data suggest a therapeutic potential for miR-128 in the treatment of epilepsy and movement disorders.

  3. Oxidative stress alters physiological and morphological neuronal properties.

    PubMed

    Hasan, Sonia M; Joe, Mary; Alshuaib, Waleed B

    2007-07-01

    We investigated the effects of H(2)O(2)-induced oxidative stress on the delayed-rectifier current (IK(DR)), neuronal physiological and morphological properties. Measurements were obtained from hippocampal CA1 neurons in control solution and from the same neurons after exposure to oxidative stress (short- and long-term H(2)O(2) external applications at 0.1, 1, and 10 mM). With short-term (6 min) H(2)O(2) (1 mM) treatment, IK(DR) measured in the H(2)O(2)-containing solution (778 +/- 23 pA, n=20), was smaller than that measured in the control Ca(2+)-free Hepes solution (1,112 +/- 38 pA, n=20). Coenzyme Q(10) (0.1 mM) pretreatment prevented the H(2)O(2)-induced inhibition of IK(DR). With long-term (40, 80 min) H(2)O(2) (0.1, 10 mM) treatment, the neuron lost its distinctive shape (rounded up) and the neurite almost disappeared. These results suggest that oxidative stress, which inhibits IK(DR), can alter neural activity. The morphological changes caused by H(2)O(2) support the idea that oxidative stress causes intracellular damage and compromises neural function.

  4. Latent herpes simplex virus infection of sensory neurons alters neuronal gene expression.

    PubMed

    Kramer, Martha F; Cook, W James; Roth, Frederick P; Zhu, Jia; Holman, Holly; Knipe, David M; Coen, Donald M

    2003-09-01

    The persistence of herpes simplex virus (HSV) and the diseases that it causes in the human population can be attributed to the maintenance of a latent infection within neurons in sensory ganglia. Little is known about the effects of latent infection on the host neuron. We have addressed the question of whether latent HSV infection affects neuronal gene expression by using microarray transcript profiling of host gene expression in ganglia from latently infected versus mock-infected mouse trigeminal ganglia. (33)P-labeled cDNA probes from pooled ganglia harvested at 30 days postinfection or post-mock infection were hybridized to nylon arrays printed with 2,556 mouse genes. Signal intensities were acquired by phosphorimager. Mean intensities (n = 4 replicates in each of three independent experiments) of signals from mock-infected versus latently infected ganglia were compared by using a variant of Student's t test. We identified significant changes in the expression of mouse neuronal genes, including several with roles in gene expression, such as the Clk2 gene, and neurotransmission, such as genes encoding potassium voltage-gated channels and a muscarinic acetylcholine receptor. We confirmed the neuronal localization of some of these transcripts by using in situ hybridization. To validate the microarray results, we performed real-time reverse transcriptase PCR analyses for a selection of the genes. These studies demonstrate that latent HSV infection can alter neuronal gene expression and might provide a new mechanism for how persistent viral infection can cause chronic disease.

  5. Colonic mucosal mediators from patients with irritable bowel syndrome excite enteric cholinergic motor neurons.

    PubMed

    Balestra, B; Vicini, R; Cremon, C; Zecchi, L; Dothel, G; Vasina, V; De Giorgio, R; Paccapelo, A; Pastoris, O; Stanghellini, V; Corinaldesi, R; De Ponti, F; Tonini, M; Barbara, G

    2012-12-01

    Mediators released in the mucosal milieu have been suggested to be involved in visceral hypersensitivity and abdominal pain in patients with irritable bowel syndrome (IBS). However, their impact on myenteric neurons remains unsettled. Mucosal biopsies were obtained from the descending colon of patients with IBS and controls. Mucosal mast cells were identified immunohistochemically. The impact of spontaneously released mucosal mediators on guinea pig electrically stimulated longitudinal muscle myenteric plexus (LMMP) preparations was assessed in vitro by means of selective receptor antagonists and inhibitors. Patients with IBS showed an increased mast cell count compared with controls. Application of mucosal mediators of IBS to LMMPs potentiated cholinergic twitch contractions, an effect directly correlated with mast cell counts. Enhanced contractions were inhibited by 50.3% with the prostaglandin D2 antagonist BW A868C, by 31.3% and 39% with the TRPV1 antagonists capsazepine and HC-030031, respectively, and by 60.5% with purinergic P2X antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid. Conversely, the serotonin1-4, histamine1-3, tachykinin1-3 receptor blockade, and serine protease inhibition had no significant effect. Colonic mucosal mediators from patients with IBS excite myenteric cholinergic motor neurons. These effects were correlated with mast cell counts and mediated by activation of prostanoid receptors, TRPV1, and P2X receptors. These results support the role of mucosal inflammatory mediators and mast cell activation in altered motor function of IBS. © 2012 Blackwell Publishing Ltd.

  6. 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.

  7. Self-organization of synchronous activity propagation in neuronal networks driven by local excitation

    PubMed Central

    Bayati, Mehdi; Valizadeh, Alireza; Abbassian, Abdolhossein; Cheng, Sen

    2015-01-01

    Many experimental and theoretical studies have suggested that the reliable propagation of synchronous neural activity is crucial for neural information processing. The propagation of synchronous firing activity in so-called synfire chains has been studied extensively in feed-forward networks of spiking neurons. However, it remains unclear how such neural activity could emerge in recurrent neuronal networks through synaptic plasticity. In this study, we investigate whether local excitation, i.e., neurons that fire at a higher frequency than the other, spontaneously active neurons in the network, can shape a network to allow for synchronous activity propagation. We use two-dimensional, locally connected and heterogeneous neuronal networks with spike-timing dependent plasticity (STDP). We find that, in our model, local excitation drives profound network changes within seconds. In the emergent network, neural activity propagates synchronously through the network. This activity originates from the site of the local excitation and propagates through the network. The synchronous activity propagation persists, even when the local excitation is removed, since it derives from the synaptic weight matrix. Importantly, once this connectivity is established it remains stable even in the presence of spontaneous activity. Our results suggest that synfire-chain-like activity can emerge in a relatively simple way in realistic neural networks by locally exciting the desired origin of the neuronal sequence. PMID:26089794

  8. Self-organization of synchronous activity propagation in neuronal networks driven by local excitation.

    PubMed

    Bayati, Mehdi; Valizadeh, Alireza; Abbassian, Abdolhossein; Cheng, Sen

    2015-01-01

    Many experimental and theoretical studies have suggested that the reliable propagation of synchronous neural activity is crucial for neural information processing. The propagation of synchronous firing activity in so-called synfire chains has been studied extensively in feed-forward networks of spiking neurons. However, it remains unclear how such neural activity could emerge in recurrent neuronal networks through synaptic plasticity. In this study, we investigate whether local excitation, i.e., neurons that fire at a higher frequency than the other, spontaneously active neurons in the network, can shape a network to allow for synchronous activity propagation. We use two-dimensional, locally connected and heterogeneous neuronal networks with spike-timing dependent plasticity (STDP). We find that, in our model, local excitation drives profound network changes within seconds. In the emergent network, neural activity propagates synchronously through the network. This activity originates from the site of the local excitation and propagates through the network. The synchronous activity propagation persists, even when the local excitation is removed, since it derives from the synaptic weight matrix. Importantly, once this connectivity is established it remains stable even in the presence of spontaneous activity. Our results suggest that synfire-chain-like activity can emerge in a relatively simple way in realistic neural networks by locally exciting the desired origin of the neuronal sequence.

  9. Leading role of thalamic over cortical neurons during postinhibitory rebound excitation

    PubMed Central

    Grenier, F.; Timofeev, I.; Steriade, M.

    1998-01-01

    The postinhibitory rebound excitation is an intrinsic property of thalamic and cortical neurons that is implicated in a variety of normal and abnormal operations of neuronal networks, such as slow or fast brain rhythms during different states of vigilance as well as seizures. We used dual simultaneous intracellular recordings of thalamocortical neurons from the ventrolateral nucleus and neurons from the motor cortex, together with thalamic and cortical field potentials, to investigate the temporal relations between thalamic and cortical events during the rebound excitation that follows prolonged periods of stimulus-induced inhibition. Invariably, the rebound spike-bursts in thalamocortical cells occurred before the rebound depolarization in cortical neurons and preceded the peak of the depth-negative, rebound field potential in cortical areas. Also, the inhibitory-rebound sequences were more pronounced and prolonged in cortical neurons when elicited by thalamic stimuli, compared with cortical stimuli. The role of thalamocortical loops in the rebound excitation of cortical neurons was shown further by the absence of rebound activity in isolated cortical slabs. However, whereas thalamocortical neurons remained hyperpolarized after rebound excitation, because of the prolonged spike-bursts in inhibitory thalamic reticular neurons, the rebound depolarization in cortical neurons was prolonged, suggesting the role of intracortical excitatory circuits in this sustained activity. The role of intrathalamic events in triggering rebound cortical activity should be taken into consideration when analyzing information processes at the cortical level; at each step, corticothalamic volleys can set into action thalamic inhibitory neurons, leading to rebound spike-bursts that are transferred back to the cortex, thus modifying cortical activities. PMID:9811903

  10. Adiponectin modulates excitability of rat paraventricular nucleus neurons by differential modulation of potassium currents.

    PubMed

    Hoyda, Ted D; Ferguson, Alastair V

    2010-07-01

    The adipocyte-derived hormone adiponectin acts at two seven-transmembrane domain receptors, adiponectin receptor 1 and adiponectin receptor 2, present in the paraventricular nucleus of the hypothalamus to regulate neuronal excitability and endocrine function. Adiponectin depolarizes rat parvocellular preautonomic neurons that secrete either thyrotropin releasing hormone or oxytocin and parvocellular neuroendocrine corticotropin releasing hormone neurons, leading to an increase in plasma adrenocorticotropin hormone concentrations while also hyperpolarizing a subgroup of neurons. In the present study, we investigate the ionic mechanisms responsible for these changes in excitability in parvocellular paraventricular nucleus neurons. Patch clamp recordings of currents elicited from slow voltage ramps and voltage steps indicate that adiponectin inhibits noninactivating delayed rectifier potassium current (I(K)) in a majority of neurons. This inhibition produced a broadening of the action potential in cells that depolarized in the presence of adiponectin. The depolarizing effects of adiponectin were abolished in cells pretreated with tetraethyl ammonium (0/15 cells depolarize). Slow voltage ramps performed during adiponectin-induced hyperpolarization indicate the activation of voltage-independent potassium current. These hyperpolarizing responses were abolished in the presence of glibenclamide [an ATP-sensitive potassium (K(ATP)) channel blocker] (0/12 cells hyperpolarize). The results presented in this study suggest that adiponectin controls neuronal excitability through the modulation of different potassium conductances, effects which contribute to changes in excitability and action potential profiles responsible for peptidergic release into the circulation.

  11. CAMKII activation is not required for maintenance of learning-induced enhancement of neuronal excitability.

    PubMed

    Liraz, Ori; Rosenblum, Kobi; Barkai, Edi

    2009-01-01

    Pyramidal neurons in the piriform cortex from olfactory-discrimination trained rats show enhanced intrinsic neuronal excitability that lasts for several days after learning. Such enhanced intrinsic excitability is mediated by long-term reduction in the post-burst after-hyperpolarization (AHP) which is generated by repetitive spike firing. AHP reduction is due to decreased conductance of a calcium-dependent potassium current, the sI(AHP). We have previously shown that learning-induced AHP reduction is maintained by persistent protein kinase C (PKC) and extracellular regulated kinase (ERK) activation. However, the molecular machinery underlying this long-lasting modulation of intrinsic excitability is yet to be fully described. Here we examine whether the CaMKII, which is known to be crucial in learning, memory and synaptic plasticity processes, is instrumental for the maintenance of learning-induced AHP reduction. KN93, that selectively blocks CaMKII autophosphorylation at Thr286, reduced the AHP in neurons from trained and control rat to the same extent. Consequently, the differences in AHP amplitude and neuronal adaptation between neurons from trained rats and controls remained. Accordingly, the level of activated CaMKII was similar in pirifrom cortex samples taken form trained and control rats. Our data show that although CaMKII modulates the amplitude of AHP of pyramidal neurons in the piriform cortex, its activation is not required for maintaining learning-induced enhancement of neuronal excitability.

  12. CAMKII Activation Is Not Required for Maintenance of Learning-Induced Enhancement of Neuronal Excitability

    PubMed Central

    Liraz, Ori; Rosenblum, Kobi; Barkai, Edi

    2009-01-01

    Pyramidal neurons in the piriform cortex from olfactory-discrimination trained rats show enhanced intrinsic neuronal excitability that lasts for several days after learning. Such enhanced intrinsic excitability is mediated by long-term reduction in the post-burst after-hyperpolarization (AHP) which is generated by repetitive spike firing. AHP reduction is due to decreased conductance of a calcium-dependent potassium current, the sIAHP. We have previously shown that learning-induced AHP reduction is maintained by persistent protein kinase C (PKC) and extracellular regulated kinase (ERK) activation. However, the molecular machinery underlying this long-lasting modulation of intrinsic excitability is yet to be fully described. Here we examine whether the CaMKII, which is known to be crucial in learning, memory and synaptic plasticity processes, is instrumental for the maintenance of learning-induced AHP reduction. KN93, that selectively blocks CaMKII autophosphorylation at Thr286, reduced the AHP in neurons from trained and control rat to the same extent. Consequently, the differences in AHP amplitude and neuronal adaptation between neurons from trained rats and controls remained. Accordingly, the level of activated CaMKII was similar in pirifrom cortex samples taken form trained and control rats. Our data show that although CaMKII modulates the amplitude of AHP of pyramidal neurons in the piriform cortex, its activation is not required for maintaining learning-induced enhancement of neuronal excitability. PMID:19172997

  13. High-frequency stimulation-induced peptide release synchronizes arcuate kisspeptin neurons and excites GnRH neurons

    PubMed Central

    Qiu, Jian; Nestor, Casey C; Zhang, Chunguang; Padilla, Stephanie L; Palmiter, Richard D

    2016-01-01

    Kisspeptin (Kiss1) and neurokinin B (NKB) neurocircuits are essential for pubertal development and fertility. Kisspeptin neurons in the hypothalamic arcuate nucleus (Kiss1ARH) co-express Kiss1, NKB, dynorphin and glutamate and are postulated to provide an episodic, excitatory drive to gonadotropin-releasing hormone 1 (GnRH) neurons, the synaptic mechanisms of which are unknown. We characterized the cellular basis for synchronized Kiss1ARH neuronal activity using optogenetics, whole-cell electrophysiology, molecular pharmacology and single cell RT-PCR in mice. High-frequency photostimulation of Kiss1ARH neurons evoked local release of excitatory (NKB) and inhibitory (dynorphin) neuropeptides, which were found to synchronize the Kiss1ARH neuronal firing. The light-evoked synchronous activity caused robust excitation of GnRH neurons by a synaptic mechanism that also involved glutamatergic input to preoptic Kiss1 neurons from Kiss1ARH neurons. We propose that Kiss1ARH neurons play a dual role of driving episodic secretion of GnRH through the differential release of peptide and amino acid neurotransmitters to coordinate reproductive function. DOI: http://dx.doi.org/10.7554/eLife.16246.001 PMID:27549338

  14. [Effect of weak static magnetic fields on the excitability of a neuron].

    PubMed

    Novikov, S M; Maksimov, G V; Volkov, V V; Shalygin, A N

    2008-01-01

    Changes in the excitability of the neuron (amplitude, excitability threshold, rate of action potential transduction), as well as changes in the viscosity of the plasma membrane of the nerve and membranes of subcellular organelles, induced by the action of a weak magnetic field, have been studied by the methods of extracellular registration of membrane potential and combination scattering. It was found that only the threshold of excitability in intact nervous fibers increases by the action of this field. It was proven that the conformation of C40 carotenoids localized not only in plasma membranes but also in subcellular membranes of the neuron changes in a weak magnetic field. It is assumed that the changes in the excitability of the neuron by the action of weak magnetic field are due to changes in the orderliness of membrane lipids and the content of oxygen in the cytoplasm.

  15. Bicarbonate contributes to GABAA receptor-mediated neuronal excitation in surgically resected human hypothalamic hamartomas.

    PubMed

    Kim, Do-Young; Fenoglio, Kristina A; Kerrigan, John F; Rho, Jong M

    2009-01-01

    The role of bicarbonate (HCO(3)(-)) in GABA(A) receptor-mediated depolarization of human hypothalamic hamartoma (HH) neurons was investigated using cellular electrophysiological and calcium imaging techniques. Activation of GABA(A) receptors with muscimol (30 microM) provoked neuronal excitation in over 70% of large (18-22 microM) HH neurons in HCO(3)(-) buffer. Subsequent perfusion of HCO(3)(-)-free HEPES buffer produced partial suppression of muscimol-induced excitation. Additionally, 53% of large HH neurons under HCO(3)(-)-free conditions exhibited reduced intracellular calcium accumulation by muscimol. These results suggest that HCO(3)(-) efflux through GABA(A) receptors on a subpopulation of large HH neurons may contribute to membrane depolarization and subsequent activation of L-type calcium channels.

  16. GABA excitation in mouse hilar neuropeptide Y neurons

    PubMed Central

    Fu, Li-Ying; van den Pol, Anthony N

    2007-01-01

    Neuropeptide Y-containing interneurons in the dentate hilar area play an important role in inhibiting the activity of hippocampal circuitry. Hilar cells are often among the first lost in hippocampal epilepsy. As many types of neurons are found in the hilus, we used a new transgenic mouse expressing green fluorescent protein (GFP) in a subset of neurons that colocalized neuropeptide Y (NPY), somatostatin (SST), and GABA for whole-cell, perforated, and cell-attached recording in 240 neurons. As these neurons have not previously been identifiable in live slices, they have not been the focus of physiological analysis. Hilar NPY neurons showed modest spike frequency adaptation, a large 15.6 ± 1.0 mV afterhyperpolarization, a mean input resistance of 335 ± 26 mΩ, and were capable of fast-firing. Muscimol-mediated excitatory actions were found in a nominally Ca2+-free/high-Mg2+ bath solution using cell-attached recording. GABAA receptor antagonists inhibited half the recorded neurons and blocked burst firing. Gramicidin perforated-patch recording revealed a GABA reversal potential positive to both the resting membrane potential and spike threshold. Together, these data suggest GABA is excitatory to many NPY cells. NPY and SST consistently hyperpolarized and reduced spike frequency in these neurons. No hyperpolarization of NPY on membrane potential was detected in the presence of tetrodotoxin, AP5, CNQX and bicuculline, supporting an indirect effect. Under similar conditions, SST hyperpolarized the cells, suggesting a direct postsynaptic action. Depolarizing actions of GABA and GABA-dependent burst-firing may synchronize a rapid release of GABA, NPY, and SST, leading to pre- and postsynaptic inhibition of excitatory hippocampal circuits. PMID:17204505

  17. Reduced motor neuron excitability is an important contributor to weakness in a rat model of sepsis.

    PubMed

    Nardelli, Paul; Vincent, Jacob A; Powers, Randall; Cope, Tim C; Rich, Mark M

    2016-08-01

    The mechanisms by which sepsis triggers intensive care unit acquired weakness (ICUAW) remain unclear. We previously identified difficulty with motor unit recruitment in patients as a novel contributor to ICUAW. To study the mechanism underlying poor recruitment of motor units we used the rat cecal ligation and puncture model of sepsis. We identified striking dysfunction of alpha motor neurons during repetitive firing. Firing was more erratic, and often intermittent. Our data raised the possibility that reduced excitability of motor neurons was a significant contributor to weakness induced by sepsis. In this study we quantified the contribution of reduced motor neuron excitability and compared its magnitude to the contributions of myopathy, neuropathy and failure of neuromuscular transmission. We injected constant depolarizing current pulses (5s) into the soma of alpha motor neurons in the lumbosacral spinal cord of anesthetized rats to trigger repetitive firing. In response to constant depolarization, motor neurons in untreated control rats fired at steady and continuous firing rates and generated smooth and sustained tetanic motor unit force as expected. In contrast, following induction of sepsis, motor neurons were often unable to sustain firing throughout the 5s current injection such that force production was reduced. Even when firing, motor neurons from septic rats fired erratically and discontinuously, leading to irregular production of motor unit force. Both fast and slow type motor neurons had similar disruption of excitability. We followed rats after recovery from sepsis to determine the time course of resolution of the defect in motor neuron excitability. By one week, rats appeared to have recovered from sepsis as they had no piloerection and appeared to be in no distress. The defects in motor neuron repetitive firing were still striking at 2weeks and, although improved, were present at one month. We infer that rats suffered from weakness due to reduced

  18. Reduced motor neuron excitability is an important contributor to weakness in a rat model of sepsis

    PubMed Central

    Nardelli, Paul; Vincent, Jacob A.; Powers, Randall; Cope, Tim C.; Rich, Mark M.

    2016-01-01

    The mechanisms by which sepsis triggers intensive care unit acquired weakness (ICUAW) remain unclear. We previously identified difficulty with motor unit recruitment in patients as a novel contributor to ICUAW. To study the mechanism underlying poor recruitment of motor units we used the rat cecal ligation and puncture model of sepsis. We identified striking dysfunction of alpha motor neurons during repetitive firing. Firing was more erratic, and often intermittent. Our data raised the possibility that reduced excitability of motor neurons was a significant contributor to weakness induced by sepsis. In this study we quantified the contribution of reduced motor neuron excitability and compared its magnitude to the contributions of myopathy, neuropathy and failure of neuromuscular transmission. We injected constant depolarizing current pulses (5 sec) into the soma of alpha motor neurons in the lumbosacral spinal cord of anesthetized rats to trigger repetitive firing. In response to constant depolarization, motor neurons in untreated control rats fired at steady and continuous firing rates and generated smooth and sustained tetanic motor unit force as expected. In contrast, following induction of sepsis, motor neurons were often unable to sustain firing throughout the 5s current injection such that force production was reduced. Even when firing, motor neurons from septic rats fired erratically and discontinuously, leading to irregular production of motor unit force. Both fast and slow type motor neurons had similar disruption of excitability. We followed rats after recovery from sepsis to determine the time course of resolution of the defect in motor neuron excitability. By one week, rats appeared to have recovered from sepsis as they had no piloerection and appeared to be in no distress. The defects in motor neuron repetitive firing were still striking at 2 weeks and, although improved, were present at one month. We infer that rats suffered from weakness due to

  19. (-)-Deprenyl reduces neuronal apoptosis and facilitates neuronal outgrowth by altering protein synthesis without inhibiting monoamine oxidase.

    PubMed

    Tatton, W G; Wadia, J S; Ju, W Y; Chalmers-Redman, R M; Tatton, N A

    1996-01-01

    (-)-Deprenyl stereospecifically reduces neuronal death even after neurons have sustained seemingly lethal damage at concentrations too small to cause monoamine oxidase-B (MAO-B) inhibition. (-)-Deprenyl can also influence the process growth of some glial and neuronal populations and can reduce the concentrations of oxidative radicals in damaged cells at concentrations too small to inhibit MAO. In accord with the earlier work of others, we showed that (-)-deprenyl alters the expression of a number mRNAs or proteins in nerve and glial cells and that the alterations in gene expression/protein synthesis are the result of a selective action on transcription. The alterations in gene expression/protein synthesis are accompanied by a decrease in DNA fragmentation characteristic of apoptosis and the death of responsive cells. The onco-proteins Bcl-2 and Bax and the scavenger proteins Cu/Zn superoxide dismutase (SOD1) and Mn superoxide dismutase (SOD2) are among the 40-50 proteins whose synthesis is altered by (-)-deprenyl. Since mitochondrial ATP production depends on mitochondrial membrane potential (MMP) and mitochondrial failure has been shown to be one of the earliest events in apoptosis, we used confocal laser imaging techniques in living cells to show that the transcriptional changes induced by (-)-deprenyl are accompanied by a maintenance of mitochondrial membrane potential, a decrease in intramitochondrial calcium and a decrease in cytoplasmic oxidative radical levels. We therefore propose that (-)-deprenyl acts on gene expression to maintain mitochondrial function and to decrease cytoplasmic oxidative radical levels and thereby to reduce apoptosis. An understanding of the molecular steps by which (-)-deprenyl selectively alters transcription may contribute to the development of new therapies for neurodegenerative diseases.

  20. Trace Fear Conditioning Differentially Modulates Intrinsic Excitability of Medial Prefrontal Cortex-Basolateral Complex of Amygdala Projection Neurons in Infralimbic and Prelimbic Cortices.

    PubMed

    Song, Chenghui; Ehlers, Vanessa L; Moyer, James R

    2015-09-30

    combination of electrophysiological recordings from fluorescently labeled mPFC-to-amygdala projection neurons in rats with acquisition and extinction of trace fear conditioning to determine how specific neurons change during behavior. This is the first study to demonstrate that trace fear conditioning significantly alters the intrinsic excitability of mPFC-to-amygdala projection neurons in a subregion- and cell-type-specific manner, which is also transient and reversed by extinction. These data are of broad interest to the neuroscientific community, and the results will inspire additional studies investigating the cellular mechanisms underlying circuit-specific changes within the brain as a result of associative learning and memory.

  1. Trace Fear Conditioning Differentially Modulates Intrinsic Excitability of Medial Prefrontal Cortex–Basolateral Complex of Amygdala Projection Neurons in Infralimbic and Prelimbic Cortices

    PubMed Central

    Song, Chenghui; Ehlers, Vanessa L.

    2015-01-01

    combination of electrophysiological recordings from fluorescently labeled mPFC-to-amygdala projection neurons in rats with acquisition and extinction of trace fear conditioning to determine how specific neurons change during behavior. This is the first study to demonstrate that trace fear conditioning significantly alters the intrinsic excitability of mPFC-to-amygdala projection neurons in a subregion- and cell-type-specific manner, which is also transient and reversed by extinction. These data are of broad interest to the neuroscientific community, and the results will inspire additional studies investigating the cellular mechanisms underlying circuit-specific changes within the brain as a result of associative learning and memory. PMID:26424895

  2. Leptin excites POMC neurons via activation of TRPC channels

    PubMed Central

    Qiu, Jian; Fang, Yuan; Rønnekleiv, Oline K.; Kelly, Martin J.

    2010-01-01

    Leptin can exert its potent appetite-suppressing effects via activation of hypothalamic proopiomelanocortin (POMC) neurons. It depolarizes POMC neurons via activation of a yet unidentified non-selective cation current. Therefore, we sought to identify the conductance activated by leptin using whole cell recording in EGFP-POMC neurons from transgenic mice. The TRPC channel blockers SKF96365, FFA and 2-APB potently inhibited the leptin-induced current. Also, lanthanum (La3+) and intracellular Ca2+ potentiated the effects of leptin. Moreover, the DAG permeable analog OAG failed to activate any TRPC current. Using a Cs+-gluconate-based internal solution, leptin-activated current reversed near -20 mV. After replacement of external Na+ and K+ with Cs+, the reversal shifted to near 0 mV, and the I/V curve exhibited a negative slope conductance at voltages more negative than –40 mV. Based on scRT-PCR, TRPC1 and TRPC4-7 mRNA were expressed in POMC neurons with TRPC5 being the most prevalent. The leptin-induced current was blocked by Jak2 inhibitor AG490, the PI3 Kinase inhibitor wortmannin and the phospholipase C inhibitors, U73122 and ET-18-OCH3. Notably, we identified PLCγ1 transcripts in the majority of POMC neurons. Therefore, leptin through a Jak2-PI3 kinase-PLCγ pathway activates TRPC channels, and TRPC1, 4 and 5 appear to be the key channels mediating the depolarizing effects of leptin in POMC neurons. PMID:20107083

  3. Insulin Excites Anorexigenic Proopiomelanocortin Neurons via Activation of Canonical Transient Receptor Potential Channels

    PubMed Central

    Qiu, Jian; Zhang, Chunguang; Borgquist, Amanda; Nestor, Casey C; Smith, Arik W.; Bosch, Martha A.; Ku, Stephen; Wagner, Edward J.; Rønnekleiv, Oline K.; Kelly, Martin J.

    2014-01-01

    SUMMARY Proopiomelanocortin (POMC) neurons within the hypothalamic arcuate nucleus are vital anorexigenic neurons. Although both the leptin receptor and insulin receptor are coupled to activation of phosphatidylinositide3-kinase (PI3K) in POMC neurons, they are thought to have disparate actions on POMC excitability. Using whole-cell recording and selective pharmacological tools, we have found that similar to leptin, purified insulin depolarized POMC, and adjacent kisspeptin neurons via activation of TRPC5 channels, which are highly expressed in these neurons. In contrast, insulin hyperpolarized and inhibited NPY/AgRP neurons via activation of KATP channels. Moreover, Zn2+, which is found in insulin formulations at nanomolar concentrations, inhibited POMC neurons via activation of KATP channels. Finally as predicted, insulin given intracerebroventrically robustly inhibited food intake and activated c-fos expression in arcuate POMC neurons. Our results show that purified insulin excites POMC neurons in the arcuate nucleus, which we propose is a major mechanism by which insulin regulates energy homeostasis. PMID:24703699

  4. Dissecting mechanisms of brain aging by studying the intrinsic excitability of neurons

    PubMed Central

    Rizzo, Valerio; Richman, Jeffrey; Puthanveettil, Sathyanarayanan V.

    2015-01-01

    Several studies using vertebrate and invertebrate animal models have shown aging associated changes in brain function. Importantly, changes in soma size, loss or regression of dendrites and dendritic spines and alterations in the expression of neurotransmitter receptors in specific neurons were described. Despite this understanding, how aging impacts intrinsic properties of individual neurons or circuits that govern a defined behavior is yet to be determined. Here we discuss current understanding of specific electrophysiological changes in individual neurons and circuits during aging. PMID:25610394

  5. Proteomic profiling of neuromas reveals alterations in protein composition and local protein synthesis in hyper-excitable nerves

    PubMed Central

    Huang, Hong-Lei; Cendan, Cruz-Miguel; Roza, Carolina; Okuse, Kenji; Cramer, Rainer; Timms, John F; Wood, John N

    2008-01-01

    Neuropathic pain may arise following peripheral nerve injury though the molecular mechanisms associated with this are unclear. We used proteomic profiling to examine changes in protein expression associated with the formation of hyper-excitable neuromas derived from rodent saphenous nerves. A two-dimensional difference gel electrophoresis (2D-DIGE) profiling strategy was employed to examine protein expression changes between developing neuromas and normal nerves in whole tissue lysates. We found around 200 proteins which displayed a >1.75-fold change in expression between neuroma and normal nerve and identified 55 of these proteins using mass spectrometry. We also used immunoblotting to examine the expression of low-abundance ion channels Nav1.3, Nav1.8 and calcium channel α2δ-1 subunit in this model, since they have previously been implicated in neuronal hyperexcitability associated with neuropathic pain. Finally, S35methionine in vitro labelling of neuroma and control samples was used to demonstrate local protein synthesis of neuron-specific genes. A number of cytoskeletal proteins, enzymes and proteins associated with oxidative stress were up-regulated in neuromas, whilst overall levels of voltage-gated ion channel proteins were unaffected. We conclude that altered mRNA levels reported in the somata of damaged DRG neurons do not necessarily reflect levels of altered proteins in hyper-excitable damaged nerve endings. An altered repertoire of protein expression, local protein synthesis and topological re-arrangements of ion channels may all play important roles in neuroma hyper-excitability. PMID:18700027

  6. Contributions of Kv3 channels to neuronal excitability.

    PubMed

    Rudy, B; Chow, A; Lau, D; Amarillo, Y; Ozaita, A; Saganich, M; Moreno, H; Nadal, M S; Hernandez-Pineda, R; Hernandez-Cruz, A; Erisir, A; Leonard, C; Vega-Saenz de Miera, E

    1999-04-30

    Four mammalian Kv3 genes have been identified, each of which generates, by alternative splicing, multiple protein products differing in their C-terminal sequence. Products of the Kv3.1 and Kv3.2 genes express similar delayed-rectifier type currents in heterologous expression systems, while Kv3.3 and Kv3.4 proteins express A-type currents. All Kv3 currents activate relatively fast at voltages more positive than -10 mV, and deactivate very fast. The distribution of Kv3 mRNAs in the rodent CNS was studied by in situ hybridization, and the localization of Kv3.1 and Kv3.2 proteins has been studied by immunohistochemistry. Most Kv3.2 mRNAs (approximately 90%) are present in thalamic-relay neurons throughout the dorsal thalamus. The protein is expressed mainly in the axons and terminals of these neurons. Kv3.2 channels are thought to be important for thalamocortical signal transmission. Kv3.1 and Kv3.2 proteins are coexpressed in some neuronal populations such as in fast-spiking interneurons of the cortex and hippocampus, and neurons in the globus pallidus. Coprecipitation studies suggest that in these cells the two types of protein form heteromeric channels. Kv3 proteins appear to mediate, in native neurons, similar currents to those seen in heterologous expression systems. The activation voltage and fast deactivation rates are believed to allow these channels to help repolarize action potentials fast without affecting the threshold for action potential generation. The fast deactivating current generates a quickly recovering after hyperpolarization, thus maximizing the rate of recovery of Na+ channel inactivation without contributing to an increase in the duration of the refractory period. These properties are believed to contribute to the ability of neurons to fire at high frequencies and to help regulate the fidelity of synaptic transmission. Experimental evidence has now become available showing that Kv3.1-Kv3.2 channels play critical roles in the generation of fast

  7. Dietary cholesterol modulates the excitability of rabbit hippocampal CA1 pyramidal neurons.

    PubMed

    Wang, Desheng; Schreurs, Bernard G

    2010-08-02

    Previous work has shown high dietary cholesterol can affect learning and memory including rabbit eyeblink conditioning and this effect may be due to increased membrane cholesterol and enhanced hippocampal amyloid beta production. This study investigated whether dietary cholesterol modulates rabbit hippocampal CA1 neuron membrane properties known to be involved in rabbit eyeblink conditioning. Whole-cell current clamp recordings in hippocampal neurons from rabbits fed 2 percent cholesterol or normal chow for 8 weeks revealed changes including decreased after-hyperpolarization amplitudes (AHPs) - an index of membrane excitability shown to be important for rabbit eyeblink conditioning. This index was reversed by adding copper to drinking water - a dietary manipulation that can retard rabbit eyeblink conditioning. Evidence of cholesterol effects on membrane excitability was provided by application of methyl-beta-cyclodextrin, a compound that reduces membrane cholesterol, which increased the excitability of hippocampal CA1 neurons.

  8. miR-128 regulates neuronal migration, outgrowth and intrinsic excitability via the intellectual disability gene Phf6

    PubMed Central

    Franzoni, Eleonora; Booker, Sam A; Parthasarathy, Srinivas; Rehfeld, Frederick; Grosser, Sabine; Srivatsa, Swathi; Fuchs, Heiko R; Tarabykin, Victor; Vida, Imre; Wulczyn, F Gregory

    2015-01-01

    miR-128, a brain-enriched microRNA, has been implicated in the control of neurogenesis and synaptogenesis but its potential roles in intervening processes have not been addressed. We show that post-transcriptional mechanisms restrict miR-128 accumulation to post-mitotic neurons during mouse corticogenesis and in adult stem cell niches. Whereas premature miR-128 expression in progenitors for upper layer neurons leads to impaired neuronal migration and inappropriate branching, sponge-mediated inhibition results in overmigration. Within the upper layers, premature miR-128 expression reduces the complexity of dendritic arborization, associated with altered electrophysiological properties. We show that Phf6, a gene mutated in the cognitive disorder Börjeson-Forssman-Lehmann syndrome, is an important regulatory target for miR-128. Restoring PHF6 expression counteracts the deleterious effect of miR-128 on neuronal migration, outgrowth and intrinsic physiological properties. Our results place miR-128 upstream of PHF6 in a pathway vital for cortical lamination as well as for the development of neuronal morphology and intrinsic excitability. DOI: http://dx.doi.org/10.7554/eLife.04263.001 PMID:25556700

  9. Neuronal Atrophy Early in Degenerative Ataxia Is a Compensatory Mechanism to Regulate Membrane Excitability.

    PubMed

    Dell'Orco, James M; Wasserman, Aaron H; Chopra, Ravi; Ingram, Melissa A C; Hu, Yuan-Shih; Singh, Vikrant; Wulff, Heike; Opal, Puneet; Orr, Harry T; Shakkottai, Vikram G

    2015-08-12

    Neuronal atrophy in neurodegenerative diseases is commonly viewed as an early event in a continuum that ultimately results in neuronal loss. In a mouse model of the polyglutamine disorder spinocerebellar ataxia type 1 (SCA1), we tested the hypothesis that cerebellar Purkinje neuron atrophy serves an adaptive role rather than being simply a nonspecific response to injury. In acute cerebellar slices from SCA1 mice, we find that Purkinje neuron pacemaker firing is initially normal but, with the onset of motor dysfunction, becomes disrupted, accompanied by abnormal depolarization. Remarkably, subsequent Purkinje cell atrophy is associated with a restoration of pacemaker firing. The early inability of Purkinje neurons to support repetitive spiking is due to unopposed calcium currents resulting from a reduction in large-conductance calcium-activated potassium (BK) and subthreshold-activated potassium channels. The subsequent restoration of SCA1 Purkinje neuron firing correlates with the recovery of the density of these potassium channels that accompanies cell atrophy. Supporting a critical role for BK channels, viral-mediated increases in BK channel expression in SCA1 Purkinje neurons improves motor dysfunction and partially restores Purkinje neuron morphology. Cerebellar perfusion of flufenamic acid, an agent that restores the depolarized membrane potential of SCA1 Purkinje neurons by activating potassium channels, prevents Purkinje neuron dendritic atrophy. These results suggest that Purkinje neuron dendritic remodeling in ataxia is an adaptive response to increases in intrinsic membrane excitability. Similar adaptive remodeling could apply to other vulnerable neuronal populations in neurodegenerative disease. In neurodegenerative disease, neuronal atrophy has long been assumed to be an early nonspecific event preceding neuronal loss. However, in a mouse model of spinocerebellar ataxia type 1 (SCA1), we identify a previously unappreciated compensatory role for neuronal

  10. Effect of voltage sensitive fluorescent proteins on neuronal excitability.

    PubMed

    Akemann, Walther; Lundby, Alicia; Mutoh, Hiroki; Knöpfel, Thomas

    2009-05-20

    Fluorescent protein voltage sensors are recombinant proteins that are designed as genetically encoded cellular probes of membrane potential using mechanisms of voltage-dependent modulation of fluorescence. Several such proteins, including VSFP2.3 and VSFP3.1, were recently reported with reliable function in mammalian cells. They were designed as molecular fusions of the voltage sensor of Ciona intestinalis voltage sensor containing phosphatase with a fluorescence reporter domain. Expression of these proteins in cell membranes is accompanied by additional dynamic membrane capacitance, or "sensing capacitance", with feedback effect on the native electro-responsiveness of targeted cells. We used recordings of sensing currents and fluorescence responses of VSFP2.3 and of VSFP3.1 to derive kinetic models of the voltage-dependent signaling of these proteins. Using computational neuron simulations, we quantitatively investigated the perturbing effects of sensing capacitance on the input/output relationship in two central neuron models, a cerebellar Purkinje and a layer 5 pyramidal neuron. Probe-induced sensing capacitance manifested as time shifts of action potentials and increased synaptic input thresholds for somatic action potential initiation with linear dependence on the membrane density of the probe. Whereas the fluorescence signal/noise grows with the square root of the surface density of the probe, the growth of sensing capacitance is linear. We analyzed the trade-off between minimization of sensing capacitance and signal/noise of the optical read-out depending on kinetic properties and cellular distribution of the probe. The simulation results suggest ways to reduce capacitive effects at a given level of signal/noise. Yet, the simulations indicate that significant improvement of existing probes will still be required to report action potentials in individual neurons in mammalian brain tissue in single trials.

  11. Snx14 Regulates Neuronal Excitability, Promotes Synaptic Transmission, and Is Imprinted in the Brain of Mice

    PubMed Central

    Huang, Hsien-Sung; Yoon, Bong-June; Brooks, Sherian; Bakal, Robert; Berrios, Janet; Larsen, Rylan S.; Wallace, Michael L.; Han, Ji Eun; Chung, Eui Hwan; Zylka, Mark J.; Philpot, Benjamin D.

    2014-01-01

    Genomic imprinting describes an epigenetic process through which genes can be expressed in a parent-of-origin-specific manner. The monoallelic expression of imprinted genes renders them particularly susceptible to disease causing mutations. A large proportion of imprinted genes are expressed in the brain, but little is known about their functions. Indeed, it has proven difficult to identify cell type-specific imprinted genes due to the heterogeneity of cell types within the brain. Here we used laser capture microdissection of visual cortical neurons and found evidence that sorting nexin 14 (Snx14) is a neuronally imprinted gene in mice. SNX14 protein levels are high in the brain and progressively increase during neuronal development and maturation. Snx14 knockdown reduces intrinsic excitability and severely impairs both excitatory and inhibitory synaptic transmission. These data reveal a role for monoallelic Snx14 expression in maintaining normal neuronal excitability and synaptic transmission. PMID:24859318

  12. Effects of guanidine on transmitter release and neuronal excitability.

    PubMed Central

    Matthews, G; Wickelgren, W O

    1977-01-01

    1. Guanidine hydrochloride (CH5N3-HCl) was applied to frog neuromuscular junctions blocked by reduced external Ca2+, or increased external Mg2+ concentration, or by both. Guanidine produced a dose-dependent increase in the average number of quanta released by presynaptic action potentials, the threshold dose being 0-1-0-2 mM. No post-synaptic effects were observed. 2. Guanidine also increased the excitability of the motor nerve fibres, as evidenced by multiple firing to single electrical stimuli and finally by spontaneous action potentials. These effects were studied in greater detail in giant axons (Müller axons) in the spinal cord of lamprey. Exposure to guanidine produced in these axons a progressive increase in excitability, manifested by repetitive firing to a single electrical stimulus, spontaneous membrane potential oscillations and spontaneous bursts of action potentials. Guanidine had no effect on the resting potential. 3. The effect of guanidine on the excitability of Müller axons was mimicked in every detail simply by reducing the divalent cation concentration of the bathing solution. 4. Guanidine also produced dose-dependent increases in the duration of action potentials in Müller axons. This effect always preceded in time the appearance of the excitability effects and was not mimicked by reducing the divalent cation concentration. It is suggested that the broadening of the action potential is separate from the excitability effects and may reflect a decrease of delayed rectification. 5. Guanidine (0-3 mM) increased the frequency of miniature end-plate potentials (min. e.p.p.) in solutions containing 2-11 mM-K+ in such a way as to shift the relationship between min. e.p.p. frequency and extracellular K+ toward lower values of K+. This effect was interpreted to mean that guanidine produced a depolarization of the nerve terminal which summed with the depolarization produced by a given concentration of K+. The calculated depolarization produced by 0-3 m

  13. Histamine excites rat lateral vestibular nuclear neurons through activation of post-synaptic H2 receptors.

    PubMed

    Zhang, Jun; Han, Xiao-Hu; Li, Hong-Zhao; Zhu, Jing-Ning; Wang, Jian-Jun

    2008-12-19

    Through whole-cell patch recordings in brainstem slices, the effects of histamine on neuronal activity of the lateral vestibular nucleus (LVN) were investigated. Bath application of histamine elicited a concentration-dependent excitation of both spontaneous firing (n=19) and silent (n=7) LVN neurons. Moreover, histamine induced a stable inward current in the LVN neurons (n=5) and the histamine-induced depolarization of membrane potential persisted in the presence of tetrodotoxin (n=4), indicating a direct post-synaptic effect of the histamine on the LVN neurons. Selective histamine H2 receptor antagonist ranitidine effectively blocked the histamine-evoked excitatory responses on the LVN neurons (n=4), but selective histamine H1 receptor antagonist triprolidine did not (n=4). In addition, selective histamine H2 receptor agonist dimaprit (n=3) rather than 2-pyridylethylamine (n=4), a selective histamine H1 receptor agonist, mimicked the excitatory action of histamine on LVN neurons. The results demonstrate that histamine excites the LVN neurons via post-synaptic histamine H2 receptors and suggest that the central histaminergic projection arising from the hypothalamus may modulate LVN neurons activity and actively influence the vestibular reflexes and functions.

  14. Activation of A-type gamma-aminobutyric acid receptors excites gonadotropin-releasing hormone neurons.

    PubMed

    DeFazio, R Anthony; Heger, Sabine; Ojeda, Sergio R; Moenter, Suzanne M

    2002-12-01

    Gamma-aminobutyric acid (GABA), acting through GABA(A) receptors (GABA(A)R), is hypothesized to suppress reproduction by inhibiting GnRH secretion, but GABA actions directly on GnRH neurons are not well established. In green fluorescent protein-identified adult mouse GnRH neurons in brain slices, gramicidin-perforated-patch-clamp experiments revealed the reversal potential (E(GABA)) for current through GABA(A)Rs was depolarized relative to the resting potential. Furthermore, rapid GABA application elicited action potentials in GnRH neurons but not controls. The consequence of GABA(A)R activation depends on intracellular chloride levels, which are maintained by homeostatic mechanisms. Membrane proteins that typically extrude chloride (KCC-2 cotransporter, CLC-2 channel) were absent from the GT1-7 immortalized GnRH cell line and GnRH neurons in situ or were not localized to the proper cell compartment for function. In contrast, GT1-7 cells and some GnRH neurons expressed the chloride-accumulating cotransporter, NKCC-1. Patch-clamp experiments showed that blockade of NKCC hyperpolarized E(GABA) by lowering intracellular chloride. Regardless of reproductive state, rapid GABA application excited GnRH neurons. In contrast, bath application of the GABA(A)R agonist muscimol transiently increased then suppressed firing; suppression persisted 4-15 min. Rapid activation of GABA(A)R thus excites GnRH neurons whereas prolonged activation reduces excitability, suggesting the physiological consequence of synaptic activation of GABA(A)R in GnRH neurons is excitation.

  15. [Electrical excitability of the apical dendrites of mammalian cortical pyramidal neurons].

    PubMed

    Fan, Shih-Fang

    2012-12-25

    The electrical excitability of the dendrites of the cortical neurons was first studied on the apical dendrites of the pyramidal neurons. Professor ZHANG Xiang-Tong (H-T Chang) made important contributions in the fifties of last century on this topic. Through numerous studies later on, it has been established that the electrical excitability of dendrites of different types of neurons, even different dendrites in the same neuron is different. For the apical dendrites of the cortical pyramidal neurons, neither a single nor a train of repetitive action potentials with constant frequency can reach its terminal portion. However, some of the burst repetitive responses with non-constant frequency of the apical dendrite elicited by direct current injected into the soma may reach the terminal portion. This may be due to: (1) the calcium ion concentration in the apical dendrite is increased by the burst activities, which, in turn, increases the electrical excitability of the apical dendrite and /or (2) some retrograde collaterals of axon of the activated soma reach the apical dendrite and release neurotransmitter glutamate, which changes the properties of the voltage-gated ion channels in the apical dendrite. Low electrical excitability of the apical dendrites seems to be essential for the processing of numerous income signals to the terminal portion of the apical dendrites.

  16. The ADAR RNA editing enzyme controls neuronal excitability in Drosophila melanogaster

    PubMed Central

    Li, Xianghua; Overton, Ian M.; Baines, Richard A.; Keegan, Liam P.; O’Connell, Mary A.

    2014-01-01

    RNA editing by deamination of specific adenosine bases to inosines during pre-mRNA processing generates edited isoforms of proteins. Recoding RNA editing is more widespread in Drosophila than in vertebrates. Editing levels rise strongly at metamorphosis, and Adar5G1 null mutant flies lack editing events in hundreds of CNS transcripts; mutant flies have reduced viability, severely defective locomotion and age-dependent neurodegeneration. On the other hand, overexpressing an adult dADAR isoform with high enzymatic activity ubiquitously during larval and pupal stages is lethal. Advantage was taken of this to screen for genetic modifiers; Adar overexpression lethality is rescued by reduced dosage of the Rdl (Resistant to dieldrin), gene encoding a subunit of inhibitory GABA receptors. Reduced dosage of the Gad1 gene encoding the GABA synthetase also rescues Adar overexpression lethality. Drosophila Adar5G1 mutant phenotypes are ameliorated by feeding GABA modulators. We demonstrate that neuronal excitability is linked to dADAR expression levels in individual neurons; Adar-overexpressing larval motor neurons show reduced excitability whereas Adar5G1 null mutant or targeted Adar knockdown motor neurons exhibit increased excitability. GABA inhibitory signalling is impaired in human epileptic and autistic conditions, and vertebrate ADARs may have a relevant evolutionarily conserved control over neuronal excitability. PMID:24137011

  17. Balance between excitation and inhibition controls the temporal organization of neuronal avalanches.

    PubMed

    Lombardi, F; Herrmann, H J; Perrone-Capano, C; Plenz, D; de Arcangelis, L

    2012-06-01

    Neuronal avalanches, measured in vitro and in vivo, exhibit a robust critical behavior. Their temporal organization hides the presence of correlations. Here we present experimental measurements of the waiting time distribution between successive avalanches in the rat cortex in vitro. This exhibits a nonmonotonic behavior not usually found in other natural processes. Numerical simulations provide evidence that this behavior is a consequence of the alternation between states of high and low activity, named up and down states, leading to a balance between excitation and inhibition controlled by a single parameter. During these periods, both the single neuron state and the network excitability level, keeping memory of past activity, are tuned by homeostatic mechanisms.

  18. Intrinsic excitability of CA1 pyramidal neurones from the rat dorsal and ventral hippocampus.

    PubMed

    Dougherty, Kelly A; Islam, Tasnim; Johnston, Daniel

    2012-11-15

    The hippocampus has a central role in learning and memory. Although once considered a relatively homogenous structure along the longitudinal axis, it has become clear that the rodent hippocampus can be anatomically and functionally divided into a dorsal component generally associated with spatial navigation, and a ventral component primarily associated with non-spatial functions that involve an emotional component. The ventral hippocampus (VHC) is also more sensitive to epileptogenic stimuli than the dorsal hippocampus (DHC), and seizures tend to originate in the VHC before spreading to other brain regions. Although synaptic and biochemical differences in DHC and VHC have been investigated, the intrinsic excitability of individual neurones from the DHC and VHC has received surprisingly little attention. In this study, we have characterized the intrinsic electrophysiological properties of CA1 pyramidal neurones from the DHC and the VHC using the whole-cell current-clamp method. Our results demonstrate that somatic current injections of equal magnitude elicit significantly more action potentials in VHC neurones than DHC neurones, and that this difference stems from the more depolarized resting membrane potential (RMP; 7 mV) and higher input resistance (R(in); 46 M measured from RMP) observed in VHC neurones. These differences in RMP and R(in) were also observed in dendritic whole-cell current-clamp recordings. Furthermore, morphological reconstructions of individual neurones revealed significant differences in the dendritic branching pattern between DHC and VHC neurones that could, in principle, contribute to the lower somatic R(in) of DHC neurones. Together, our results highlight significant differences in the intrinsic electrophysiological properties of CA1 pyramidal neurones across the longitudinal hippocampal axis, and suggest that VHC neurones are intrinsically more excitable than DHC neurones. This difference is likely to predispose the VHC to hyperexcitability.

  19. Intrinsic excitability of CA1 pyramidal neurones from the rat dorsal and ventral hippocampus

    PubMed Central

    Dougherty, Kelly A; Islam, Tasnim; Johnston, Daniel

    2012-01-01

    The hippocampus has a central role in learning and memory. Although once considered a relatively homogenous structure along the longitudinal axis, it has become clear that the rodent hippocampus can be anatomically and functionally divided into a dorsal component generally associated with spatial navigation, and a ventral component primarily associated with non-spatial functions that involve an emotional component. The ventral hippocampus (VHC) is also more sensitive to epileptogenic stimuli than the dorsal hippocampus (DHC), and seizures tend to originate in the VHC before spreading to other brain regions. Although synaptic and biochemical differences in DHC and VHC have been investigated, the intrinsic excitability of individual neurones from the DHC and VHC has received surprisingly little attention. In this study, we have characterized the intrinsic electrophysiological properties of CA1 pyramidal neurones from the DHC and the VHC using the whole-cell current-clamp method. Our results demonstrate that somatic current injections of equal magnitude elicit significantly more action potentials in VHC neurones than DHC neurones, and that this difference stems from the more depolarized resting membrane potential (RMP; Δ7 mV) and higher input resistance (Rin; Δ46 MΩ measured from RMP) observed in VHC neurones. These differences in RMP and Rin were also observed in dendritic whole-cell current-clamp recordings. Furthermore, morphological reconstructions of individual neurones revealed significant differences in the dendritic branching pattern between DHC and VHC neurones that could, in principle, contribute to the lower somatic Rin of DHC neurones. Together, our results highlight significant differences in the intrinsic electrophysiological properties of CA1 pyramidal neurones across the longitudinal hippocampal axis, and suggest that VHC neurones are intrinsically more excitable than DHC neurones. This difference is likely to predispose the VHC to hyperexcitability

  20. Menthol Alone Upregulates Midbrain nAChRs, Alters nAChR Subtype Stoichiometry, Alters Dopamine Neuron Firing Frequency, and Prevents Nicotine Reward.

    PubMed

    Henderson, Brandon J; Wall, Teagan R; Henley, Beverley M; Kim, Charlene H; Nichols, Weston A; Moaddel, Ruin; Xiao, Cheng; Lester, Henry A

    2016-03-09

    Upregulation of β2 subunit-containing (β2*) nicotinic acetylcholine receptors (nAChRs) is implicated in several aspects of nicotine addiction, and menthol cigarette smokers tend to upregulate β2* nAChRs more than nonmenthol cigarette smokers. We investigated the effect of long-term menthol alone on midbrain neurons containing nAChRs. In midbrain dopaminergic (DA) neurons from mice containing fluorescent nAChR subunits, menthol alone increased the number of α4 and α6 nAChR subunits, but this upregulation did not occur in midbrain GABAergic neurons. Thus, chronic menthol produces a cell-type-selective upregulation of α4* nAChRs, complementing that of chronic nicotine alone, which upregulates α4 subunit-containing (α4*) nAChRs in GABAergic but not DA neurons. In mouse brain slices and cultured midbrain neurons, menthol reduced DA neuron firing frequency and altered DA neuron excitability following nAChR activation. Furthermore, menthol exposure before nicotine abolished nicotine reward-related behavior in mice. In neuroblastoma cells transfected with fluorescent nAChR subunits, exposure to 500 nm menthol alone also increased nAChR number and favored the formation of (α4)3(β2)2 nAChRs; this contrasts with the action of nicotine itself, which favors (α4)2(β2)3 nAChRs. Menthol alone also increases the number of α6β2 receptors that exclude the β3 subunit. Thus, menthol stabilizes lower-sensitivity α4* and α6 subunit-containing nAChRs, possibly by acting as a chemical chaperone. The abolition of nicotine reward-related behavior may be mediated through menthol's ability to stabilize lower-sensitivity nAChRs and alter DA neuron excitability. We conclude that menthol is more than a tobacco flavorant: administered alone chronically, it alters midbrain DA neurons of the nicotine reward-related pathway.

  1. COMPENSATION FOR VARIABLE INTRINSIC NEURONAL EXCITABILITY BY CIRCUIT-SYNAPTIC INTERACTIONS

    PubMed Central

    Grashow, Rachel; Brookings, Ted; Marder, Eve

    2010-01-01

    Recent theoretical and experimental work indicates that neurons tune themselves to maintain target levels of excitation by modulating ion channel expression and synaptic strengths. As a result, functionally equivalent circuits can produce similar activity despite disparate underlying network and cellular properties. To experimentally test the extent to which synaptic and intrinsic conductances can produce target activity in the presence of variability in neuronal intrinsic properties, we used the dynamic clamp to create hybrid two-cell circuits built from four types of stomatogastric (STG) neurons coupled to the same model Morris-Lecar neuron by reciprocal inhibition. We measured six intrinsic properties (input resistance, minimum membrane potential, firing rate in response to +1nA of injected current, slope of the FI curve, spike height and spike voltage threshold) of Dorsal Gastric (DG), Gastric Mill (GM), Lateral Pyloric (LP) and Pyloric Dilator (PD) neurons from male crabs, Cancer borealis. The intrinsic properties varied two to seven-fold in each cell type. We coupled each biological neuron to the Morris-Lecar model with seven different values of inhibitory synaptic conductance, and also used the dynamic clamp to add seven different values of an artificial h-conductance, thus creating 49 different circuits for each biological neuron. Despite the variability in intrinsic excitability, networks formed from each neuron produced similar circuit performance at some values of synaptic and h-conductances. This work experimentally confirms results from previous modeling studies; tuning synaptic and intrinsic conductances can yield similar circuit output from neurons with variable intrinsic excitability. PMID:20610748

  2. GABA mediated excitation in immature rat CA3 hippocampal neurons.

    PubMed

    Cherubini, E; Rovira, C; Gaiarsa, J L; Corradetti, R; Ben Ari, Y

    1990-01-01

    Intracellular recordings from rat hippocampal neurons in vitro during the first postnatal week revealed the presence of spontaneous giant depolarizing potentials (GDPs). These were generated by the synchronous discharge of a population of neurons. GDPs reversed polarity at -27 and -51 mV when recorded with KCl or K-methylsulphate filled electrodes, respectively. GDPs were blocked by the GABAA receptor antagonist bicuculline (10 microM). Iontophoretic or bath applications of GABA (10-300 microM) in the presence of tetrodotoxin (1 microM), induced a membrane depolarization or in voltage clamp experiments an inward current which reversed polarity at the same potential as GDPs. The response to GABA was blocked in a non-competitive manner by bicuculline (10 microM) and did not desensitize. GABA mediated GDPs were presynaptically modulated by N-methyl-D-aspartate (NMDA) and non-NMDA receptors. Their frequency was reduced or blocked by NMDA receptor antagonists and by the rather specific non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). The frequency of GDPs was enhanced by glycine and D-serine (10-30 microM) in a strychnine insensitive manner. This effect was blocked by AP-5, suggesting that it was mediated by the allosteric modulatory site of the NMDA receptor. These observations suggest that most of the 'excitatory' drive in immature neurons is mediated by GABA acting on GABAA receptors; furthermore excitatory amino acids modulate the release of GABA by a presynaptic action on GABAergic interneurons.

  3. Alterations of striatal indirect pathway neurons precede motor deficits in two mouse models of Huntington's disease.

    PubMed

    Sebastianutto, Irene; Cenci, Maria Angela; Fieblinger, Tim

    2017-09-01

    Striatal neurons forming the indirect pathway (iSPNs) are particularly vulnerable in Huntington's disease (HD). In this study we set out to investigate morphological and physiological alterations of iSPNs in two mouse models of HD with relatively slow disease progression (long CAG repeat R6/2 and zQ175-KI). Both were crossed with a transgenic mouse line expressing eGFP in iSPNs. Using the open-field and rotarod tests, we first defined two time points in relation to the occurrence of motor deficits in each model. Then, we investigated electrophysiological and morphological properties of iSPNs at both ages. Both HD models exhibited increased iSPN excitability already before the onset of motor deficits, associated with a reduced number of primary dendrites and decreased function of Kir- and voltage-gated potassium channels. Alterations that specifically occurred at symptomatic ages included increased calcium release by back-propagating action potentials in proximal dendrites, due to enhanced engagement of intracellular calcium stores. Moreover, motorically impaired mice of both HD models showed a reduction in iSPN spine density and progressive formation of huntingtin (Htt) aggregates in the striatum. Our study therefore reports iSPN-specific alterations relative to the development of a motor phenotype in two different mouse models of HD. While some alterations occur early and are partly non-progressive, others potentially provide a pathophysiological marker of an overt disease state. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Maternal mobile phone exposure alters intrinsic electrophysiological properties of CA1 pyramidal neurons in rat offspring.

    PubMed

    Razavinasab, Moazamehosadat; Moazzami, Kasra; Shabani, Mohammad

    2016-06-01

    Some studies have shown that exposure to electromagnetic field (EMF) may result in structural damage to neurons. In this study, we have elucidated the alteration in the hippocampal function of offspring Wistar rats (n = 8 rats in each group) that were chronically exposed to mobile phones during their gestational period by applying behavioral, histological, and electrophysiological tests. Rats in the EMF group were exposed to 900 MHz pulsed-EMF irradiation for 6 h/day. Whole cell recordings in hippocampal pyramidal cells in the mobile phone groups did show a decrease in neuronal excitability. Mobile phone exposure was mostly associated with a decrease in the number of action potentials fired in spontaneous activity and in response to current injection in both male and female groups. There was an increase in the amplitude of the afterhyperpolarization (AHP) in mobile phone rats compared with the control. The results of the passive avoidance and Morris water maze assessment of learning and memory performance showed that phone exposure significantly altered learning acquisition and memory retention in male and female rats compared with the control rats. Light microscopy study of brain sections of the control and mobile phone-exposed rats showed normal morphology.Our results suggest that exposure to mobile phones adversely affects the cognitive performance of both female and male offspring rats using behavioral and electrophysiological techniques. © The Author(s) 2014.

  5. Intrinsic Hippocampal Excitability Changes of Opposite Signs and Different Origins in CA1 and CA3 Pyramidal Neurons Underlie Aging-Related Cognitive Deficits

    PubMed Central

    Oh, M. Matthew; Simkin, Dina; Disterhoft, John F.

    2016-01-01

    Aging-related cognitive deficits have been attributed to dysfunction of neurons due to failures at synaptic or intrinsic loci, or both. Given the importance of the hippocampus for successful encoding of memory and that the main output of the hippocampus is via the CA1 pyramidal neurons, much of the research has been focused on identifying the aging-related changes of these CA1 pyramidal neurons. We and others have discovered that the postburst afterhyperpolarization (AHP) following a train of action potentials is greatly enlarged in CA1 pyramidal neurons of aged animals. This enlarged postburst AHP is a significant factor in reducing the intrinsic excitability of these neurons, and thus limiting their activity in the neural network during learning. Based on these data, it has largely been thought that aging-related cognitive deficits are attributable to reduced activity of pyramidal neurons. However, recent in vivo and ex vivo studies provide compelling evidence that aging-related deficits could also be due to a converse change in CA3 pyramidal neurons, which show increased activity with aging. In this review, we will incorporate these recent findings and posit that an interdependent dynamic dysfunctional change occurs within the hippocampal network, largely due to altered intrinsic excitability in CA1 and CA3 hippocampal pyramidal neurons, which ultimately leads to the aging-related cognitive deficits. PMID:27375440

  6. Cholecystokinin facilitates neuronal excitability in the entorhinal cortex via activation of TRPC-like channels.

    PubMed

    Wang, Shouping; Zhang, An-Ping; Kurada, Lalitha; Matsui, Toshimitsu; Lei, Saobo

    2011-09-01

    Cholecystokinin (CCK) is one of the most abundant neuropeptides in the brain, where it interacts with two G protein-coupled receptors (CCK-1 and CCK-2). Activation of both CCK receptors increases the activity of PLC, resulting in increases in intracellular calcium ion (Ca(2+)) release and activation of PKC. Whereas high density of CCK receptors has been detected in the superficial layers of the entorhinal cortex (EC), the functions of CCK in this brain region have not been determined. Here, we studied the effects of CCK on neuronal excitability of layer III pyramidal neurons in the EC. Our results showed that CCK remarkably increased the firing frequency of action potentials (APs). The effects of CCK on neuronal excitability were mediated via activation of CCK-2 receptors and required the functions of G proteins and PLC. However, CCK-mediated facilitation of neuronal excitability was independent of inositol trisphosphate receptors and PKC. CCK facilitated neuronal excitability by activating a cationic channel to generate membrane depolarization. The effects of CCK were suppressed by the generic, nonselective cationic channel blockers, 2-aminoethyldiphenyl borate and flufenamic acid, but potentiated by gadolinium ion and lanthanum ion at 100 μM. Depletion of extracellular Ca(2+) also counteracted CCK-induced increases in AC firing frequency. Moreover, CCK-induced enhancement of neuronal excitability was inhibited significantly by intracellular application of the antibody to transient receptor potential channel 5 (TRPC5), suggesting the involvement of TRPC5 channels. Our results provide a cellular and molecular mechanism to help explain the functions of CCK in vivo.

  7. Reverberation of excitation in neuronal networks interconnected through voltage-gated gap junction channels

    PubMed Central

    Maciunas, Kestutis; Snipas, Mindaugas; Paulauskas, Nerijus

    2016-01-01

    We combined Hodgkin–Huxley equations and gating models of gap junction (GJ) channels to simulate the spread of excitation in two-dimensional networks composed of neurons interconnected by voltage-gated GJs. Each GJ channel contains two fast and slow gates, each exhibiting current–voltage (I-V) rectification and gating properties that depend on transjunctional voltage (Vj). The data obtained show how junctional conductance (gj), which is necessary for synchronization of the neuronal network, depends on its size and the intrinsic firing rate of neurons. A phase shift between action potentials (APs) of neighboring neurons creates bipolar, short-lasting Vj spikes of approximately ±100 mV that induce Vj gating, leading to a small decay of gj, which can accumulate into larger decays during bursting activity of neurons. We show that I-V rectification of GJs in local regions of the two-dimensional network of neurons can lead to unidirectional AP transfer and consequently to reverberation of excitation. This reverberation can be initiated by a single electrical pulse and terminated by a low-amplitude pulse applied in a specific window of reverberation cycle. Thus, the model accounts for the influence of dynamically modulatable electrical synapses in shaping the function of a neuronal network and the formation of reverberation, which, as proposed earlier, may be important for the development of short-term memory and its consolidation into long-term memory. PMID:26880752

  8. Central clock excites vasopressin neurons by waking osmosensory afferents during late sleep.

    PubMed

    Trudel, Eric; Bourque, Charles W

    2010-04-01

    Osmoregulated vasopressin release is facilitated during the late sleep period (LSP) to prevent dehydration and enuresis. Previous work has shown that clock neurons in the suprachiasmatic nucleus (SCN) have low firing rates during the LSP, but it is not known how this reduced activity enhances vasopressin release. We found that synaptic excitation of rat supraoptic nucleus neurons by osmosensory afferents is facilitated during the LSP. Stimulation of the SCN at this time inhibited excitatory synaptic currents induced in supraoptic neurons by activation of osmosensory afferents. This effect was associated with an increased rate of synaptic failures and occurred without changes in frequency facilitation, quantal size or in the ratio of postsynaptic responses mediated by AMPA and NMDA receptors. We conclude that clock neurons mediate an activity-dependent presynaptic silencing of osmosensory afferent synapses onto vasopressin neurons and that osmoregulatory gain is enhanced by removal of this effect during late sleep.

  9. Intracellular activities related to in vitro hippocampal sharp waves are altered in CA3 pyramidal neurons of aged mice.

    PubMed

    Moradi-Chameh, H; Peng, J; Wu, C; Zhang, L

    2014-09-26

    Pyramidal neurons in the hippocampal CA3 area interconnect intensively via recurrent axonal collaterals, and such CA3-to-CA3 recurrent circuitry plays important roles in the generation of hippocampal network activities. In particular, the CA3 circuitry is able to generate spontaneous sharp waves (SPWs) when examined in vitro. These in vitro SPWs are thought to result from the network activity of GABAergic inhibitory interneurons as SPW-correlating intracellular activities are featured with strong IPSPs in pyramidal neurons and EPSPs or spikes in GABAergic interneurons. In view of accumulating evidence indicating a decrease in subgroups of hippocampal GABAergic interneurons in aged animals, we test the hypothesis that the intracellular activities related to in vitro SPWs are altered in CA3 pyramidal neurons of aged mice. Hippocampal slices were prepared from adult and aged C57 black mice (ages 3-6 and 24-28months respectively). Population and single-cell activities were examined via extracellular and whole-cell patch-clamp recordings. CA3 SPW frequencies were not significantly different between the slices of adult and aged mice but SPW-correlating intracellular activities featured weaker IPSC components in aged CA3 pyramidal neurons compared to adult neurons. It was unlikely that this latter phenomenon was due to general impairments of GABAergic synapses in the aged CA3 circuitry as evoked IPSC responses and pharmacologically isolated IPSCs were observed in aged CA3 pyramidal neurons. In addition, aged CA3 pyramidal neurons displayed more positive resting potentials and had a higher propensity of burst firing than adult neurons. We postulate that alterations of GABAergic network activity may explain the reduced IPCS contributions to in vitro SPWs in aged CA3 pyramidal neurons. Overall, our present observations are supportive of the notion that excitability of hippocampal CA3 circuitry is increased in aged mice.

  10. Genistein excitation of gonadotrophin-releasing hormone neurones in juvenile female mice.

    PubMed

    Bhattarai, J P; Abrahám, I M; Han, S K

    2013-05-01

    We investigated the effects of the phytoestrogen genistein on gonadotrophin-releasing hormone (GnRH) neurones using single-cell electrophysiology on GnRH-green fluorescent protein (GFP) transgenic juvenile female mice. Perforated patch-clamp recordings from GnRH-GFP neurones showed that approximately 83% of GnRH neurones responded to 30 μm genistein with a markedly prolonged membrane depolarisation. This effect not only persisted in the presence of tetrodotoxin, but also in the presence of amino acid receptor antagonists, indicating the direct site of action on postsynaptic GnRH neurones. Using a voltage clamp technique, we found that 30 μm genistein increased the frequency of synaptic current of GnRH neurones clamped at -60 mV in the presence of glutamate receptor blocker but not GABAA receptor blocker. Pre-incubation of GnRH neurones with 30 μm genistein enhanced kisspeptin-induced membrane depolarisation and firing. GnRH neurones of juvenile mice injected with genistein in vivo showed an enhanced kisspeptin response compared to vehicle-injected controls. The transient receptor potential channel (TRPC) blocker 2-aminoethoxydiphenyl borate (75 μm) blocked the genistein-mediated response on GnRH neurones. These results demonstrate that genistein acts on GnRH neurones in juvenile female mice to induce excitation via GABA neurotransmission and TRPCs to enhance kisspeptin-induced activation. © 2013 British Society for Neuroendocrinology.

  11. TRESK channel contribution to nociceptive sensory neurons excitability: modulation by nerve injury

    PubMed Central

    2011-01-01

    Background Neuronal hyperexcitability is a crucial phenomenon underlying spontaneous and evoked pain. In invertebrate nociceptors, the S-type leak K+ channel (analogous to TREK-1 in mammals) plays a critical role of in determining neuronal excitability following nerve injury. Few data are available on the role of leak K2P channels after peripheral axotomy in mammals. Results Here we describe that rat sciatic nerve axotomy induces hyperexcitability of L4-L5 DRG sensory neurons and decreases TRESK (K2P18.1) expression, a channel with a major contribution to total leak current in DRGs. While the expression of other channels from the same family did not significantly change, injury markers ATF3 and Cacna2d1 were highly upregulated. Similarly, acute sensory neuron dissociation (in vitro axotomy) produced marked hyperexcitability and similar total background currents compared with neurons injured in vivo. In addition, the sanshool derivative IBA, which blocked TRESK currents in transfected HEK293 cells and DRGs, increased intracellular calcium in 49% of DRG neurons in culture. Most IBA-responding neurons (71%) also responded to the TRPV1 agonist capsaicin, indicating that they were nociceptors. Additional evidence of a biological role of TRESK channels was provided by behavioral evidence of pain (flinching and licking), in vivo electrophysiological evidence of C-nociceptor activation following IBA injection in the rat hindpaw, and increased sensitivity to painful pressure after TRESK knockdown in vivo. Conclusions In summary, our results clearly support an important role of TRESK channels in determining neuronal excitability in specific DRG neurons subpopulations, and show that axonal injury down-regulates TRESK channels, therefore contributing to neuronal hyperexcitability. PMID:21527011

  12. Large-conductance calcium-activated potassium current modulates excitability in isolated canine intracardiac neurons

    PubMed Central

    Pérez, Guillermo J.; Desai, Mayurika; Anderson, Seth

    2013-01-01

    We studied principal neurons from canine intracardiac (IC) ganglia to determine whether large-conductance calcium-activated potassium (BK) channels play a role in their excitability. We performed whole cell recordings in voltage- and current-clamp modes to measure ion currents and changes in membrane potential from isolated canine IC neurons. Whole cell currents from these neurons showed fast- and slow-activated outward components. Both current components decreased in the absence of calcium and following 1–2 mM tetraethylammonium (TEA) or paxilline. These results suggest that BK channels underlie these current components. Single-channel analysis showed that BK channels from IC neurons do not inactivate in a time-dependent manner, suggesting that the dynamic of the decay of the fast current component is akin to that of intracellular calcium. Immunohistochemical studies showed that BK channels and type 2 ryanodine receptors are coexpressed in IC principal neurons. We tested whether BK current activation in these neurons occurred via a calcium-induced calcium release mechanism. We found that the outward currents of these neurons were not affected by the calcium depletion of intracellular stores with 10 mM caffeine and 10 μM cyclopiazonic acid. Thus, in canine intracardiac neurons, BK currents are directly activated by calcium influx. Membrane potential changes elicited by long (400 ms) current injections showed a tonic firing response that was decreased by TEA or paxilline. These data strongly suggest that the BK current present in canine intracardiac neurons regulates action potential activity and could increase these neurons excitability. PMID:23195072

  13. Membrane capacitive memory alters spiking in neurons described by the fractional-order Hodgkin-Huxley model.

    PubMed

    Weinberg, Seth H

    2015-01-01

    Excitable cells and cell membranes are often modeled by the simple yet elegant parallel resistor-capacitor circuit. However, studies have shown that the passive properties of membranes may be more appropriately modeled with a non-ideal capacitor, in which the current-voltage relationship is given by a fractional-order derivative. Fractional-order membrane potential dynamics introduce capacitive memory effects, i.e., dynamics are influenced by a weighted sum of the membrane potential prior history. However, it is not clear to what extent fractional-order dynamics may alter the properties of active excitable cells. In this study, we investigate the spiking properties of the neuronal membrane patch, nerve axon, and neural networks described by the fractional-order Hodgkin-Huxley neuron model. We find that in the membrane patch model, as fractional-order decreases, i.e., a greater influence of membrane potential memory, peak sodium and potassium currents are altered, and spike frequency and amplitude are generally reduced. In the nerve axon, the velocity of spike propagation increases as fractional-order decreases, while in a neural network, electrical activity is more likely to cease for smaller fractional-order. Importantly, we demonstrate that the modulation of the peak ionic currents that occurs for reduced fractional-order alone fails to reproduce many of the key alterations in spiking properties, suggesting that membrane capacitive memory and fractional-order membrane potential dynamics are important and necessary to reproduce neuronal electrical activity.

  14. Membrane Capacitive Memory Alters Spiking in Neurons Described by the Fractional-Order Hodgkin-Huxley Model

    PubMed Central

    Weinberg, Seth H.

    2015-01-01

    Excitable cells and cell membranes are often modeled by the simple yet elegant parallel resistor-capacitor circuit. However, studies have shown that the passive properties of membranes may be more appropriately modeled with a non-ideal capacitor, in which the current-voltage relationship is given by a fractional-order derivative. Fractional-order membrane potential dynamics introduce capacitive memory effects, i.e., dynamics are influenced by a weighted sum of the membrane potential prior history. However, it is not clear to what extent fractional-order dynamics may alter the properties of active excitable cells. In this study, we investigate the spiking properties of the neuronal membrane patch, nerve axon, and neural networks described by the fractional-order Hodgkin-Huxley neuron model. We find that in the membrane patch model, as fractional-order decreases, i.e., a greater influence of membrane potential memory, peak sodium and potassium currents are altered, and spike frequency and amplitude are generally reduced. In the nerve axon, the velocity of spike propagation increases as fractional-order decreases, while in a neural network, electrical activity is more likely to cease for smaller fractional-order. Importantly, we demonstrate that the modulation of the peak ionic currents that occurs for reduced fractional-order alone fails to reproduce many of the key alterations in spiking properties, suggesting that membrane capacitive memory and fractional-order membrane potential dynamics are important and necessary to reproduce neuronal electrical activity. PMID:25970534

  15. Nitric oxide is an activity-dependent regulator of target neuron intrinsic excitability.

    PubMed

    Steinert, Joern R; Robinson, Susan W; Tong, Huaxia; Haustein, Martin D; Kopp-Scheinpflug, Cornelia; Forsythe, Ian D

    2011-07-28

    Activity-dependent changes in synaptic strength are well established as mediating long-term plasticity underlying learning and memory, but modulation of target neuron excitability could complement changes in synaptic strength and regulate network activity. It is thought that homeostatic mechanisms match intrinsic excitability to the incoming synaptic drive, but evidence for involvement of voltage-gated conductances is sparse. Here, we show that glutamatergic synaptic activity modulates target neuron excitability and switches the basis of action potential repolarization from Kv3 to Kv2 potassium channel dominance, thereby adjusting neuronal signaling between low and high activity states, respectively. This nitric oxide-mediated signaling dramatically increases Kv2 currents in both the auditory brain stem and hippocampus (>3-fold) transforming synaptic integration and information transmission but with only modest changes in action potential waveform. We conclude that nitric oxide is a homeostatic regulator, tuning neuronal excitability to the recent history of excitatory synaptic inputs over intervals of minutes to hours. Copyright © 2011 Elsevier Inc. All rights reserved.

  16. Memory Deficits Are Associated with Impaired Ability to Modulate Neuronal Excitability in Middle-Aged Mice

    ERIC Educational Resources Information Center

    Kaczorowski, Catherine C.; Disterhoft, John F.

    2009-01-01

    Normal aging disrupts hippocampal neuroplasticity and learning and memory. Aging deficits were exposed in a subset (30%) of middle-aged mice that performed below criterion on a hippocampal-dependent contextual fear conditioning task. Basal neuronal excitability was comparable in middle-aged and young mice, but learning-related modulation of the…

  17. The insecticide esfenvalerate modulates neuronal excitability in mammalian central nervous system in vitro.

    PubMed

    Varró, Petra; Kovács, Melinda; Világi, Ildikó

    2017-02-05

    Pyrethroids are neurotoxic insecticides showing significant selective toxicity on insects over mammals, but effects on mammalian nervous system are not negligible. These substances act on the voltage-gated sodium channel, prolonging the duration of the open state. The present study focused on the effect of the pyrethroid esfenvalerate on the excitability of neuronal networks in vitro. From isolated rat brain slices, neocortical and hippocampal evoked field potentials were recorded; four concentrations (5-40μM) of esfenvalerate were tested using in vitro administration of the commercial product Sumi-Alpha 5 EC(®). Basic excitability and short- and long-term synaptic plasticity were studied. Application of the lowest concentration elicited epileptiform discharges in neocortex, while the highest concentration exerted a strong inhibitory effect on the excitability of both brain areas. The amplitude of population spikes in hippocampal slices was decreased by all applied concentrations. Significant decrease in basic excitability was accompanied by increase of paired-pulse facilitation in hippocampus and decreased efficacy of the development of long-term potentiation in both regions. Pyrethroids have been scarcely studied on brain slices so far, but our results are in concordance with literary data obtained on other in vitro neuronal test systems. It has been described previously that lower concentrations of pyrethroids lead to overexcitation of neurons and repetitive firing (which is in the background of hyperexcitatory symptoms occurring in case of in vivo exposure). Higher concentrations, however, may lead to depolarization block and to inhibition of neuronal firing.

  18. Memory Deficits Are Associated with Impaired Ability to Modulate Neuronal Excitability in Middle-Aged Mice

    ERIC Educational Resources Information Center

    Kaczorowski, Catherine C.; Disterhoft, John F.

    2009-01-01

    Normal aging disrupts hippocampal neuroplasticity and learning and memory. Aging deficits were exposed in a subset (30%) of middle-aged mice that performed below criterion on a hippocampal-dependent contextual fear conditioning task. Basal neuronal excitability was comparable in middle-aged and young mice, but learning-related modulation of the…

  19. Glia-derived ATP inversely regulates excitability of pyramidal and CCK-positive neurons

    PubMed Central

    Tan, Zhibing; Liu, Yu; Xi, Wang; Lou, Hui-fang; Zhu, Liya; Guo, Zhifei; Mei, Lin; Duan, Shumin

    2017-01-01

    Astrocyte responds to neuronal activity with calcium waves and modulates synaptic transmission through the release of gliotransmitters. However, little is known about the direct effect of gliotransmitters on the excitability of neuronal networks beyond synapses. Here we show that selective stimulation of astrocytes expressing channelrhodopsin-2 in the CA1 area specifically increases the firing frequency of CCK-positive but not parvalbumin-positive interneurons and decreases the firing rate of pyramidal neurons, phenomena mimicked by exogenously applied ATP. Further evidences indicate that ATP-induced increase and decrease of excitability are caused, respectively, by P2Y1 receptor-mediated inhibition of a two-pore domain potassium channel and A1 receptor-mediated opening of a G-protein-coupled inwardly rectifying potassium channel. Moreover, the activation of ChR2-expressing astrocytes reduces the power of kainate-induced hippocampal ex vivo gamma oscillation. Thus, through distinct receptor subtypes coupled with different K+ channels, astrocyte-derived ATP differentially modulates the excitability of different types of neurons and efficiently controls the activity of neuronal network. PMID:28128211

  20. TRPV4 activation at the physiological temperature is a critical determinant of neuronal excitability and behavior.

    PubMed

    Shibasaki, Koji; Sugio, Shouta; Takao, Keizo; Yamanaka, Akihiro; Miyakawa, Tsuyoshi; Tominaga, Makoto; Ishizaki, Yasuki

    2015-12-01

    For homeothermic animals, constant body temperature is an important determinant of brain function. It is well established that changes in brain temperature dynamically influence hippocampal activity. We previously reported that the thermosensor TRPV4 (activated above 34 °C) is activated at the physiological temperature in hippocampal neurons and controls neuronal excitability in vitro. Here, we examined if TRPV4 regulates neuronal excitability through its activation at the physiological temperature in vivo. We found that TRPV4-deficient (TRPV4KO) mice exhibit reduced depression-like and social behaviors compared to wild-type (WT) mice, and the number of c-fos positive cells in the dentate gyrus was significantly reduced upon the depression-like behaviors. We measured resting membrane potentials (RMPs) in the hippocampal granule cells from slice preparations at 35 °C and found that TRPV4-positive neurons significantly depolarized the RMPs through TRPV4 activation at the physiological temperature. The depolarization increased the spike numbers depending on the enhancement of TRPV4 activation. We also found that theta-frequency electroencephalogram (EEG) activities in TRPV4KO mice during wake periods were significantly reduced compared with those in WT mice. Taken together, we report for the first time that TRPV4 activation at the physiological temperature is important to regulate neuronal excitability and behaviors in mammals.

  1. Dopaminergic regulation of neuronal excitability through modulation of Ih in layer V entorhinal cortex.

    PubMed

    Rosenkranz, J Amiel; Johnston, Daniel

    2006-03-22

    The entorhinal cortex (EC) is a significant component of the systems that underlie certain forms of memory formation and recall. Evidence has been emerging that the dopaminergic system in the EC facilitates these and other functions of the EC. The effects of dopamine (DA) on membrane properties and excitability of EC neurons, however, are not known. We used in vitro whole-cell patch-clamp recordings from layer V pyramidal neuronal somata and dendrites of the adult rat lateral EC to investigate the effects of DA on the excitability of these neurons. We found that brief application of DA caused a reduction in the excitability of layer V EC pyramidal neurons. This effect was attributable to voltage-dependent modification of membrane properties that can best be explained by an increase in a hyperpolarization-activated conductance. Furthermore, the effects of DA were blocked by pharmacological blockade of h-channels, but not by any of a number of other ion channels. These actions were produced by a D1 receptor-mediated increase of cAMP but were independent of protein kinase A. A portion of the actions of DA can be attributed to effects in the apical dendrites. The data suggest that DA can directly influence the membrane properties of layer V EC pyramidal neurons by modulation of h-channels. These actions may underlie some of the effects of DA on memory formation.

  2. Interruption of central noradrenergic pathways and morphine withdrawal excitation of oxytocin neurones in the rat

    PubMed Central

    Brown, C H; Murphy, N P; Munro, G; Ludwig, M; Bull, P M; Leng, G; Russell, J A

    1998-01-01

    We have tested the hypothesis that morphine withdrawal excitation of oxytocin neurones that follows from administration of naloxone to morphine-dependent rats is a consequence of excitation of noradrenergic neurones. Female rats were made morphine dependent by intracerebroventricular (i.c.v.) infusion of the opioid at increasing doses over 5 days. On the sixth day, the rats were anaesthetized with urethane or pentobarbitone and prepared for blood sampling to determine plasma oxytocin by radioimmunoassay or for in vivo extracellular recording of the firing rate of identified oxytocin neurones from the supraoptic nucleus. Morphine withdrawal was induced by intravenous (i.v.) injection of the opioid antagonist naloxone (5 mg kg−1). In one group of rats the noradrenergic projections to the hypothalamus were lesioned by i.c.v. injection of 6-hydroxydopamine immediately prior to the induction of morphine dependence. In these rats the oxytocin secretion induced by i.v. cholecystokinin was reduced to 9% of that seen in sham-lesioned rats but in contrast, no attenuation of morphine withdrawal-induced oxytocin secretion was observed. i.c.v. infusion of the α1-adrenoreceptor antagonist benoxathian, at up to 5.3 μg min−1, dose-dependently inhibited the withdrawal excitation of oxytocin neurones in morphine-dependent rats under urethane anaesthesia, and benoxathian reduced withdrawal-induced oxytocin secretion to 37% of that of vehicle-infused rats. i.c.v. benoxathian also inhibited the activity of oxytocin neurones in morphine-naïve rats. Similarly, microdialysis administration of 2 mm benoxathian directly onto the surface of the supraoptic nucleus reduced the activity of oxytocin neurones by 53%. Thus noradrenergic systems are not essential for the expression of morphine withdrawal excitation, since chronic neurotoxic destruction of the noradrenergic inputs to the hypothalamus did not affect the magnitude of withdrawal-induced oxytocin secretion. However, tonically

  3. Excess Dietary Salt Intake Alters the Excitability of Central Sympathetic Networks

    PubMed Central

    Stocker, Sean D.; Madden, Christopher J.; Sved, Alan F.

    2010-01-01

    The ingestion of excess dietary salt (defined as NaCl) is strongly correlated with cardiovascular disease, morbidity, mortality, and is regarded as a major contributing factor to the pathogenesis of hypertension. Although several mechanisms contribute to the adverse consequences of dietary salt intake, accumulating evidence suggest that dietary salt loading produces neurogenically-mediated increases in total peripheral resistance to raise arterial blood pressure (ABP). Evidence from clinical studies and experimental models clearly establish a hypertensive effect of dietary salt loading in a subset of individuals who are deemed “salt-sensitive”. However, we will discuss and present evidence to develop a novel hypothesis to suggest that while chronic increases in dietary salt intake do not elevate mean ABP in “non-salt-sensitive” animals, dietary salt intake does enhance several sympathetic reflexes thereby predisposing these animals and/or individuals to the development of salt-sensitive hypertension. Additional evidence raises an intriguing hypothesis that these enhanced sympathetic reflexes are largely attributed to the ability of excess dietary salt intake to selectively enhance the excitability of sympathetic-regulatory neurons in the rostral ventrolateral medulla. Insight into the cellular mechanisms by which dietary salt intake alters the responsiveness of RVLM circuits will likely provide a foundation for developing new therapeutic approaches to treat salt-sensitive hypertension. PMID:20434471

  4. Asynchronous inputs alter excitability, spike timing, and topography in primary auditory cortex

    PubMed Central

    Pandya, Pritesh K.; Moucha, Raluca; Engineer, Navzer D.; Rathbun, Daniel L.; Vazquez, Jessica; Kilgard, Michael P.

    2010-01-01

    Correlation-based synaptic plasticity provides a potential cellular mechanism for learning and memory. Studies in the visual and somatosensory systems have shown that behavioral and surgical manipulation of sensory inputs leads to changes in cortical organization that are consistent with the operation of these learning rules. In this study, we examine how the organization of primary auditory cortex (A1) is altered by tones designed to decrease the average input correlation across the frequency map. After one month of separately pairing nucleus basalis stimulation with 2 and 14 kHz tones, a greater proportion of A1 neurons responded to frequencies below 2 kHz and above 14 kHz. Despite the expanded representation of these tones, cortical excitability was specifically reduced in the high and low frequency regions of A1, as evidenced by increased neural thresholds and decreased response strength. In contrast, in the frequency region between the two paired tones, driven rates were unaffected and spontaneous firing rate was increased. Neural response latencies were increased across the frequency map when nucleus basalis stimulation was associated with asynchronous activation of the high and low frequency regions of A1. This set of changes did not occur when pulsed noise bursts were paired with nucleus basalis stimulation. These results are consistent with earlier observations that sensory input statistics can shape cortical map organization and spike timing. PMID:15855025

  5. PYRETHROID MODULATION OF SPONTANEOUS NEURONAL EXCITABILITY AND NEUROTRANSMISSION IN HIPPOCAMPAL NEURONS IN CULTURE

    EPA Science Inventory

    Pyrethroid insecticides have potent actions on voltage-gated sodium channels, inhibiting inactivation and increasing channel open times. These are thought to underlie, at least in part, the clinical symptoms of pyrethroid intoxication. However, disruption of neuronal activity at ...

  6. PYRETHROID MODULATION OF SPONTANEOUS NEURONAL EXCITABILITY AND NEUROTRANSMISSION IN HIPPOCAMPAL NEURONS IN CULTURE

    EPA Science Inventory

    Pyrethroid insecticides have potent actions on voltage-gated sodium channels, inhibiting inactivation and increasing channel open times. These are thought to underlie, at least in part, the clinical symptoms of pyrethroid intoxication. However, disruption of neuronal activity at ...

  7. Cell-Specific Fine-Tuning of Neuronal Excitability by Differential Expression of Modulator Protein Isoforms

    PubMed Central

    Jepson, James; Sheldon, Amanda; Shahidullah, Mohammad; Fei, Hong; Koh, Kyunghee

    2013-01-01

    SLOB (SLOWPOKE-binding protein) modulates the Drosophila SLOWPOKE calcium-activated potassium channel. We have shown previously that SLOB deletion or RNAi knockdown decreases excitability of neurosecretory pars intercerebralis (PI) neurons in the adult Drosophila brain. In contrast, we found that SLOB deletion/knockdown enhances neurotransmitter release from motor neurons at the fly larval neuromuscular junction, suggesting an increase in excitability. Because two prominent SLOB isoforms, SLOB57 and SLOB71, modulate SLOWPOKE channels in opposite directions in vitro, we investigated whether divergent expression patterns of these two isoforms might underlie the differential modulation of excitability in PI and motor neurons. By performing detailed in vitro and in vivo analysis, we found strikingly different modes of regulatory control by the slob57 and slob71 promoters. The slob71, but not slob57, promoter contains binding sites for the Hunchback and Mirror transcriptional repressors. Furthermore, several core promoter elements that are absent in the slob57 promoter coordinately drive robust expression of a luciferase vector by the slob71 promoter in vitro. In addition, we visualized the expression patterns of the slob57 and slob71 promoters in vivo and found clear spatiotemporal differences in promoter activity. SLOB57 is expressed prominently in adult PI neurons, whereas larval motor neurons exclusively express SLOB71. In contrast, at the larval neuromuscular junction, SLOB57 expression appears to be restricted mainly to a subset of glial cells. Our results illustrate how the use of alternative transcriptional start sites within an ion channel modulator locus coupled with functionally relevant alternative splicing can be used to fine-tune neuronal excitability in a cell-specific manner. PMID:24133277

  8. Control of neuronal excitability by Group I metabotropic glutamate receptors.

    PubMed

    Correa, Ana Maria Bernal; Guimarães, Jennifer Diniz Soares; Dos Santos E Alhadas, Everton; Kushmerick, Christopher

    2017-08-23

    Metabotropic glutamate (mGlu) receptors couple through G proteins to regulate a large number of cell functions. Eight mGlu receptor isoforms have been cloned and classified into three Groups based on sequence, signal transduction mechanisms and pharmacology. This review will focus on Group I mGlu receptors, comprising the isoforms mGlu1 and mGlu5. Activation of these receptors initiates both G protein-dependent and -independent signal transduction pathways. The G-protein-dependent pathway involves mainly Gαq, which can activate PLCβ, leading initially to the formation of IP3 and diacylglycerol. IP3 can release Ca(2+) from cellular stores resulting in activation of Ca(2+)-dependent ion channels. Intracellular Ca(2+), together with diacylglycerol, activates PKC, which has many protein targets, including ion channels. Thus, activation of the G-protein-dependent pathway affects cellular excitability though several different effectors. In parallel, G protein-independent pathways lead to activation of non-selective cationic currents and metabotropic synaptic currents and potentials. Here, we provide a survey of the membrane transport proteins responsible for these electrical effects of Group I metabotropic glutamate receptors.

  9. Effects of cold temperatures on the excitability of rat trigeminal ganglion neurons that are not for cold-sensing

    PubMed Central

    Kanda, Hirosato; Gu, Jianguo G.

    2016-01-01

    Except a small population of primary afferent neurons for sensing cold to generate the sensations of innocuous and noxious cold, it is generally believed that cold temperatures suppress the excitability of other primary afferent neurons that are not for cold-sensing. These not-for-cold-sensing neurons include the majority of non-nociceptive and nociceptive afferent neurons. In the present study we have found that not-for-cold-sensing neurons of rat trigeminal ganglia (TG) change their excitability in several ways at cooling temperatures. In nearly 70% of not-for-cold-sensing TG neurons, the cooling temperature of 15°C increases their membrane excitability. We regard these neurons as cold-active neurons. For the remaining 30% of not-for-cold-sensing TG neurons, the cooling temperature of 15°C either has no effect (regarded as cold-ineffective neurons) or suppress (regarded as cold-suppressive neurons) their membrane excitability. For cold-active neurons, the cold temperature of 15°C increases their excitability as is evidenced by the increases in action potential (AP) firing numbers and/or reduction of AP rheobase when these neurons are depolarized electrically. The cold temperature of 15°C significantly inhibits M-currents and increases membrane input resistance of cold-active neurons. Retigabine, an M-current activator, abolishes the effect of cold temperatures on AP firing but not the effect of cold temperature on AP rheobase levels. The inhibition of M-currents and the increases of membrane input resistance are likely two mechanisms by which cooling temperatures increase the excitability of not-for-cold-sensing TG neurons. PMID:26709732

  10. Neural Excitability Alterations After Anterior Cruciate Ligament Reconstruction

    PubMed Central

    Pietrosimone, Brian G.; Lepley, Adam S.; Ericksen, Hayley M.; Clements, Amy; Sohn, David H.; Gribble, Phillip A.

    2015-01-01

    Context Neuromuscular dysfunction is common after anterior cruciate ligament reconstruction (ACL-R). However, little is known about quadriceps spinal-reflex and descending corticomotor excitability after ACL-R. Understanding the effects of ACL-R on spinal-reflex and corticomotor excitability will help elucidate the origins of neuromuscular dysfunction. Objective To determine whether spinal-reflex excitability and corticomotor excitability differed between the injured and uninjured limbs of patients with unilateral ACL-R and between these limbs and the matched limbs of healthy participants. Design Case-control study. Setting Laboratory. Patients or Other Participants A total of 28 patients with unilateral ACL-R (9 men, 19 women; age = 21.28 ± 3.79 years, height = 170.95 ± 10.04 cm, mass = 73.18 ± 18.02 kg, time after surgery = 48.10 ± 36.17 months) and 29 participants serving as healthy controls (9 men, 20 women; age = 21.55 ± 2.70 years, height = 170.59 ± 8.93 cm, mass = 71.89 ± 12.70 kg) volunteered. Main Outcome Measure(s) Active motor thresholds (AMTs) were collected from the vastus medialis (VM) using transcranial magnetic stimulation. We evaluated VM spinal reflexes using the Hoffmann reflex normalized to maximal muscle responses (H : M ratio). Voluntary quadriceps activation was measured with the superimposed-burst technique and calculated using the central activation ratio (CAR). We also evaluated whether ACL-R patients with high or low voluntary activation had different outcomes. Results The AMT was higher in the injured than in the uninjured limb in the ACL-R group (t27 = 3.32, P = .003) and in the matched limb of the control group (t55 = 2.05, P = .04). The H : M ratio was bilaterally higher in the ACL-R than the control group (F1,55 = 5.17, P = .03). The quadriceps CAR was bilaterally lower in the ACL-R compared with the control group (F1,55 = 10.5, P = .002). The ACL-R group with low voluntary activation (CAR < 0.95) had higher AMT than

  11. Regulation of persistent sodium currents by glycogen synthase kinase 3 encodes daily rhythms of neuronal excitability

    NASA Astrophysics Data System (ADS)

    Paul, Jodi R.; Dewoskin, Daniel; McMeekin, Laura J.; Cowell, Rita M.; Forger, Daniel B.; Gamble, Karen L.

    2016-11-01

    How neurons encode intracellular biochemical signalling cascades into electrical signals is not fully understood. Neurons in the central circadian clock in mammals provide a model system to investigate electrical encoding of biochemical timing signals. Here, using experimental and modelling approaches, we show how the activation of glycogen synthase kinase 3 (GSK3) contributes to neuronal excitability through regulation of the persistent sodium current (INaP). INaP exhibits a day/night difference in peak magnitude and is regulated by GSK3. Using mathematical modelling, we predict and confirm that GSK3 activation of INaP affects the action potential afterhyperpolarization, which increases the spontaneous firing rate without affecting the resting membrane potential. Together, these results demonstrate a crucial link between the molecular circadian clock and electrical activity, providing examples of kinase regulation of electrical activity and the propagation of intracellular signals in neuronal networks.

  12. The excitation and depression of mammalian cortical neurones by amino acids

    PubMed Central

    Crawford, J. M.; Curtis, D. R.

    1964-01-01

    Amino acids related to L-glutamic and γ-amino-n-butyric acid have been administered electrophoretically, and by pressure ejection, into the extraneuronal environment of single neurones in the pericruciate cortex of cats anaesthetized with allobarbitone or allobarbitone-urethane. Acidic amino acids related to glutamic acid, particularly N-methyl-D-aspartic acid, excited cortical neurones. Neutral amino acids related to γ-amino-n-butyric acid, particularly 3-amino-1-propanesulphonic acid, depressed cortical neurones. Some of the depressants blocked the antidromic invasion of Betz cells by pyramidal volleys. There are no essential differences between the sensitivities of cortical and spinal neurones towards locally administered amino acids. A transmitter function of such amino acids within the mammalian central nervous system is considered unlikely. PMID:14228133

  13. Regulation of persistent sodium currents by glycogen synthase kinase 3 encodes daily rhythms of neuronal excitability

    PubMed Central

    Paul, Jodi R.; DeWoskin, Daniel; McMeekin, Laura J.; Cowell, Rita M.; Forger, Daniel B.; Gamble, Karen L.

    2016-01-01

    How neurons encode intracellular biochemical signalling cascades into electrical signals is not fully understood. Neurons in the central circadian clock in mammals provide a model system to investigate electrical encoding of biochemical timing signals. Here, using experimental and modelling approaches, we show how the activation of glycogen synthase kinase 3 (GSK3) contributes to neuronal excitability through regulation of the persistent sodium current (INaP). INaP exhibits a day/night difference in peak magnitude and is regulated by GSK3. Using mathematical modelling, we predict and confirm that GSK3 activation of INaP affects the action potential afterhyperpolarization, which increases the spontaneous firing rate without affecting the resting membrane potential. Together, these results demonstrate a crucial link between the molecular circadian clock and electrical activity, providing examples of kinase regulation of electrical activity and the propagation of intracellular signals in neuronal networks. PMID:27841351

  14. Combined Changes in Chloride Regulation and Neuronal Excitability Enable Primary Afferent Depolarization to Elicit Spiking without Compromising its Inhibitory Effects

    PubMed Central

    2016-01-01

    The central terminals of primary afferent fibers experience depolarization upon activation of GABAA receptors (GABAAR) because their intracellular chloride concentration is maintained above electrochemical equilibrium. Primary afferent depolarization (PAD) normally mediates inhibition via sodium channel inactivation and shunting but can evoke spikes under certain conditions. Antidromic (centrifugal) conduction of these spikes may contribute to neurogenic inflammation while orthodromic (centripetal) conduction could contribute to pain in the case of nociceptive fibers. PAD-induced spiking is assumed to override presynaptic inhibition. Using computer simulations and dynamic clamp experiments, we sought to identify which biophysical changes are required to enable PAD-induced spiking and whether those changes necessarily compromise PAD-mediated inhibition. According to computational modeling, a depolarizing shift in GABA reversal potential (EGABA) and increased intrinsic excitability (manifest as altered spike initiation properties) were necessary for PAD-induced spiking, whereas increased GABAAR conductance density (ḡGABA) had mixed effects. We tested our predictions experimentally by using dynamic clamp to insert virtual GABAAR conductances with different EGABA and kinetics into acutely dissociated dorsal root ganglion (DRG) neuron somata. Comparable experiments in central axon terminals are prohibitively difficult but the biophysical requirements for PAD-induced spiking are arguably similar in soma and axon. Neurons from naïve (i.e. uninjured) rats were compared before and after pharmacological manipulation of intrinsic excitability, and against neurons from nerve-injured rats. Experimental data confirmed that, in most neurons, both predicted changes were necessary to yield PAD-induced spiking. Importantly, such changes did not prevent PAD from inhibiting other spiking or from blocking spike propagation. In fact, since the high value of ḡGABA required for PAD

  15. Altered Astrocyte-Neuron Interactions and Epileptogenesis in Tuberous Sclerosis Complex Disorder

    DTIC Science & Technology

    2015-06-01

    Tsc1-deficient astrocytes on neuronal morphology and neuronal activity associated with seizures. 2. KEY WORDS epilepsy , seizure, tuberous sclerosis... epilepsy . These data suggest that granule cells may rely on non-mTOR mechanisms to regulate cell size. Alternatively, because of turnover of these...excitatory synapses may contribute to the pathogenesis of epilepsy in TS by producing neuronal over-excitability. We examined excitatory synaptic

  16. Neurotensin excitation of serotonergic neurons in the rat nucleus raphe magnus: ionic and molecular mechanisms.

    PubMed

    Li, A H; Yeh, T H; Tan, P P; Hwang, H M; Wang, H L

    2001-06-01

    To understand the cellular and molecular mechanisms by which neurotensin (NT) induces an analgesic effect in the nucleus raphe magnus (NRM), whole-cell patch-clamp recordings were performed to investigate the electrophysiological effects of NT on acutely dissociated NRM neurons. Two subtypes of neurons, primary serotonergic and secondary non-serotonergic cells, were identified from acutely isolated NRM neurons. During current-clamp recordings, NT depolarized NRM serotonergic neurons and evoked action potentials. Voltage-clamp recordings showed that NT excited serotonergic neurons by enhancing a voltage-insensitive and non-selective cationic conductance. Both SR48692, a selective antagonist of subtype 1 neurotensin receptor (NTR-1), and SR 142948A, a non-selective antagonist of NTR-1 and subtype 2 neurotensin receptor (NTR-2), failed to prevent neurotensin from exciting NRM serotonergic neurons. NT-evoked cationic current was inhibited by the intracellular administration of GDP-beta-S. NT failed to induce cationic currents after dialyzing serotonergic neurons with the anti-G(alphaq/11) antibody. Cellular Ca(2+) imaging study using fura-2 showed that NT induced the calcium release from the intracellular store. NT-evoked current was blocked after the internal perfusion of heparin, an IP(3) receptor antagonist, or BAPTA, a fast Ca(2+) chelator. It is concluded that neurotensin enhancement of the cationic conductance of NRM serotonergic neurons is mediated by a novel subtype of neurotensin receptors. The coupling mechanism via G(alphaq/11) proteins is likely to involve the generation of IP(3), and subsequent IP(3)-evoked Ca(2+) release from intracellular stores results in activating the non-selective cationic conductance.

  17. Presynaptic Excitation via GABAB Receptors in Habenula Cholinergic Neurons Regulates Fear Memory Expression.

    PubMed

    Zhang, Juen; Tan, Lubin; Ren, Yuqi; Liang, Jingwen; Lin, Rui; Feng, Qiru; Zhou, Jingfeng; Hu, Fei; Ren, Jing; Wei, Chao; Yu, Tao; Zhuang, Yinghua; Bettler, Bernhard; Wang, Fengchao; Luo, Minmin

    2016-07-28

    Fear behaviors are regulated by adaptive mechanisms that dampen their expression in the absence of danger. By studying circuits and the molecular mechanisms underlying this adaptive response, we show that cholinergic neurons of the medial habenula reduce fear memory expression through GABAB presynaptic excitation. Ablating these neurons or inactivating their GABAB receptors impairs fear extinction in mice, whereas activating the neurons or their axonal GABAB receptors reduces conditioned fear. Although considered exclusively inhibitory, here, GABAB mediates excitation by amplifying presynaptic Ca(2+) entry through Cav2.3 channels and potentiating co-release of glutamate, acetylcholine, and neurokinin B to excite interpeduncular neurons. Activating the receptors for these neurotransmitters or enhancing neurotransmission with a phosphodiesterase inhibitor reduces fear responses of both wild-type and GABAB mutant mice. We identify the role of an extra-amygdalar circuit and presynaptic GABAB receptors in fear control, suggesting that boosting neurotransmission in this pathway might ameliorate some fear disorders. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Cellular and Network Contributions to Excitability of Layer 5 Neocortical Pyramidal Neurons in the Rat

    PubMed Central

    Bar-Yehuda, Dan; Korngreen, Alon

    2007-01-01

    There is a considerable gap between investigating the dynamics of single neurons and the computational aspects of neural networks. A growing number of studies have attempted to overcome this gap using the excitation in brain slices elicited by various chemical manipulations of the bath solution. However, there has been no quantitative study on the effects of these manipulations on the cellular and network factors controlling excitability. Using the whole-cell configuration of the patch-clamp technique we recorded the membrane potential from the soma of layer 5 pyramidal neurons in acute brain slices from the somatosensory cortex of young rats at 22°C and 35°C. Using blockers of synaptic transmission, we show distinct changes in cellular properties following modification of the ionic composition of the artificial cerebrospinal fluid (ACSF). Thus both cellular and network changes may contribute to the observed effects of slice excitation solutions on the physiology of single neurons. Furthermore, our data suggest that the difference in the ionic composition of current standard ACSF from that of CSF measured in vivo cause ACSF to depress network activity in acute brain slices. This may affect outcomes of experiments investigating biophysical and physiological properties of neurons in such preparations. Our results strongly advocate the necessity of redesigning experiments routinely carried out in the quiescent acute brain slice preparation. PMID:18030343

  19. Opening of pannexin- and connexin-based channels increases the excitability of nodose ganglion sensory neurons

    PubMed Central

    Retamal, Mauricio A.; Alcayaga, Julio; Verdugo, Christian A.; Bultynck, Geert; Leybaert, Luc; Sáez, Pablo J.; Fernández, Ricardo; León, Luis E.; Sáez, Juan C.

    2014-01-01

    Satellite glial cells (SGCs) are the main glia in sensory ganglia. They surround neuronal bodies and form a cap that prevents the formation of chemical or electrical synapses between neighboring neurons. SGCs have been suggested to establish bidirectional paracrine communication with sensory neurons. However, the molecular mechanism involved in this cellular communication is unknown. In the central nervous system (CNS), astrocytes present connexin43 (Cx43) hemichannels and pannexin1 (Panx1) channels, and the opening of these channels allows the release of signal molecules, such as ATP and glutamate. We propose that these channels could play a role in glia-neuron communication in sensory ganglia. Therefore, we studied the expression and function of Cx43 and Panx1 in rat and mouse nodose-petrosal-jugular complexes (NPJcs) using confocal immunofluorescence, molecular and electrophysiological techniques. Cx43 and Panx1 were detected in SGCs and in sensory neurons, respectively. In the rat and mouse, the electrical activity of vagal nerve increased significantly after nodose neurons were exposed to a Ca2+/Mg2+-free solution, a condition that increases the open probability of Cx hemichannels. This response was partially mimicked by a cell-permeable peptide corresponding to the last 10 amino acids of Cx43 (TAT-Cx43CT). Enhanced neuronal activity was reduced by Cx hemichannel, Panx1 channel and P2X7 receptor blockers. Moreover, the role of Panx1 was confirmed in NPJc, because in those from Panx1 knockout mice showed a reduced increase of neuronal activity induced by Ca2+/Mg2+-free extracellular conditions. The data suggest that Cx hemichannels and Panx channels serve as paracrine communication pathways between SGCs and neurons by modulating the excitability of sensory neurons. PMID:24999316

  20. Opening of pannexin- and connexin-based channels increases the excitability of nodose ganglion sensory neurons.

    PubMed

    Retamal, Mauricio A; Alcayaga, Julio; Verdugo, Christian A; Bultynck, Geert; Leybaert, Luc; Sáez, Pablo J; Fernández, Ricardo; León, Luis E; Sáez, Juan C

    2014-01-01

    Satellite glial cells (SGCs) are the main glia in sensory ganglia. They surround neuronal bodies and form a cap that prevents the formation of chemical or electrical synapses between neighboring neurons. SGCs have been suggested to establish bidirectional paracrine communication with sensory neurons. However, the molecular mechanism involved in this cellular communication is unknown. In the central nervous system (CNS), astrocytes present connexin43 (Cx43) hemichannels and pannexin1 (Panx1) channels, and the opening of these channels allows the release of signal molecules, such as ATP and glutamate. We propose that these channels could play a role in glia-neuron communication in sensory ganglia. Therefore, we studied the expression and function of Cx43 and Panx1 in rat and mouse nodose-petrosal-jugular complexes (NPJcs) using confocal immunofluorescence, molecular and electrophysiological techniques. Cx43 and Panx1 were detected in SGCs and in sensory neurons, respectively. In the rat and mouse, the electrical activity of vagal nerve increased significantly after nodose neurons were exposed to a Ca(2+)/Mg(2+)-free solution, a condition that increases the open probability of Cx hemichannels. This response was partially mimicked by a cell-permeable peptide corresponding to the last 10 amino acids of Cx43 (TAT-Cx43CT). Enhanced neuronal activity was reduced by Cx hemichannel, Panx1 channel and P2X7 receptor blockers. Moreover, the role of Panx1 was confirmed in NPJc, because in those from Panx1 knockout mice showed a reduced increase of neuronal activity induced by Ca(2+)/Mg(2+)-free extracellular conditions. The data suggest that Cx hemichannels and Panx channels serve as paracrine communication pathways between SGCs and neurons by modulating the excitability of sensory neurons.

  1. Control of ventricular excitability by neurons of the dorsal motor nucleus of the vagus nerve

    PubMed Central

    Machhada, Asif; Ang, Richard; Ackland, Gareth L.; Ninkina, Natalia; Buchman, Vladimir L.; Lythgoe, Mark F.; Trapp, Stefan; Tinker, Andrew; Marina, Nephtali; Gourine, Alexander V.

    2015-01-01

    Background The central nervous origins of functional parasympathetic innervation of cardiac ventricles remain controversial. Objective This study aimed to identify a population of vagal preganglionic neurons that contribute to the control of ventricular excitability. An animal model of synuclein pathology relevant to Parkinson’s disease was used to determine whether age-related loss of the activity of the identified group of neurons is associated with changes in ventricular electrophysiology. Methods In vivo cardiac electrophysiology was performed in anesthetized rats in conditions of selective inhibition of the dorsal vagal motor nucleus (DVMN) neurons by pharmacogenetic approach and in mice with global genetic deletion of all family members of the synuclein protein. Results In rats anesthetized with urethane (in conditions of systemic beta-adrenoceptor blockade), muscarinic and neuronal nitric oxide synthase blockade confirmed the existence of a tonic parasympathetic control of cardiac excitability mediated by the actions of acetylcholine and nitric oxide. Acute DVMN silencing led to shortening of the ventricular effective refractory period (vERP), a lowering of the threshold for triggered ventricular tachycardia, and prolongation of the corrected QT (QTc) interval. Lower resting activity of the DVMN neurons in aging synuclein-deficient mice was found to be associated with vERP shortening and QTc interval prolongation. Conclusion Activity of the DVMN vagal preganglionic neurons is responsible for tonic parasympathetic control of ventricular excitability, likely to be mediated by nitric oxide. These findings provide the first insight into the central nervous substrate that underlies functional parasympathetic innervation of the ventricles and highlight its vulnerability in neurodegenerative diseases. PMID:26051529

  2. 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.

  3. In Vivo Role of a Potassium Channel-binding Protein in Regulating Neuronal Excitability and Behavior

    PubMed Central

    Shahidullah, Mohammad; Reddy, Smitha; Fei, Hong; Levitan, Irwin B.

    2009-01-01

    Molecular details of ion channel interactions with modulatory subunits have been investigated widely in transfected cells, but the physiological roles of ion channel modulatory protein complexes in native neurons remain largely unexplored. The Drosophila large conductance calcium-activated potassium channel (dSlo) binds to and is modulated by its binding partner Slob. We have constructed flies in which Slob expression is manipulated by P-element mutagenesis, or by transgenic expression of Slob protein or Slob-RNAi. In vivo recordings of both macroscopic and single dSlo channel currents in identified neurosecretory neurons in the pars intercerebralis (PI) region of the Drosophila brain reveal that whole cell potassium current and properties of single dSlo channels are modulated by Slob expression level. Furthermore, Slob genotype influences action potential duration in vivo. This unprecedented combination of current clamp, macroscopic current and single channel recordings from neurons in brains of living flies defines a critical role for an ion channel modulatory protein complex in the control of neuronal excitability. We show further that Slob null flies exhibit significantly longer lifespan than controls under conditions of complete food deprivation. Crosses with deficiency lines demonstrate that this enhanced resistance to starvation-induced death maps close to the slob locus. Taken together, these results indicate that Slob may serve a novel regulatory function in feeding behavior, possibly by influencing the excitability of the PI neurons. PMID:19846720

  4. Behavioral aging is associated with reduced sensory neuron excitability in Aplysia californica

    PubMed Central

    Kempsell, Andrew T.; Fieber, Lynne A.

    2014-01-01

    Invertebrate models have advantages for understanding the basis of behavioral aging due to their simple nervous systems and short lifespans. The potential usefulness of Aplysia californica in aging research is apparent from its long history of neurobiological research, but it has been underexploited in this model use. Aging of simple reflexes at both single sensory neuron and neural circuit levels was studied to connect behavioral aging to neurophysiological aging. The tail withdrawal reflex (TWR), righting reflex, and biting response were measured throughout sexual maturity in 3 cohorts of hatchery-reared animals of known age. Reflex times increased and reflex amplitudes decreased significantly during aging. Aging in sensory neurons of animals with deficits in measures of the TWR and biting response resulted in significantly reduced excitability in old animals compared to their younger siblings. The threshold for firing increased while the number of action potentials in response to depolarizing current injection decreased during aging in sensory neurons, but not in tail motoneurons. Glutamate receptor-activated responses in sensory neurons also decreased with aging. In old tail motoneurons, the amplitude of evoked EPSPs following tail shock decreased, presumably due to reduced sensory neuron excitability during aging. The results were used to develop stages of aging relevant to both hatchery-reared and wild-caught Aplysia. Aplysia is a viable aging model in which the contributions of differential aging of components of neural circuits may be assessed. PMID:24847260

  5. Exciting fear in adolescence: Does pubertal development alter threat processing?

    PubMed Central

    Spielberg, Jeffrey M.; Olino, Thomas M.; Forbes, Erika E.; Dahl, Ronald E.

    2014-01-01

    Adolescent development encompasses an ostensible paradox in threat processing. Risk taking increases dramatically after the onset of puberty, contributing to a 200% increase in mortality. Yet, pubertal maturation is associated with increased reactivity in threat-avoidance systems. In the first part of this paper we propose a heuristic model of adolescent affective development that may help to reconcile aspects of this paradox, which focuses on hypothesized pubertal increases in the capacity to experience (some) fear-evoking experiences as an exciting thrill. In the second part of this paper, we test key features of this model by examining brain activation to threat cues in a longitudinal study that disentangled pubertal and age effects. Pubertal increases in testosterone predicted increased activation to threat cues, not only in regions associated with threat avoidance (i.e., amygdala), but also regions associated with reward pursuit (i.e., nucleus accumbens). These findings are consistent with our hypothesis that puberty is associated with a maturational shift toward more complex processing of threat cues–which may contribute to adolescent tendencies to explore and enjoy some types of risky experiences. PMID:24548554

  6. Optical controling dynamic and fluctuation processes in ensemble of neurons at pulsed electrical excitation ex vivo

    NASA Astrophysics Data System (ADS)

    Akchurin, Garif G.; Seliverstov, George A.; Akchurin, Alexander G.; Akchurin, George G.

    2004-05-01

    Dynamic response of the somatic frog nerve on electrical pulsed excitation was investigated ex vivo. Strong fluctuation of consequence compound action potential in ensemble of neurons near-threshold was discovered. The nonlinear response of the Hodgkin-Huxley model neurons with external electrical pulsed was investigated and numeral results correlation with experiments. Complex dynamic of compound action potential was discovered when on-line time of stimulatory electrical pulses comparable with nerve refractory period. New techniques research nonlinear behavior using photodynamic reactions or UV-A radiation at somatic frog nerve was approved. This nonlinear dynamic regime was controlling laser induced inactivation of processes in membrane of nerve.

  7. Augmented sodium currents contribute to the enhanced excitability of small diameter capsaicin-sensitive sensory neurons isolated from Nf1+/⁻ mice.

    PubMed

    Wang, Yue; Duan, J-H; Hingtgen, C M; Nicol, G D

    2010-04-01

    Neurofibromin, the product of the Nf1 gene, is a guanosine triphosphatase activating protein (GAP) for p21ras (Ras) that accelerates conversion of active Ras-GTP to inactive Ras-GDP. Sensory neurons with reduced levels of neurofibromin likely have augmented Ras-GTP activity. We reported previously that sensory neurons isolated from a mouse model with a heterozygous mutation of the Nf1 gene (Nf1+/⁻) exhibited greater excitability compared with wild-type mice. To determine the mechanism giving rise to the augmented excitability, differences in specific membrane currents were examined. Consistent with the enhanced excitability of Nf1+/⁻ neurons, peak current densities of both tetrodotoxin-resistant sodium current (TTX-R I(Na)) and TTX-sensitive (TTX-S) I(Na) were significantly larger in Nf1+/⁻ than in wild-type neurons. Although the voltages for half-maximal activation (V(0.5)) were not different, there was a significant depolarizing shift in the V(0.5) for steady-state inactivation of both TTX-R and TTX-S I(Na) in Nf1+/⁻ neurons. In addition, levels of persistent I(Na) were significantly larger in Nf1+/⁻ neurons. Neither delayed rectifier nor A-type potassium currents were altered in Nf1+/⁻ neurons. These results demonstrate that enhanced production of action potentials in Nf1+/⁻ neurons results, in part, from larger current densities and a depolarized voltage dependence of steady-state inactivation for I(Na) that potentially leads to a greater availability of sodium channels at voltages near the firing threshold for the action potential.

  8. Menthol Alone Upregulates Midbrain nAChRs, Alters nAChR Subtype Stoichiometry, Alters Dopamine Neuron Firing Frequency, and Prevents Nicotine Reward

    PubMed Central

    Henderson, Brandon J.; Wall, Teagan R.; Henley, Beverley M.; Kim, Charlene H.; Nichols, Weston A.; Moaddel, Ruin; Xiao, Cheng

    2016-01-01

    Upregulation of β2 subunit-containing (β2*) nicotinic acetylcholine receptors (nAChRs) is implicated in several aspects of nicotine addiction, and menthol cigarette smokers tend to upregulate β2* nAChRs more than nonmenthol cigarette smokers. We investigated the effect of long-term menthol alone on midbrain neurons containing nAChRs. In midbrain dopaminergic (DA) neurons from mice containing fluorescent nAChR subunits, menthol alone increased the number of α4 and α6 nAChR subunits, but this upregulation did not occur in midbrain GABAergic neurons. Thus, chronic menthol produces a cell-type-selective upregulation of α4* nAChRs, complementing that of chronic nicotine alone, which upregulates α4 subunit-containing (α4*) nAChRs in GABAergic but not DA neurons. In mouse brain slices and cultured midbrain neurons, menthol reduced DA neuron firing frequency and altered DA neuron excitability following nAChR activation. Furthermore, menthol exposure before nicotine abolished nicotine reward-related behavior in mice. In neuroblastoma cells transfected with fluorescent nAChR subunits, exposure to 500 nm menthol alone also increased nAChR number and favored the formation of (α4)3(β2)2 nAChRs; this contrasts with the action of nicotine itself, which favors (α4)2(β2)3 nAChRs. Menthol alone also increases the number of α6β2 receptors that exclude the β3 subunit. Thus, menthol stabilizes lower-sensitivity α4* and α6 subunit-containing nAChRs, possibly by acting as a chemical chaperone. The abolition of nicotine reward-related behavior may be mediated through menthol's ability to stabilize lower-sensitivity nAChRs and alter DA neuron excitability. We conclude that menthol is more than a tobacco flavorant: administered alone chronically, it alters midbrain DA neurons of the nicotine reward-related pathway. SIGNIFICANCE STATEMENT Menthol, the most popular flavorant for tobacco products, has been considered simply a benign flavor additive. However, as we show here

  9. Activation of protease activated receptor 1 increases the excitability of the dentate granule neurons of hippocampus

    PubMed Central

    2011-01-01

    Protease activated receptor-1 (PAR1) is expressed in multiple cell types in the CNS, with the most prominent expression in glial cells. PAR1 activation enhances excitatory synaptic transmission secondary to the release of glutamate from astrocytes following activation of astrocytically-expressed PAR1. In addition, PAR1 activation exacerbates neuronal damage in multiple in vivo models of brain injury in a manner that is dependent on NMDA receptors. In the hippocampal formation, PAR1 mRNA appears to be expressed by a subset of neurons, including granule cells in the dentate gyrus. In this study we investigate the role of PAR activation in controlling neuronal excitability of dentate granule cells. We confirm that PAR1 protein is expressed in neurons of the dentate cell body layer as well as in astrocytes throughout the dentate. Activation of PAR1 receptors by the selective peptide agonist TFLLR increased the intracellular Ca2+ concentration in a subset of acutely dissociated dentate neurons as well as non-neuronal cells. Bath application of TFLLR in acute hippocampal slices depolarized the dentate gyrus, including the hilar region in wild type but not in the PAR1-/- mice. PAR1 activation increased the frequency of action potential generation in a subset of dentate granule neurons; cells in which PAR1 activation triggered action potentials showed a significant depolarization. The activation of PAR1 by thrombin increased the amplitude of NMDA receptor-mediated component of EPSPs. These data suggest that activation of PAR1 during normal function or pathological conditions, such as during ischemia or hemorrhage, can increase the excitability of dentate granule cells. PMID:21827709

  10. A novel selective and orally bioavailable Nav1.8 channel blocker, PF-01247324, attenuates nociception and sensory neuron excitability

    PubMed Central

    Payne, Claire Elizabeth; Brown, Adam R; Theile, Jonathon W; Loucif, Alexandre J C; Alexandrou, Aristos J; Fuller, Mathew D; Mahoney, John H; Antonio, Brett M; Gerlach, Aaron C; Printzenhoff, David M; Prime, Rebecca L; Stockbridge, Gillian; Kirkup, Anthony J; Bannon, Anthony W; England, Steve; Chapman, Mark L; Bagal, Sharan; Roeloffs, Rosemarie; Anand, Uma; Anand, Praveen; Bungay, Peter J; Kemp, Mark; Butt, Richard P; Stevens, Edward B

    2015-01-01

    Background and Purpose NaV1.8 ion channels have been highlighted as important molecular targets for the design of low MW blockers for the treatment of chronic pain. Here, we describe the effects of PF-01247324, a new generation, selective, orally bioavailable Nav1.8 channel blocker of novel chemotype. Experimental Approach The inhibition of Nav1.8 channels by PF-01247324 was studied using in vitro patch-clamp electrophysiology and the oral bioavailability and antinociceptive effects demonstrated using in vivo rodent models of inflammatory and neuropathic pain. Key Results PF-01247324 inhibited native tetrodotoxin-resistant (TTX-R) currents in human dorsal root ganglion (DRG) neurons (IC50: 331 nM) and in recombinantly expressed h Nav1.8 channels (IC50: 196 nM), with 50-fold selectivity over recombinantly expressed TTX-R hNav1.5 channels (IC50: ∼10 μM) and 65–100-fold selectivity over TTX-sensitive (TTX-S) channels (IC50: ∼10–18 μM). Native TTX-R currents in small-diameter rodent DRG neurons were inhibited with an IC50 448 nM, and the block of both human recombinant Nav1.8 channels and TTX-R from rat DRG neurons was both frequency and state dependent. In vitro current clamp showed that PF-01247324 reduced excitability in both rat and human DRG neurons and also altered the waveform of the action potential. In vivo experiments n rodents demonstrated efficacy in both inflammatory and neuropathic pain models. Conclusions and Implications Using PF-01247324, we have confirmed a role for Nav1.8 channels in both inflammatory and neuropathic pain. We have also demonstrated a key role for Nav1.8 channels in action potential upstroke and repetitive firing of rat and human DRG neurons. PMID:25625641

  11. Substance P excites GABAergic neurons in the mouse central amygdala through neurokinin 1 receptor activation

    PubMed Central

    Sosulina, L.; Strippel, C.; Romo-Parra, H.; Walter, A. L.; Kanyshkova, T.; Sartori, S. B.; Lange, M. D.; Singewald, N.

    2015-01-01

    Substance P (SP) is implicated in stress regulation and affective and anxiety-related behavior. Particularly high expression has been found in the main output region of the amygdala complex, the central amygdala (CE). Here we investigated the cellular mechanisms of SP in CE in vitro, taking advantage of glutamic acid decarboxylase-green fluorescent protein (GAD67-GFP) knockin mice that yield a reliable labeling of GABAergic neurons, which comprise 95% of the neuronal population in the lateral section of CE (CEl). In GFP-positive neurons within CEl, SP caused a membrane depolarization and increase in input resistance, associated with an increase in action potential firing frequency. Under voltage-clamp conditions, the SP-specific membrane current reversed at −101.5 ± 2.8 mV and displayed inwardly rectifying properties indicative of a membrane K+ conductance. Moreover, SP responses were blocked by the neurokinin type 1 receptor (NK1R) antagonist L-822429 and mimicked by the NK1R agonist [Sar9,Met(O2)11]-SP. Immunofluorescence staining confirmed localization of NK1R in GFP-positive neurons in CEl, predominantly in PKCδ-negative neurons (80%) and in few PKCδ-positive neurons (17%). Differences in SP responses were not observed between the major types of CEl neurons (late firing, regular spiking, low-threshold bursting). In addition, SP increased the frequency and amplitude of GABAergic synaptic events in CEl neurons depending on upstream spike activity. These data indicate a NK1R-mediated increase in excitability and GABAergic activity in CEl neurons, which seems to mostly involve the PKCδ-negative subpopulation. This influence can be assumed to increase reciprocal interactions between CElon and CEloff pathways, thereby boosting the medial CE (CEm) output pathway and contributing to the anxiogenic-like action of SP in the amygdala. PMID:26334021

  12. Endogenous opioids regulate moment-to-moment neuronal communication and excitability

    PubMed Central

    Winters, Bryony L.; Gregoriou, Gabrielle C.; Kissiwaa, Sarah A.; Wells, Oliver A.; Medagoda, Danashi I.; Hermes, Sam M.; Burford, Neil T.; Alt, Andrew; Aicher, Sue A.; Bagley, Elena E.

    2017-01-01

    Fear and emotional learning are modulated by endogenous opioids but the cellular basis for this is unknown. The intercalated cells (ITCs) gate amygdala output and thus regulate the fear response. Here we find endogenous opioids are released by synaptic stimulation to act via two distinct mechanisms within the main ITC cluster. Endogenously released opioids inhibit glutamate release through the δ-opioid receptor (DOR), an effect potentiated by a DOR-positive allosteric modulator. Postsynaptically, the opioids activate a potassium conductance through the μ-opioid receptor (MOR), suggesting for the first time that endogenously released opioids directly regulate neuronal excitability. Ultrastructural localization of endogenous ligands support these functional findings. This study demonstrates a new role for endogenously released opioids as neuromodulators engaged by synaptic activity to regulate moment-to-moment neuronal communication and excitability. These distinct actions through MOR and DOR may underlie the opposing effect of these receptor systems on anxiety and fear. PMID:28327612

  13. Abrupt and gradual transitions between low and hyperexcited firing frequencies in neuronal models with fast synaptic excitation: A comparative study

    NASA Astrophysics Data System (ADS)

    Rotstein, Horacio G.

    2013-12-01

    Hyperexcitability of neuronal networks is one of the hallmarks of epileptic brain seizure generation, and results from a net imbalance between excitation and inhibition that promotes excessive abnormal firing frequencies. The transition between low and high firing frequencies as the levels of recurrent AMPA excitation change can occur either gradually or abruptly. We used modeling, numerical simulations, and dynamical systems tools to investigate the biophysical and dynamic mechanisms that underlie these two identified modes of transition in recurrently connected neurons via AMPA excitation. We compare our results and demonstrate that these two modes of transition are qualitatively different and can be linked to different intrinsic properties of the participating neurons.

  14. Enhanced excitability of thalamic sensory neurons and slow-wave EEG pattern after stimuli that induce spinal long-term potentiation.

    PubMed

    Sanoja, Raul; Taepavarapruk, Niwat; Benda, Elke; Tadavarty, Ramakrishna; Soja, Peter J

    2013-09-18

    Spinal nociceptive neurons are well known to undergo a process of long-term potentiation (LTP) following conditioning by high-frequency sciatic nerve stimulation (HFS) at intensities recruiting C-fibers. However, little if any information exists as to whether such HFS conditioning that produces spinal LTP affects sensory transmission at supraspinal levels. The present study explored this possibility. Conventional extracellular recording methods were used to examine the consequences of HFS versus sham HFS conditioning on individual wide-dynamic range thalamic neurons located in the ventro-postero-lateral (VPL) nucleus in isoflurane-anesthetized rats. Following HFS, the ongoing firing rate and stimulus-evoked (brush, pinch, sciatic nerve) responses were markedly enhanced as were responses to juxtacellular, microiontophoretic applications of glutamate. These HFS-induced enhancements lasted throughout the recording period. Sham stimuli had no effect on VPL neuron excitability. Cortical electroencephalographic (EEG) wave activities were also measured around HFS in conjunction with VPL neuron recordings. The cortical EEG pattern under baseline conditions consisted of recurring short duration bursts of high-amplitude slow waves followed by longer periods of flat EEG. Following HFS, the EEG shifted to a continuous large-amplitude, slow-wave pattern within the 0.5-8.0 Hz bandwidth lasting throughout the recording period. Sham HFS did not alter EEG activity. Sciatic nerve conditioning at A-δ fiber strength, known to reverse spinal LTP, did not alter enhanced neuronal excitability or the EEG slow-wave pattern induced by HFS. These data support the concept that HFS conditioning of the sciatic nerve, which leads to spinal LTP, is associated with distinct, long-lasting changes in the excitability of neurons comprising thalamocortical networks.

  15. Multifaceted Modulation of K+ Channels by Protein-tyrosine Phosphatase ϵ Tunes Neuronal Excitability*

    PubMed Central

    Ebner-Bennatan, Sharon; Patrich, Eti; Peretz, Asher; Kornilov, Polina; Tiran, Zohar; Elson, Ari; Attali, Bernard

    2012-01-01

    Non-receptor-tyrosine kinases (protein-tyrosine kinases) and non-receptor tyrosine phosphatases (PTPs) have been implicated in the regulation of ion channels, neuronal excitability, and synaptic plasticity. We previously showed that protein-tyrosine kinases such as Src kinase and PTPs such as PTPα and PTPϵ modulate the activity of delayed-rectifier K+ channels (IK). Here we show cultured cortical neurons from PTPϵ knock-out (EKO) mice to exhibit increased excitability when compared with wild type (WT) mice, with larger spike discharge frequency, enhanced fast after-hyperpolarization, increased after-depolarization, and reduced spike width. A decrease in IK and a rise in large-conductance Ca2+-activated K+ currents (mBK) were observed in EKO cortical neurons compared with WT. Parallel studies in transfected CHO cells indicate that Kv1.1, Kv1.2, Kv7.2/7.3, and mBK are plausible molecular correlates of this multifaceted modulation of K+ channels by PTPϵ. In CHO cells, Kv1.1, Kv1.2, and Kv7.2/7.3 K+ currents were up-regulated by PTPϵ, whereas mBK channel activity was reduced. The levels of tyrosine phosphorylation of Kv1.1, Kv1.2, Kv7.3, and mBK potassium channels were increased in the brain cortices of neonatal and adult EKO mice compared with WT, suggesting that PTPϵ in the brain modulates these channel proteins. Our data indicate that in EKO mice, the lack of PTPϵ-mediated dephosphorylation of Kv1.1, Kv1.2, and Kv7.3 leads to decreased IK density and enhanced after-depolarization. In addition, the deficient PTPϵ-mediated dephosphorylation of mBK channels likely contributes to enhanced mBK and fast after-hyperpolarization, spike shortening, and consequent increase in neuronal excitability observed in cortical neurons from EKO mice. PMID:22722941

  16. Reaction-diffusion waves in neuronal tissue and the window of cortical excitability

    NASA Astrophysics Data System (ADS)

    Dahlem, M. A.; Müller, S. C.

    2004-07-01

    Spreading depression (SD) is a dynamic wave phenomenon occurring in all gray matter regions of the central nervous systems (CNS). It is characterized by a sudden breakdown of neuronal activity and accompanied by a massive influx and efflux of ions across the membrane of neurons. The retina is a constituent of the CNS in which one can easily observe the dynamic behavior of the SD wave fronts, because SD changes the optical properties of the tissue. There is ample evidence that SD belongs to the self-organization processes due to the coupling of reaction with diffusion in excitable medium. It is assumed that the occurrence of SD is associated with some neurological symptoms of migraine with aura. A frequently reported aura symptom is a traveling visual blind region (scotoma) with a preceding figure of scintillating line segments. The characteristic form and development of the scotoma suggests that the underlying phenomenon is a wave propagating through the primary visual cortex, most likely the cortical spreading depression. In this article we discuss similarities between SD waves and the migraine aura on the basis of properties of reaction-diffusion waves known from other excitable media. In particular, the propagation velocities, the shape and the dynamics of the waves are compared with each other. We find that the assumption of the neuronal tissue to be in a state of only weak excitability explains some properties of the migraine aura, such as the confined appearance and its propagation with a stable velocity.

  17. Redistribution of Kv1 and Kv7 enhances neuronal excitability during structural axon initial segment plasticity

    PubMed Central

    Kuba, Hiroshi; Yamada, Rei; Ishiguro, Go; Adachi, Ryota

    2015-01-01

    Structural plasticity of the axon initial segment (AIS), the trigger zone of neurons, is a powerful means for regulating neuronal activity. Here, we show that AIS plasticity is not limited to structural changes; it also occurs as changes in ion-channel expression, which substantially augments the efficacy of regulation. In the avian cochlear nucleus, depriving afferent inputs by removing cochlea elongated the AIS, and simultaneously switched the dominant Kv channels at the AIS from Kv1.1 to Kv7.2. Due to the slow activation kinetics of Kv7.2, the redistribution of the Kv channels reduced the shunting conductance at the elongated AIS during the initiation of action potentials and effectively enhanced the excitability of the deprived neurons. The results indicate that the functional plasticity of the AIS works cooperatively with the structural plasticity and compensates for the loss of afferent inputs to maintain the homeostasis of auditory circuits after hearing loss by cochlea removal. PMID:26581625

  18. Transportation in the Interstitial Space of the Brain Can Be Regulated by Neuronal Excitation

    PubMed Central

    Shi, Chunyan; Lei, Yiming; Han, Hongbin; Zuo, Long; Yan, Junhao; He, Qingyuan; Yuan, Lan; Liu, Huipo; Xu, Ge; Xu, Weiguo

    2015-01-01

    The transportation of substances in the interstitial space (ISS) is crucial for the maintenance of brain homeostasis, however its link to neuronal activity remains unclear. Here, we report a marked reduction in substance transportation in the ISS after neuronal excitation. Using a tracer-based method, water molecules in the interstitial fluid (ISF) could be specifically visualized in magnetic resonance (MR) imaging. We first observed the flow of ISF in the thalamus and caudate nucleus of a rat. The ISF flow was then modulated using a painful stimulation model. We demonstrated that the flow of ISF slowed significantly following neuronal activity in the thalamus. This reduction in ISF flow continued for hours and was not accompanied by slow diffusion into the ISS. This observation suggests that the transportation of substances into the ISS can be regulated with a selective external stimulation. PMID:26631412

  19. Sensitivity of temporal excitation properties to the neuronal element activated by extracellular stimulation.

    PubMed

    Miocinovic, Svjetlana; Grill, Warren M

    2004-01-15

    Measurements of the chronaxies and refractory periods with extracellular stimuli have been used to conclude that large diameter axons are responsible for the effects of deep brain stimulation (DBS). We hypothesized that because action potential initiation by extracellular stimulation occurs in the axons of central nervous system (CNS) neurons, the chronaxies and refractory periods determined using extracellular stimulation would be similar for cells and axons. Computer simulation was used to determine the sensitivity of chronaxie and refractory period to the neural element stimulated. The results demonstrate that chronaxies and refractory periods were dependent on the polarity of the extracellular stimulus and the electrode-to-neuron distance, and indicate that there is little systematic difference in either chronaxies or refractory periods between local cells or axons of passage with extracellular stimulation. This finding points out the difficulty in drawing conclusions regarding which neuronal elements are activated based on extracellular measurements of temporal excitation properties.

  20. Redistribution of Kv1 and Kv7 enhances neuronal excitability during structural axon initial segment plasticity.

    PubMed

    Kuba, Hiroshi; Yamada, Rei; Ishiguro, Go; Adachi, Ryota

    2015-11-19

    Structural plasticity of the axon initial segment (AIS), the trigger zone of neurons, is a powerful means for regulating neuronal activity. Here, we show that AIS plasticity is not limited to structural changes; it also occurs as changes in ion-channel expression, which substantially augments the efficacy of regulation. In the avian cochlear nucleus, depriving afferent inputs by removing cochlea elongated the AIS, and simultaneously switched the dominant Kv channels at the AIS from Kv1.1 to Kv7.2. Due to the slow activation kinetics of Kv7.2, the redistribution of the Kv channels reduced the shunting conductance at the elongated AIS during the initiation of action potentials and effectively enhanced the excitability of the deprived neurons. The results indicate that the functional plasticity of the AIS works cooperatively with the structural plasticity and compensates for the loss of afferent inputs to maintain the homeostasis of auditory circuits after hearing loss by cochlea removal.

  1. Transportation in the Interstitial Space of the Brain Can Be Regulated by Neuronal Excitation.

    PubMed

    Shi, Chunyan; Lei, Yiming; Han, Hongbin; Zuo, Long; Yan, Junhao; He, Qingyuan; Yuan, Lan; Liu, Huipo; Xu, Ge; Xu, Weiguo

    2015-12-03

    The transportation of substances in the interstitial space (ISS) is crucial for the maintenance of brain homeostasis, however its link to neuronal activity remains unclear. Here, we report a marked reduction in substance transportation in the ISS after neuronal excitation. Using a tracer-based method, water molecules in the interstitial fluid (ISF) could be specifically visualized in magnetic resonance (MR) imaging. We first observed the flow of ISF in the thalamus and caudate nucleus of a rat. The ISF flow was then modulated using a painful stimulation model. We demonstrated that the flow of ISF slowed significantly following neuronal activity in the thalamus. This reduction in ISF flow continued for hours and was not accompanied by slow diffusion into the ISS. This observation suggests that the transportation of substances into the ISS can be regulated with a selective external stimulation.

  2. Suppression of voltage-gated Na(+) channels and neuronal excitability by imperatorin.

    PubMed

    Wu, King-Chuen; Chen, Yi-Hung; Cheng, Ka-Shun; Kuo, Yueh-Hsiung; Yang, Chin-Tsang; Wong, Kar-Lok; Tu, Yuan-Kun; Chan, Paul; Leung, Yuk-Man

    2013-12-05

    Imperatorin is a naturally occurring furocoumarin compound isolated from plants such as Angelica archangelica and Cnidium monnieri. It has multiple pharmacological effects including anticonvulsant effects. Here we determined the effects of imperatorin on voltage-gated Na(+) channels (VGSC) using whole-cell patch clamp techniques in differentiated neuronal NG108-15 cells. We showed that imperatorin inhibited VGSC; such inhibition did not show state-dependence. Imperatorin caused a left shift in the steady-state inactivation curve without affecting activation gating. The inhibition of VGSC by imperatorin displayed a mild frequency-dependence. Imperatorin was also shown to inhibit VGSC and action potential amplitude without affecting voltage-gated K(+) channels in rat hippocampal CA1 neurons. In conclusion, our results suggest that imperatorin dampens neuronal excitability by inhibiting VGSC.

  3. Transportation in the Interstitial Space of the Brain Can Be Regulated by Neuronal Excitation

    NASA Astrophysics Data System (ADS)

    Shi, Chunyan; Lei, Yiming; Han, Hongbin; Zuo, Long; Yan, Junhao; He, Qingyuan; Yuan, Lan; Liu, Huipo; Xu, Ge; Xu, Weiguo

    2015-12-01

    The transportation of substances in the interstitial space (ISS) is crucial for the maintenance of brain homeostasis, however its link to neuronal activity remains unclear. Here, we report a marked reduction in substance transportation in the ISS after neuronal excitation. Using a tracer-based method, water molecules in the interstitial fluid (ISF) could be specifically visualized in magnetic resonance (MR) imaging. We first observed the flow of ISF in the thalamus and caudate nucleus of a rat. The ISF flow was then modulated using a painful stimulation model. We demonstrated that the flow of ISF slowed significantly following neuronal activity in the thalamus. This reduction in ISF flow continued for hours and was not accompanied by slow diffusion into the ISS. This observation suggests that the transportation of substances into the ISS can be regulated with a selective external stimulation.

  4. Caffeine inhibits hypothalamic A1R to excite oxytocin neuron and ameliorate dietary obesity in mice

    PubMed Central

    Wu, Liufeng; Meng, Jia; Shen, Qing; Zhang, Yi; Pan, Susu; Chen, Zhuo; Zhu, Ling-Qiang; Lu, Youming; Huang, Yuan; Zhang, Guo

    2017-01-01

    Caffeine, an antagonist of the adenosine receptor A1R, is used as a dietary supplement to reduce body weight, although the underlying mechanism is unclear. Here, we report that adenosine level in the cerebrospinal fluid, and hypothalamic expression of A1R, are increased in the diet-induced obesity (DIO) mouse. We find that mice with overexpression of A1R in the neurons of paraventricular nucleus (PVN) of the hypothalamus are hyperphagic, have glucose intolerance and high body weight. Central or peripheral administration of caffeine reduces the body weight of DIO mice by the suppression of appetite and increasing of energy expenditure. We also show that caffeine excites oxytocin expressing neurons, and blockade of the action of oxytocin significantly attenuates the effect of caffeine on energy balance. These data suggest that caffeine inhibits A1Rs expressed on PVN oxytocin neurons to negatively regulate energy balance in DIO mice. PMID:28654087

  5. Effects of alcohol on the membrane excitability and synaptic transmission of medium spiny neurons in the nucleus accumbens

    PubMed Central

    Marty, Vincent N.; Spigelman, Igor

    2013-01-01

    Chronic and excessive alcohol drinking lead to alcohol dependence and loss of control over alcohol consumption, with serious detrimental health consequences. Chronic alcohol exposure followed by protracted withdrawal causes profound alterations in the brain reward system that leads to marked changes in reinforcement mechanisms and motivational state. These long-lasting neuroadaptations are thought to contribute to the development of cravings and relapse. The nucleus accumbens (NAcc), a central component of the brain reward system, plays a critical role in alcohol-induced neuroadaptive changes underlying alcohol-seeking behaviors. Here we review the findings that chronic alcohol exposure produces long-lasting neuroadaptive changes in various ion channels that govern intrinsic membrane properties and neuronal excitability, as well as excitatory and inhibitory synaptic transmission in the NAcc that underlie alcohol-seeking behavior during protracted withdrawal. PMID:22445807

  6. Pungent agents from Szechuan peppers excite sensory neurons by inhibiting two-pore potassium channels

    PubMed Central

    Bautista, Diana M; Sigal, Yaron M; Milstein, Aaron D; Garrison, Jennifer L; Zorn, Julie A; Tsuruda, Pamela R; Nicoll, Roger A; Julius, David

    2011-01-01

    In traditional folk medicine, Xanthoxylum plants are referred to as ‘toothache trees’ because their anesthetic or counter-irritant properties render them useful in the treatment of pain. Psychophysical studies have identified hydroxy-α-sanshool as the compound most responsible for the unique tingling and buzzing sensations produced by Szechuan peppercorns or other Xanthoxylum preparations. Although it is generally agreed that sanshool elicits its effects by activating somatosensory neurons, the underlying cellular and molecular mechanisms remain a matter of debate. Here we show that hydroxy-α-sanshool excites two types of sensory neurons, including small-diameter unmyelinated cells that respond to capsaicin (but not mustard oil) as well as large-diameter myelinated neurons that express the neurotrophin receptor TrkC. We found that hydroxy-α-sanshool excites neurons through a unique mechanism involving inhibition of pH- and anesthetic-sensitive two-pore potassium channels (KCNK3, KCNK9 and KCNK18), providing a framework for understanding the unique and complex psychophysical sensations associated with the Szechuan pepper experience. PMID:18568022

  7. Pungent agents from Szechuan peppers excite sensory neurons by inhibiting two-pore potassium channels.

    PubMed

    Bautista, Diana M; Sigal, Yaron M; Milstein, Aaron D; Garrison, Jennifer L; Zorn, Julie A; Tsuruda, Pamela R; Nicoll, Roger A; Julius, David

    2008-07-01

    In traditional folk medicine, Xanthoxylum plants are referred to as 'toothache trees' because their anesthetic or counter-irritant properties render them useful in the treatment of pain. Psychophysical studies have identified hydroxy-alpha-sanshool as the compound most responsible for the unique tingling and buzzing sensations produced by Szechuan peppercorns or other Xanthoxylum preparations. Although it is generally agreed that sanshool elicits its effects by activating somatosensory neurons, the underlying cellular and molecular mechanisms remain a matter of debate. Here we show that hydroxy-alpha-sanshool excites two types of sensory neurons, including small-diameter unmyelinated cells that respond to capsaicin (but not mustard oil) as well as large-diameter myelinated neurons that express the neurotrophin receptor TrkC. We found that hydroxy-alpha-sanshool excites neurons through a unique mechanism involving inhibition of pH- and anesthetic-sensitive two-pore potassium channels (KCNK3, KCNK9 and KCNK18), providing a framework for understanding the unique and complex psychophysical sensations associated with the Szechuan pepper experience.

  8. Fluorescence imaging of local membrane electric fields during the excitation of single neurons in culture.

    PubMed Central

    Gogan, P; Schmiedel-Jakob, I; Chitti, Y; Tyc-Dumont, S

    1995-01-01

    The spatial distribution of depolarized patches of membrane during the excitation of single neurons in culture has been recorded with a high spatial resolution (1 micron2/pixel) imaging system based on a liquid-nitrogen-cooled astronomical camera mounted on an inverted microscope. Images were captured from rat nodose neurons stained with the voltage-sensitive dye RH237. Conventional intracellular microelectrode recordings were made in synchrony with the images. During an action potential the fluorescence changes occurred in localized, unevenly distributed membrane areas, which formed clusters of depolarized sites of different sizes and intensities. When fast conductances were blocked by the addition of tetrodotoxin, a reduction in the number and the intensities of the depolarized sites was observed. The blockade by tetrodotoxin of voltage-clamped neurons also reduced the number of depolarized sites, although the same depolarizing voltage step was applied. Similarly, when a voltage-clamped neuron was depolarized by a constant-amplitude voltage step, the number of depolarized sites varied according to the degree of activation of the voltage-sensitive channels, which was modified by changing the holding potential. These results suggest that the spatial patterns of depolarization observed during excitation are related to the operations of ionic channels in the membrane. Images FIGURE 1 FIGURE 2 FIGURE 4 FIGURE 5 FIGURE 6 FIGURE 7 PMID:8527643

  9. Mutations altering synaptic connectivity between identified neurons in Drosophila.

    PubMed

    Thomas, J B; Wyman, R J

    1984-02-01

    By studying the effects of mutations on a simple circuit of identified neurons in Drosophila, we have found genes whose proper functioning is necessary to produce normal synaptic connections between the neurons. These neurons comprise the giant fiber (GF) system; the GFs are command neurons activated by a light-off stimulus and evoke a stereotyped pattern of activity in the thoracic muscles producing an escape jump. Each GF monosynaptically drives a motor neuron innervating the tergotrochanteral muscle (jump muscle, TTM). Each GF also disynaptically drives the motor neurons innervating the dorsal longitudinal flight muscle (DLM) via the peripherally synapsing interneuron (PSI) (King, D. G., and R. J. Wyman (1980) J. Neurocytol. 9: 753-770; M. A. Tanouye and R. J. Wyman (1980) J. Neurophysiol. 44: 405-421). A search was made for mutations affecting these identified synapses. Fifty thousand mutagenized flies were screened for nonjumping behavior to the light-off stimulus. Fifty-seven nonjumping mutant lines were established from individuals selected in the screen. Members of the lines were then tested for abnormal GF motor output to the TTM and DLM. From these lines, four X-linked mutations (representing three complementation groups) were isolated which affect the circuit. The mutations differentially disrupt specific synapses within the GF system. One mutation, bendless, disrupts synaptic transmission between the GF and the TTM motor neuron. Another, gfA, disrupts the synaptic connections of the PSI, and a third mutation, passover, disrupts transmission in both pathways.

  10. Association between Tetrodotoxin Resistant Channels and Lipid Rafts Regulates Sensory Neuron Excitability

    PubMed Central

    Pristerà, Alessandro; Baker, Mark D.; Okuse, Kenji

    2012-01-01

    Voltage-gated sodium channels (VGSCs) play a key role in the initiation and propagation of action potentials in neurons. NaV1.8 is a tetrodotoxin (TTX) resistant VGSC expressed in nociceptors, peripheral small-diameter neurons able to detect noxious stimuli. NaV1.8 underlies the vast majority of sodium currents during action potentials. Many studies have highlighted a key role for NaV1.8 in inflammatory and chronic pain models. Lipid rafts are microdomains of the plasma membrane highly enriched in cholesterol and sphingolipids. Lipid rafts tune the spatial and temporal organisation of proteins and lipids on the plasma membrane. They are thought to act as platforms on the membrane where proteins and lipids can be trafficked, compartmentalised and functionally clustered. In the present study we investigated NaV1.8 sub-cellular localisation and explored the idea that it is associated with lipid rafts in nociceptors. We found that NaV1.8 is distributed in clusters along the axons of DRG neurons in vitro and ex vivo. We also demonstrated, by biochemical and imaging studies, that NaV1.8 is associated with lipid rafts along the sciatic nerve ex vivo and in DRG neurons in vitro. Moreover, treatments with methyl-β-cyclodextrin (MβCD) and 7-ketocholesterol (7KC) led to the dissociation between rafts and NaV1.8. By calcium imaging we demonstrated that the lack of association between rafts and NaV1.8 correlated with impaired neuronal excitability, highlighted by a reduction in the number of neurons able to conduct mechanically- and chemically-evoked depolarisations. These findings reveal the sub-cellular localisation of NaV1.8 in nociceptors and highlight the importance of the association between NaV1.8 and lipid rafts in the control of nociceptor excitability. PMID:22870192

  11. Stim and Orai proteins in neuronal Ca(2+) signaling and excitability.

    PubMed

    Moccia, Francesco; Zuccolo, Estella; Soda, Teresa; Tanzi, Franco; Guerra, Germano; Mapelli, Lisa; Lodola, Francesco; D'Angelo, Egidio

    2015-01-01

    Stim1 and Orai1 are ubiquitous proteins that have long been known to mediate Ca(2+) release-activated Ca(2+) (CRAC) current (ICRAC) and store-operated Ca(2+) entry (SOCE) only in non-excitable cells. SOCE is activated following the depletion of the endogenous Ca(2+) stores, which are mainly located within the endoplasmic reticulum (ER), to replete the intracellular Ca(2+) reservoir and engage specific Ca(2+)-dependent processes, such as proliferation, migration, cytoskeletal remodeling, and gene expression. Their paralogs, Stim2, Orai2 and Orai3, support SOCE in heterologous expression systems, but their physiological role is still obscure. Ca(2+) inflow in neurons has long been exclusively ascribed to voltage-operated and receptor-operated channels. Nevertheless, recent work has unveiled that Stim1-2 and Orai1-2, but not Orai3, proteins are also expressed and mediate SOCE in neurons. Herein, we survey current knowledge about the neuronal distribution of Stim and Orai proteins in rodent and human brains; we further discuss that Orai2 is the main pore-forming subunit of CRAC channels in central neurons, in which it may be activated by either Stim1 or Stim2 depending on species, brain region and physiological stimuli. We examine the functions regulated by SOCE in neurons, where this pathway is activated under resting conditions to refill the ER, control spinogenesis and regulate gene transcription. Besides, we highlighted the possibility that SOCE also controls neuronal excitation and regulate synaptic plasticity. Finally, we evaluate the involvement of Stim and Orai proteins in severe neurodegenerative and neurological disorders, such as Alzheimer's disease and epilepsy.

  12. Stim and Orai proteins in neuronal Ca2+ signaling and excitability

    PubMed Central

    Moccia, Francesco; Zuccolo, Estella; Soda, Teresa; Tanzi, Franco; Guerra, Germano; Mapelli, Lisa; Lodola, Francesco; D’Angelo, Egidio

    2015-01-01

    Stim1 and Orai1 are ubiquitous proteins that have long been known to mediate Ca2+ release-activated Ca2+ (CRAC) current (ICRAC) and store-operated Ca2+ entry (SOCE) only in non-excitable cells. SOCE is activated following the depletion of the endogenous Ca2+ stores, which are mainly located within the endoplasmic reticulum (ER), to replete the intracellular Ca2+ reservoir and engage specific Ca2+-dependent processes, such as proliferation, migration, cytoskeletal remodeling, and gene expression. Their paralogs, Stim2, Orai2 and Orai3, support SOCE in heterologous expression systems, but their physiological role is still obscure. Ca2+ inflow in neurons has long been exclusively ascribed to voltage-operated and receptor-operated channels. Nevertheless, recent work has unveiled that Stim1–2 and Orai1-2, but not Orai3, proteins are also expressed and mediate SOCE in neurons. Herein, we survey current knowledge about the neuronal distribution of Stim and Orai proteins in rodent and human brains; we further discuss that Orai2 is the main pore-forming subunit of CRAC channels in central neurons, in which it may be activated by either Stim1 or Stim2 depending on species, brain region and physiological stimuli. We examine the functions regulated by SOCE in neurons, where this pathway is activated under resting conditions to refill the ER, control spinogenesis and regulate gene transcription. Besides, we highlighted the possibility that SOCE also controls neuronal excitation and regulate synaptic plasticity. Finally, we evaluate the involvement of Stim and Orai proteins in severe neurodegenerative and neurological disorders, such as Alzheimer’s disease and epilepsy. PMID:25964739

  13. Association between tetrodotoxin resistant channels and lipid rafts regulates sensory neuron excitability.

    PubMed

    Pristerà, Alessandro; Baker, Mark D; Okuse, Kenji

    2012-01-01

    Voltage-gated sodium channels (VGSCs) play a key role in the initiation and propagation of action potentials in neurons. Na(V)1.8 is a tetrodotoxin (TTX) resistant VGSC expressed in nociceptors, peripheral small-diameter neurons able to detect noxious stimuli. Na(V)1.8 underlies the vast majority of sodium currents during action potentials. Many studies have highlighted a key role for Na(V)1.8 in inflammatory and chronic pain models. Lipid rafts are microdomains of the plasma membrane highly enriched in cholesterol and sphingolipids. Lipid rafts tune the spatial and temporal organisation of proteins and lipids on the plasma membrane. They are thought to act as platforms on the membrane where proteins and lipids can be trafficked, compartmentalised and functionally clustered. In the present study we investigated Na(V)1.8 sub-cellular localisation and explored the idea that it is associated with lipid rafts in nociceptors. We found that Na(V)1.8 is distributed in clusters along the axons of DRG neurons in vitro and ex vivo. We also demonstrated, by biochemical and imaging studies, that Na(V)1.8 is associated with lipid rafts along the sciatic nerve ex vivo and in DRG neurons in vitro. Moreover, treatments with methyl-β-cyclodextrin (MβCD) and 7-ketocholesterol (7KC) led to the dissociation between rafts and Na(V)1.8. By calcium imaging we demonstrated that the lack of association between rafts and Na(V)1.8 correlated with impaired neuronal excitability, highlighted by a reduction in the number of neurons able to conduct mechanically- and chemically-evoked depolarisations. These findings reveal the sub-cellular localisation of Na(V)1.8 in nociceptors and highlight the importance of the association between Na(V)1.8 and lipid rafts in the control of nociceptor excitability.

  14. Phasic, suprathreshold excitation and sustained inhibition underlie neuronal selectivity for short-duration sounds

    PubMed Central

    Rose, Gary J.; Hanson, Jessica L.; Leary, Christopher J.; Vasquez-Opazo, Gustavo A.; Graham, Jalina A.; Wilkerson, Jeremy

    2016-01-01

    Sound duration is important in acoustic communication, including speech recognition in humans. Although duration-selective auditory neurons have been found, the underlying mechanisms are unclear. To investigate these mechanisms we combined in vivo whole-cell patch recordings from midbrain neurons, extraction of excitatory and inhibitory conductances, and focal pharmacological manipulations. We show that selectivity for short-duration stimuli results from integration of short-latency, sustained inhibition with delayed, phasic excitation; active membrane properties appeared to amplify responses to effective stimuli. Blocking GABAA receptors attenuated stimulus-related inhibition, revealed suprathreshold excitation at all stimulus durations, and decreased short-pass selectivity without changing resting potentials. Blocking AMPA and NMDA receptors to attenuate excitation confirmed that inhibition tracks stimulus duration and revealed no evidence of postinhibitory rebound depolarization inherent to coincidence models of duration selectivity. These results strongly support an anticoincidence mechanism of short-pass selectivity, wherein inhibition and suprathreshold excitation show greatest temporal overlap for long duration stimuli. PMID:26976602

  15. Intradermal endothelin-1 excites bombesin-responsive superficial dorsal horn neurons in the mouse.

    PubMed

    Akiyama, T; Nagamine, M; Davoodi, A; Iodi Carstens, M; Cevikbas, F; Steinhoff, M; Carstens, E

    2015-10-01

    Endothelin-1 (ET-1) has been implicated in nonhistaminergic itch. Here we used electrophysiological methods to investigate whether mouse superficial dorsal horn neurons respond to intradermal (id) injection of ET-1 and whether ET-1-sensitive neurons additionally respond to other pruritic and algesic stimuli or spinal superfusion of bombesin, a homolog of gastrin-releasing peptide (GRP) that excites spinal itch-signaling neurons. Single-unit recordings were made from lumbar dorsal horn neurons in pentobarbital-anesthetized C57BL/6 mice. We searched for units that exhibited elevated firing after id injection of ET-1 (1 μg/μl). Responsive units were further tested with mechanical stimuli, bombesin (spinal superfusion, 200 μg·ml(-1)·min(-1)), heating, cooling, and additional chemicals [histamine, chloroquine, allyl isothiocyanate (AITC), capsaicin]. Of 40 ET-1-responsive units, 48% responded to brush and pinch [wide dynamic range (WDR)] and 52% to pinch only [high threshold (HT)]. Ninety-three percent responded to noxious heat, 50% to cooling, and >70% to histamine, chloroquine, AITC, and capsaicin. Fifty-seven percent responded to bombesin, suggesting that they participate in spinal itch transmission. That most ET-1-sensitive spinal neurons also responded to pruritic and algesic stimuli is consistent with previous studies of pruritogen-responsive dorsal horn neurons. We previously hypothesized that pruritogen-sensitive neurons signal itch. The observation that ET-1 activates nociceptive neurons suggests that both itch and pain signals may be generated by ET-1 to result in simultaneous sensations of itch and pain, consistent with observations that ET-1 elicits both itch- and pain-related behaviors in animals and burning itch sensations in humans.

  16. Intradermal endothelin-1 excites bombesin-responsive superficial dorsal horn neurons in the mouse

    PubMed Central

    Akiyama, T.; Nagamine, M.; Davoodi, A.; Iodi Carstens, M.; Cevikbas, F.; Steinhoff, M.

    2015-01-01

    Endothelin-1 (ET-1) has been implicated in nonhistaminergic itch. Here we used electrophysiological methods to investigate whether mouse superficial dorsal horn neurons respond to intradermal (id) injection of ET-1 and whether ET-1-sensitive neurons additionally respond to other pruritic and algesic stimuli or spinal superfusion of bombesin, a homolog of gastrin-releasing peptide (GRP) that excites spinal itch-signaling neurons. Single-unit recordings were made from lumbar dorsal horn neurons in pentobarbital-anesthetized C57BL/6 mice. We searched for units that exhibited elevated firing after id injection of ET-1 (1 μg/μl). Responsive units were further tested with mechanical stimuli, bombesin (spinal superfusion, 200 μg·ml−1·min−1), heating, cooling, and additional chemicals [histamine, chloroquine, allyl isothiocyanate (AITC), capsaicin]. Of 40 ET-1-responsive units, 48% responded to brush and pinch [wide dynamic range (WDR)] and 52% to pinch only [high threshold (HT)]. Ninety-three percent responded to noxious heat, 50% to cooling, and >70% to histamine, chloroquine, AITC, and capsaicin. Fifty-seven percent responded to bombesin, suggesting that they participate in spinal itch transmission. That most ET-1-sensitive spinal neurons also responded to pruritic and algesic stimuli is consistent with previous studies of pruritogen-responsive dorsal horn neurons. We previously hypothesized that pruritogen-sensitive neurons signal itch. The observation that ET-1 activates nociceptive neurons suggests that both itch and pain signals may be generated by ET-1 to result in simultaneous sensations of itch and pain, consistent with observations that ET-1 elicits both itch- and pain-related behaviors in animals and burning itch sensations in humans. PMID:26311187

  17. Noise focusing in neuronal tissues: Symmetry breaking and localization in excitable networks with quenched disorder

    NASA Astrophysics Data System (ADS)

    Orlandi, Javier G.; Casademunt, Jaume

    2017-05-01

    We introduce a coarse-grained stochastic model for the spontaneous activity of neuronal cultures to explain the phenomenon of noise focusing, which entails localization of the noise activity in excitable networks with metric correlations. The system is modeled as a continuum excitable medium with a state-dependent spatial coupling that accounts for the dynamics of synaptic connections. The most salient feature is the emergence at the mesoscale of a vector field V (r ) , which acts as an advective carrier of the noise. This entails an explicit symmetry breaking of isotropy and homogeneity that stems from the amplification of the quenched fluctuations of the network by the activity avalanches, concomitant with the excitable dynamics. We discuss the microscopic interpretation of V (r ) and propose an explicit construction of it. The coarse-grained model shows excellent agreement with simulations at the network level. The generic nature of the observed phenomena is discussed.

  18. Apelin acts in the subfornical organ to influence neuronal excitability and cardiovascular function

    PubMed Central

    Dai, Li; Smith, Pauline M; Kuksis, Markus; Ferguson, Alastair V

    2013-01-01

    Apelin is an adipocyte-derived hormone involved in the regulation of water balance, food intake and the cardiovascular system partially through actions in the CNS. The subfornical organ (SFO) is a circumventricular organ with identified roles in body fluid homeostasis, cardiovascular control and energy balance. The SFO lacks a normal blood–brain barrier, and is thus able to detect circulating signalling molecules such as angiotensin II and leptin. In this study, we investigated actions of apelin-13, the predominant apelin isoform in brain and circulatory system, on the excitability of dissociated SFO neurons using electrophysiological approaches, and determined the cardiovascular consequences of direct administration into the SFO of anaesthetized rats. Whole cell current clamp recording revealed that bath-applied 100 nm apelin-13 directly influences the excitability of the majority of SFO neurons by eliciting either depolarizing (31.8%, mean 7.0 ± 0.8 mV) or hyperpolarizing (28.6%, mean −10.4 ± 1.8 mV) responses. Using voltage-clamp techniques, we also identified modulatory actions of apelin-13 on specific ion channels, demonstrating that apelin-13 activates a non-selective cationic conductance to depolarize SFO neurons while activation of the delayed rectifier potassium conductance underlies hyperpolarizing effects. In anaesthetized rats, microinjection of apelin into SFO decreased both blood pressure (BP) (mean area under the curve −1492.3 ± 357.1 mmHg.s, n= 5) and heart rate (HR) (−32.4 ± 10.39 beats, n= 5). Our data suggest that circulating apelin can directly affect BP and HR as a consequence of the ability of this peptide to modulate the excitability of SFO neurons. PMID:23629509

  19. Apelin acts in the subfornical organ to influence neuronal excitability and cardiovascular function.

    PubMed

    Dai, Li; Smith, Pauline M; Kuksis, Markus; Ferguson, Alastair V

    2013-07-01

    Apelin is an adipocyte-derived hormone involved in the regulation of water balance, food intake and the cardiovascular system partially through actions in the CNS. The subfornical organ (SFO) is a circumventricular organ with identified roles in body fluid homeostasis, cardiovascular control and energy balance. The SFO lacks a normal blood-brain barrier, and is thus able to detect circulating signalling molecules such as angiotensin II and leptin. In this study, we investigated actions of apelin-13, the predominant apelin isoform in brain and circulatory system, on the excitability of dissociated SFO neurons using electrophysiological approaches, and determined the cardiovascular consequences of direct administration into the SFO of anaesthetized rats. Whole cell current clamp recording revealed that bath-applied 100 nm apelin-13 directly influences the excitability of the majority of SFO neurons by eliciting either depolarizing (31.8%, mean 7.0 ± 0.8 mV) or hyperpolarizing (28.6%, mean -10.4 ± 1.8 mV) responses. Using voltage-clamp techniques, we also identified modulatory actions of apelin-13 on specific ion channels, demonstrating that apelin-13 activates a non-selective cationic conductance to depolarize SFO neurons while activation of the delayed rectifier potassium conductance underlies hyperpolarizing effects. In anaesthetized rats, microinjection of apelin into SFO decreased both blood pressure (BP) (mean area under the curve -1492.3 ± 357.1 mmHg.s, n = 5) and heart rate (HR) (-32.4 ± 10.39 beats, n = 5). Our data suggest that circulating apelin can directly affect BP and HR as a consequence of the ability of this peptide to modulate the excitability of SFO neurons.

  20. Remote excitation of neuronal circuits using low-intensity, low-frequency ultrasound.

    PubMed

    Tyler, William J; Tufail, Yusuf; Finsterwald, Michael; Tauchmann, Monica L; Olson, Emily J; Majestic, Cassondra

    2008-01-01

    Possessing the ability to noninvasively elicit brain circuit activity yields immense experimental and therapeutic power. Most currently employed neurostimulation methods rely on the somewhat invasive use of stimulating electrodes or photon-emitting devices. Due to its ability to noninvasively propagate through bone and other tissues in a focused manner, the implementation of ultrasound (US) represents a compelling alternative approach to current neuromodulation strategies. Here, we investigated the influence of low-intensity, low-frequency ultrasound (LILFU) on neuronal activity. By transmitting US waveforms through hippocampal slice cultures and ex vivo mouse brains, we determined LILFU is capable of remotely and noninvasively exciting neurons and network activity. Our results illustrate that LILFU can stimulate electrical activity in neurons by activating voltage-gated sodium channels, as well as voltage-gated calcium channels. The LILFU-induced changes in neuronal activity were sufficient to trigger SNARE-mediated exocytosis and synaptic transmission in hippocampal circuits. Because LILFU can stimulate electrical activity and calcium signaling in neurons as well as central synaptic transmission we conclude US provides a powerful tool for remotely modulating brain circuit activity.

  1. Bursts of recurrent excitation in the activation of intrinsic sensory neurons of the intestine.

    PubMed

    Bertrand, P P

    2004-01-01

    Sensory neurons intrinsic to the wall of the intestine receive input from stimuli in the lumen. These stimuli interact with the mucosal epithelium causing release of sensory mediators that depolarize the sensory nerve terminals. The depolarization and the subsequent pattern of action potential (AP) discharge controls the type and magnitude of the reflex evoked. The characteristics of this AP discharge were investigated in 60 intrinsic sensory neurons from the myenteric plexus of the guinea-pig ileum. Intracellular electrophysiological recordings were made from neurons near intact mucosa during electrical stimulation of the mucosa and/or neuronal soma. Most neurons (87%) responded to mucosal stimulation with a burst of 3.8+/-0.3 APs (average instantaneous frequency, fINT 39+/-4 Hz). In 38%, a somatically evoked AP triggered a similar burst of 2.9+/-0.3 APs (fINT 52+/-6 Hz) while in 50% of neurons, there was ongoing spontaneous bursting (3.8+/-0.2 APs, fINT 48+/-6 Hz). APs in all of these bursts had an inflection on the rising phase and they persisted during somatic hyperpolarization indicating they were generated in a distal process rather than the soma. Collision experiments confirmed this and suggested that bursts originated near the mucosal sensory nerve terminals. A reduction in membrane excitability reduced the number of APs in a burst suggesting a brief depolarizing event, such as a voltage- or ligand-gated ion channel, was responsible. Bursting behavior in the intrinsic sensory neurons is common for mucosal stimuli and may involve a novel transmitter acting at the sensory nerve terminal. Further, some bursting involves positive feedback between the nerve terminals and other elements in the epithelium. This is a novel and potentially important component of intestinal sensory transduction.

  2. Drifting States and Synchronization Induced Chaos in Autonomous Networks of Excitable Neurons

    PubMed Central

    Echeveste, Rodrigo; Gros, Claudius

    2016-01-01

    The study of balanced networks of excitatory and inhibitory neurons has led to several open questions. On the one hand it is yet unclear whether the asynchronous state observed in the brain is autonomously generated, or if it results from the interplay between external drivings and internal dynamics. It is also not known, which kind of network variabilities will lead to irregular spiking and which to synchronous firing states. Here we show how isolated networks of purely excitatory neurons generically show asynchronous firing whenever a minimal level of structural variability is present together with a refractory period. Our autonomous networks are composed of excitable units, in the form of leaky integrators spiking only in response to driving currents, remaining otherwise quiet. For a non-uniform network, composed exclusively of excitatory neurons, we find a rich repertoire of self-induced dynamical states. We show in particular that asynchronous drifting states may be stabilized in purely excitatory networks whenever a refractory period is present. Other states found are either fully synchronized or mixed, containing both drifting and synchronized components. The individual neurons considered are excitable and hence do not dispose of intrinsic natural firing frequencies. An effective network-wide distribution of natural frequencies is however generated autonomously through self-consistent feedback loops. The asynchronous drifting state is, additionally, amenable to an analytic solution. We find two types of asynchronous activity, with the individual neurons spiking regularly in the pure drifting state, albeit with a continuous distribution of firing frequencies. The activity of the drifting component, however, becomes irregular in the mixed state, due to the periodic driving of the synchronized component. We propose a new tool for the study of chaos in spiking neural networks, which consists of an analysis of the time series of pairs of consecutive interspike

  3. Drifting States and Synchronization Induced Chaos in Autonomous Networks of Excitable Neurons.

    PubMed

    Echeveste, Rodrigo; Gros, Claudius

    2016-01-01

    The study of balanced networks of excitatory and inhibitory neurons has led to several open questions. On the one hand it is yet unclear whether the asynchronous state observed in the brain is autonomously generated, or if it results from the interplay between external drivings and internal dynamics. It is also not known, which kind of network variabilities will lead to irregular spiking and which to synchronous firing states. Here we show how isolated networks of purely excitatory neurons generically show asynchronous firing whenever a minimal level of structural variability is present together with a refractory period. Our autonomous networks are composed of excitable units, in the form of leaky integrators spiking only in response to driving currents, remaining otherwise quiet. For a non-uniform network, composed exclusively of excitatory neurons, we find a rich repertoire of self-induced dynamical states. We show in particular that asynchronous drifting states may be stabilized in purely excitatory networks whenever a refractory period is present. Other states found are either fully synchronized or mixed, containing both drifting and synchronized components. The individual neurons considered are excitable and hence do not dispose of intrinsic natural firing frequencies. An effective network-wide distribution of natural frequencies is however generated autonomously through self-consistent feedback loops. The asynchronous drifting state is, additionally, amenable to an analytic solution. We find two types of asynchronous activity, with the individual neurons spiking regularly in the pure drifting state, albeit with a continuous distribution of firing frequencies. The activity of the drifting component, however, becomes irregular in the mixed state, due to the periodic driving of the synchronized component. We propose a new tool for the study of chaos in spiking neural networks, which consists of an analysis of the time series of pairs of consecutive interspike

  4. 17β-Estradiol alters the response of subfornical organ neurons that project to supraoptic nucleus to plasma angiotensin II and hypernatremia.

    PubMed

    Ciriello, John; Roder, Stefanie

    2013-08-14

    This study was done in urethane anesthetized, ovariectomized (OVX) female rats that were either implanted or not implanted with silastic capsules containing17β-estradiol (E2) to investigate the effect of systemic changes in E2 on the discharge rate of subfornical organ (SFO) neurons that projected to supraoptic nucleus (SON) and responded to changes in plasma levels of angiotensin II (ANG II) or hypernatremia. Extracellular single unit recordings were made from 146 histologically verified single units in SFO. Intra-carotid infusions of ANG II excited ~57% of these neurons, whereas ~23% were excited by hypertonic NaCl. Basal discharge rate of neurons excited by ANG II or hypertonic NaCl was significantly lower in OVX+E2 rats compared to OVX only animals. The response of SFO neurons antidromically activated by SON stimulation to intra-carotid injections of ANG II or hypertonic NaCl was greater in the OVX only compared to the OVX+E2 rats. Intra-carotid injections of E2 in either group attenuated not only the basal discharge of these neurons, but also their response to ANG II or hypertonic NaCl. In all cases this inhibitory effect of E2 was blocked by an intra-carotid injection of the E2 receptor antagonist ICI-182780, although ICI-182780 did not alter the neuron's response to ANG II or hypertonic NaCl. Additionally, ICI-182780 in the OVX+E2 animals significantly raised the basal discharge of SFO neurons and their response to ANG II or hypertonic NaCl. These data indicate that E2 alters the response of SFO neurons to ANG II or NaCl that project to SON, and suggest that E2 functions in the female to regulate neurohypophyseal function in response to circulating ANG II and plasma hypernatremia. Copyright © 2013 Elsevier B.V. All rights reserved.

  5. Activity-dependent decrease of excitability in rat hippocampal neurons through increases in I(h).

    PubMed

    Fan, Yuan; Fricker, Desdemona; Brager, Darrin H; Chen, Xixi; Lu, Hui-Chen; Chitwood, Raymond A; Johnston, Daniel

    2005-11-01

    Hippocampal long-term potentiation (LTP) induced by theta-burst pairing of Schaffer collateral inputs and postsynaptic firing is associated with localized increases in synaptic strength and dendritic excitability. Using the same protocol, we now demonstrate a decrease in cellular excitability that was blocked by the h-channel blocker ZD7288. This decrease was also induced by postsynaptic theta-burst firing alone, yet it was blocked by NMDA receptor antagonists, postsynaptic Ca2+ chelation, low concentrations of tetrodotoxin, omega-conotoxin MVIIC, calcium/calmodulin-dependent protein kinase II (CaMKII) inhibitors and a protein synthesis inhibitor. Increasing network activity with high extracellular K+ caused a similar reduction of cellular excitability and an increase in h-channel HCN1 protein. We propose that backpropagating action potentials open glutamate-bound NMDA receptors, resulting in an increase in I(h) and a decrease in overall excitability. The occurrence of such a reduction in cellular excitability in parallel with synaptic potentiation would be a negative feedback mechanism to normalize neuronal output firing and thus promote network stability.

  6. Tamoxifen mediated estrogen receptor activation protects against early impairment of hippocampal neuron excitability in an oxygen/glucose deprivation brain slice ischemia model

    PubMed Central

    Zhang, Huaqiu; Xie, Minjie; Schools, Gary P.; Feustel, Paul F.; Wang, Wei; Lei, Ting; Kimelberg, Harold K.; Zhou, Min

    2009-01-01

    Pretreatment of ovarectomized rats with estrogen shows long-term protection via activation of the estrogen receptor (ER). However, it remains unknown whether activation of the ER can provide protection against early neuronal damage when given acutely, we simulated ischemic conditions by applying oxygen and glucose deprived (OGD) solution to acute male rat hippocampal slices and examined the neuronal electrophysiological changes. Pyramidal neurons and interneurons showed a time-dependent membrane potential depolarization and reduction in evoked action potential frequency and amplitude over a 10 to 15 minute OGD exposure. These changes were largely suppressed by 10 μM TAM. The TAM effect was neuron-specific as the OGD induced astrocytic membrane potential depolarization was not altered. The TAM effect was mediated through ER activation because it could be simulated by 17β-estradiol and was completely inhibited by the ER inhibitor ICI 182, 780, and is therefore an example of TAM’s selective estrogen receptor modulator (SERM) action. We further show that TAM effects on OGD- induced impairment of neuronal excitability was largely due to activation of neuroprotective BK channels, as the TAM effect was markedly attenuated by the BK channel inhibitor paxilline at10 μM. TAM also significantly reduced the frequency and amplitude of AMPA receptor mediated spontaneous excitatory postsynaptic currents (sEPSCs) in pyramidal neurons which is an early consequence of OGD. Altogether, this study demonstrates that both 17β-estradiol and TAM attenuate neuronal excitability impairment early on in simulated ischemia model via ER activation mediated potentiation of BK K+ channels and reduction in enhanced neuronal AMPA/NMDA receptor-mediated excitotoxicity. PMID:18992727

  7. Tamoxifen mediated estrogen receptor activation protects against early impairment of hippocampal neuron excitability in an oxygen/glucose deprivation brain slice ischemia model.

    PubMed

    Zhang, Huaqiu; Xie, Minjie; Schools, Gary P; Feustel, Paul F; Wang, Wei; Lei, Ting; Kimelberg, Harold K; Zhou, Min

    2009-01-09

    Pretreatment of ovarectomized rats with estrogen shows long-term protection via activation of the estrogen receptor (ER). However, it remains unknown whether activation of the ER can provide protection against early neuronal damage when given acutely. We simulated ischemic conditions by applying oxygen and glucose deprived (OGD) solution to acute male rat hippocampal slices and examined the neuronal electrophysiological changes. Pyramidal neurons and interneurons showed a time-dependent membrane potential depolarization and reduction in evoked action potential frequency and amplitude over a 10 to 15 min OGD exposure. These changes were largely suppressed by 10 microM TAM. The TAM effect was neuron-specific as the OGD-induced astrocytic membrane potential depolarization was not altered. The TAM effect was mediated through ER activation because it could be simulated by 17beta-estradiol and was completely inhibited by the ER inhibitor ICI 182, 780, and is therefore an example of TAM's selective estrogen receptor modulator (SERM) action. We further show that TAM's effects on OGD-induced impairment of neuronal excitability was largely due to activation of neuroprotective BK channels, as the TAM effect was markedly attenuated by the BK channel inhibitor paxilline at 10 microM. TAM also significantly reduced the frequency and amplitude of AMPA receptor mediated spontaneous excitatory postsynaptic currents (sEPSCs) in pyramidal neurons which is an early consequence of OGD. Altogether, this study demonstrates that both 17beta-estradiol and TAM attenuate neuronal excitability impairment early on in a simulated ischemia model via ER activation mediated potentiation of BK K(+) channels and reduction in enhanced neuronal AMPA/NMDA receptor-mediated excitotoxicity.

  8. Analysis of the galanin-induced decrease in membrane excitability in mudpuppy parasympathetic neurons.

    PubMed

    Parsons, R L; Konopka, L M

    1991-01-01

    Previously, we showed that the neuropeptide galanin hyperpolarizes and decreases membrane excitability of mudpuppy parasympathetic neurons [Konopka L. M., McKeon T. W. and Parsons R. L. (1989) J. Physiol. 410, 107-122]. We also demonstrated that membrane excitability remains depressed when the agonist-induced potential change is negated electrotonically. We hypothesized that galanin inhibits the membrane conductances associated with spike generation. However, we cannot rule out the possibility that the decreased excitability is due to a galanin-induced increase in membrane potassium conductance which reduces the effectiveness of subsequent depolarizing stimuli. Therefore, in the present study we tested, with the galanin-induced hyperpolarization negated, whether the galanin-induced increased membrane potassium conductance was responsible for the decreased excitability. The results showed that the galanin-induced decreased excitability was not dependent on the peak amplitude of the galanin-induced hyperpolarization. Furthermore, the decreased excitability occurred in cells in which there was no measurable galanin-induced hyperpolarization. Moreover, in most cells the galanin-induced decrease in input resistance, measured at the peak of the hyperpolarization (3-25 mV), was less than 15% and when the hyperpolarization was negated electronically, the decrease was even less (approximately 2%). These results indicated that when the hyperpolarization was negated, the galanin-induced increase in potassium conductance was not responsible for the decreased excitability. In preparations pretreated with 5 mM tetraethylammonium, galanin decreased excitability which indicated that a galanin-induced decrease in the calcium-dependent potassium current was not necessary for the decreased excitability. Galanin also decreased excitability in preparations exposed to either 1-3 microM tetrodotoxin or 100-200 microM cadmium. Following galanin application, the threshold for initiation of

  9. M1 muscarinic activation induces long-lasting increase in intrinsic excitability of striatal projection neurons.

    PubMed

    Lv, Xiaohui; Dickerson, Jonathan W; Rook, Jerri M; Lindsley, Craig W; Conn, P Jeffrey; Xiang, Zixiu

    2017-05-15

    The dorsolateral striatum is critically involved in movement control and motor learning. Striatal function is regulated by a variety of neuromodulators including acetylcholine. Previous studies have shown that cholinergic activation excites striatal principal projection neurons, medium spiny neurons (MSNs), and this action is mediated by muscarinic acetylcholine subtype 1 receptors (M1) through modulating multiple potassium channels. In the present study, we used electrophysiology techniques in conjunction with optogenetic and pharmacological tools to determine the long-term effects of striatal cholinergic activation on MSN intrinsic excitability. A transient increase in acetylcholine release in the striatum by optogenetic stimulation resulted in a long-lasting increase in excitability of MSNs, which was associated with hyperpolarizing shift of action potential threshold and decrease in afterhyperpolarization (AHP) amplitude, leading to an increase in probability of EPSP-action potential coupling. The M1 selective antagonist VU0255035 prevented, while the M1 selective positive allosteric modulator (PAM) VU0453595 potentiated the cholinergic activation-induced persistent increase in MSN intrinsic excitability, suggesting that M1 receptors are critically involved in the induction of this long-lasting response. This M1 receptor-dependent long-lasting change in MSN intrinsic excitability could have significant impact on striatal processing and might provide a novel mechanism underlying cholinergic regulation of the striatum-dependent motor learning and cognitive function. Consistent with this, behavioral studies indicate that potentiation of M1 receptor signaling by VU0453595 enhanced performance of mice in cue-dependent water-based T-maze, a dorsolateral striatum-dependent learning task. Copyright © 2017. Published by Elsevier Ltd.

  10. MicroRNA-92a is a circadian modulator of neuronal excitability in Drosophila

    PubMed Central

    Chen, Xiao; Rosbash, Michael

    2017-01-01

    Many biological and behavioural processes of animals are governed by an endogenous circadian clock, which is dependent on transcriptional regulation. Here we address post-transcriptional regulation and the role of miRNAs in Drosophila circadian rhythms. At least six miRNAs show cycling expression levels within the pigment dispersing factor (PDF) cell-pacemaker neurons; only mir-92a peaks during the night. In vivo calcium monitoring, dynamics of PDF projections, ArcLight, GCaMP6 imaging and sleep assays indicate that mir-92a suppresses neuronal excitability. In addition, mir-92a levels within PDF cells respond to light pulses and also affect the phase shift response. Translating ribosome affinity purification (TRAP) and in vitro luciferase reporter assay indicate that mir-92a suppresses expression of sirt2, which is homologous to human sir2 and sirt3. sirt2 RNAi also phenocopies mir-92a overexpression. These experiments indicate that sirt2 is a functional mir-92a target and that mir-92a modulates PDF neuronal excitability via suppressing SIRT2 levels in a rhythmic manner. PMID:28276426

  11. Disruption of Slc4a10 augments neuronal excitability and modulates synaptic short-term plasticity

    PubMed Central

    Sinning, Anne; Liebmann, Lutz; Hübner, Christian A.

    2015-01-01

    Slc4a10 is a Na+-coupled Cl−-HCO3− exchanger, which is expressed in principal and inhibitory neurons as well as in choroid plexus epithelial cells of the brain. Slc4a10 knockout (KO) mice have collapsed brain ventricles and display an increased seizure threshold, while heterozygous deletions in man have been associated with idiopathic epilepsy and other neurological symptoms. To further characterize the role of Slc4a10 for network excitability, we compared input-output relations as well as short and long term changes of evoked field potentials in Slc4a10 KO and wildtype (WT) mice. While responses of CA1 pyramidal neurons to stimulation of Schaffer collaterals were increased in Slc4a10 KO mice, evoked field potentials did not differ between genotypes in the stratum radiatum or the neocortical areas analyzed. Paired pulse facilitation was diminished in the hippocampus upon disruption of Slc4a10. In the neocortex paired pulse depression was increased. Though short term plasticity is modulated via Slc4a10, long term potentiation appears independent of Slc4a10. Our data support that Slc4a10 dampens neuronal excitability and thus sheds light on the pathophysiology of SLC4A10 associated pathologies. PMID:26136660

  12. Rare variants in neuronal excitability genes influence risk for bipolar disorder.

    PubMed

    Ament, Seth A; Szelinger, Szabolcs; Glusman, Gustavo; Ashworth, Justin; Hou, Liping; Akula, Nirmala; Shekhtman, Tatyana; Badner, Judith A; Brunkow, Mary E; Mauldin, Denise E; Stittrich, Anna-Barbara; Rouleau, Katherine; Detera-Wadleigh, Sevilla D; Nurnberger, John I; Edenberg, Howard J; Gershon, Elliot S; Schork, Nicholas; Price, Nathan D; Gelinas, Richard; Hood, Leroy; Craig, David; McMahon, Francis J; Kelsoe, John R; Roach, Jared C

    2015-03-17

    We sequenced the genomes of 200 individuals from 41 families multiply affected with bipolar disorder (BD) to identify contributions of rare variants to genetic risk. We initially focused on 3,087 candidate genes with known synaptic functions or prior evidence from genome-wide association studies. BD pedigrees had an increased burden of rare variants in genes encoding neuronal ion channels, including subunits of GABAA receptors and voltage-gated calcium channels. Four uncommon coding and regulatory variants also showed significant association, including a missense variant in GABRA6. Targeted sequencing of 26 of these candidate genes in an additional 3,014 cases and 1,717 controls confirmed rare variant associations in ANK3, CACNA1B, CACNA1C, CACNA1D, CACNG2, CAMK2A, and NGF. Variants in promoters and 5' and 3' UTRs contributed more strongly than coding variants to risk for BD, both in pedigrees and in the case-control cohort. The genes and pathways identified in this study regulate diverse aspects of neuronal excitability. We conclude that rare variants in neuronal excitability genes contribute to risk for BD.

  13. Desynchronization of the Rat Cortical Network and Excitation of White Matter Neurons by Neurotensin.

    PubMed

    Case, Lovisa; Lyons, David J; Broberger, Christian

    2017-04-01

    Cortical network activity correlates with vigilance state: Deep sleep is characterized by slow, synchronized oscillations, whereas desynchronized, stochastic discharge is typical of the waking state. Neuropeptides, such as orexin and substance P but also neurotensin (NT), promote arousal. Relatively little is known about if NT can directly affect the cortical network, and if so, through which mechanisms and cellular targets. Here, we addressed these issues using rat in vitro cortex preparations. Following NT application specifically to deeper layers, slow oscillation activity was attenuated with a significant reduction in UP state frequency. The cortical response to thalamic stimulation exhibited enhanced temporal precision in the presence of NT, consistent with the transition in vivo from sleep to wakefulness. These changes were associated with a relative shift toward inhibition in the excitation/inhibition balance. Whole-cell recordings from layer 6 revealed presynaptically driven NT-induced inhibition of pyramidal neurons and excitation of fast-spiking interneurons. Deeper in the cortex, neurons within the white matter (WM) were strongly depolarized by NT application. The colocalization of NT and tyrosine hydroxylase immunoreactivities in deep layer fibers throughout the cortical mantle indicates mediation via dopaminergic systems. These data suggest a cortical mechanism for NT-induced wakefulness and support a role for WM neurons in state control. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  14. Psychostimulant-induced plasticity of intrinsic neuronal excitability in ventral subiculum.

    PubMed

    Cooper, Donald C; Moore, Shannon J; Staff, Nathan P; Spruston, Nelson

    2003-10-29

    Psychostimulant drugs such as amphetamine are prescribed to increase vigilance, suppress appetite, and treat attention disorders, but they powerfully activate the dopamine system and have serious abuse potential. Repeated psychostimulant exposure induces neuronal plasticity within the mesolimbic dopamine system. Here we present evidence that repeated amphetamine exposure results in a suppression of intrinsic neuronal excitability in the ventral subiculum, a hippocampal region that activates dopamine neurotransmission. We used patch-clamp recordings from brain slices obtained at different times after withdrawal from repeated amphetamine exposure to determine the long-term effects of amphetamine on subicular excitability. Using several postsynaptic indices of sodium channel function, our results show that excitability is decreased for days, but not weeks, after repeated amphetamine exposure. The resulting increase in action potential threshold and decrease in postsynaptic amplification of excitatory synaptic input provide the first direct evidence that psychostimulants induce plasticity of hippocampal output and suggest one mechanism by which drug withdrawal may influence limbic dopamine-dependent learning and memory.

  15. Muscarinic receptors modulate the intrinsic excitability of infralimbic neurons and consolidation of fear extinction.

    PubMed

    Santini, Edwin; Sepulveda-Orengo, Marian; Porter, James T

    2012-08-01

    There is considerable interest in identifying pharmacological compounds that could be used to facilitate fear extinction. Recently, we showed that the modulation of M-type K(+) channels regulates the intrinsic excitability of infralimbic (IL) neurons and fear expression. As muscarinic acetylcholine receptors inhibit M-type K(+) channels, cholinergic inputs to IL may have an important role in controlling IL excitability and, thereby, fear expression and extinction. To test this model, we combined whole-cell patch-clamp electrophysiology and auditory fear conditioning. In prefrontal brain slices, muscarine enhanced the intrinsic excitability of IL neurons by reducing the M-current and the slow afterhyperpolarization, resulting in an increased number of spikes with shorter inter-spike intervals. Next, we examined the role of endogenous activation of muscarinic receptors in fear extinction. Systemic injected scopolamine (Scop) (muscarinic receptor antagonist) before or immediately after extinction training impaired recall of extinction 24-h later, suggesting that muscarinic receptors are critically involved in consolidation of extinction memory. Similarly, infusion of Scop into IL before extinction training also impaired recall of extinction 24-h later. Finally, we demonstrated that systemic injections of the muscarinic agonist, cevimeline (Cev), given before or immediately after extinction training facilitated recall of extinction the following day. Taken together, these findings suggest that cholinergic inputs to IL have a critical role in modulating consolidation of fear extinction and that muscarinic agonists such as Cev might be useful for facilitating extinction memory in patients suffering from anxiety disorders.

  16. Classical conditioning analog enhanced acetylcholine responses but reduced excitability of an identified neuron.

    PubMed

    Lorenzetti, Fred D; Baxter, Douglas A; Byrne, John H

    2011-10-12

    Although classical and operant conditioning are operationally distinct, it is unclear whether these two forms of learning are mechanistically distinct or similar. Feeding behavior of Aplysia provides a useful model system for addressing this issue. Both classical and operant appetitive behavioral training enhance feeding, and neuronal correlates have been identified. Behavioral training was replicated by in vitro analogs that use isolated ganglia. Moreover, a single-cell analog of operant conditioning was developed using neuron B51, a cell important for the expression of the conditioned behavior. Here, a single-cell analog of classical conditioning was developed. Acetylcholine (ACh) mediated the conditioned stimulus (CS)-elicited excitation of B51 in ganglia and mimicked the CS in the single-cell analog of classical conditioning. Pairing ACh with dopamine, which mediates the unconditioned stimulus in ganglia, decreased the excitability of B51, and increased the CS-elicited excitation of B51, similar to results following both in vivo and in vitro classical training. Finally, a D1 dopamine receptor (D1R) agonist failed to support classical conditioning in the cellular analog, whereas D1R mediates reinforcement in operant conditioning.

  17. Synthetic ciguatoxin CTX 3C induces a rapid imbalance in neuronal excitability.

    PubMed

    Martín, Victor; Vale, Carmen; Hirama, Masahiro; Yamashita, Shuji; Rubiolo, Juan Andrés; Vieytes, Mercedes R; Botana, Luis M

    2015-06-15

    Ciguatera is a human global disease caused by the consumption of contaminated fish that have accumulated ciguatoxins (CTXs), sodium channel activator toxins. Symptoms of ciguatera include neurological alterations such as paraesthesiae, dysaesthesiae, depression, and heightened nociperception, among others. An important issue to understand these long-term neurological alterations is to establish the role that changes in activity produced by CTX 3C represent to neurons. Here, the effects of synthetic ciguatoxin CTX 3C on membrane potential, spontaneous spiking, and properties of synaptic transmission in cultured cortical neurons of 11-18 days in vitro (DIV) were evaluated using electrophysiological approaches. CTX 3C induced a large depolarization that decreased neuronal firing and caused a rapid inward tonic current that was primarily GABAergic. Moreover, the toxin enhanced the amplitude of miniature postsynaptic inhibitory currents (mIPSCs), whereas it decreased the amplitude of miniature postsynaptic excitatory currents (mEPSCs). The frequency of mIPSCs increased, whereas the frequency of mEPSCs remained unaltered. We describe, for the first time, that a rapid membrane depolarization caused by CTX 3C in cortical neurons activates mechanisms that tend to suppress electrical activity by shifting the balance between excitatory and inhibitory synaptic transmission toward inhibition. Indeed, these results suggest that the acute effects of CTX on synaptic transmission could underlie some of the neurological symptoms caused by ciguatera in humans.

  18. Motor-Neuron Pool Excitability of the Lower Leg Muscles After Acute Lateral Ankle Sprain

    PubMed Central

    Klykken, Lindsey W.; Pietrosimone, Brian G.; Kim, Kyung-Min; Ingersoll, Christopher D.; Hertel, Jay

    2011-01-01

    Context: Neuromuscular deficits in leg muscles that are associated with arthrogenic muscle inhibition have been reported in people with chronic ankle instability, yet whether these neuromuscular alterations are present in individuals with acute sprains is unknown. Objective: To compare the effect of acute lateral ankle sprain on the motor-neuron pool excitability (MNPE) of injured leg muscles with that of uninjured contralateral leg muscles and the leg muscles of healthy controls. Design: Case-control study. Setting: Laboratory. Patients or Other Participants: Ten individuals with acute ankle sprains (6 females, 4 males; age = 19.2 ± 3.8 years, height = 169.4 ± 8.5 cm, mass = 66.3 ±11.6 kg) and 10 healthy individuals (6 females, 4 males; age = 20.6 ± 4.0 years, height = 169.9 ± 10.6 cm, mass = 66.3 ± 10.2 kg) participated. Intervention(s): The independent variables were group (acute ankle sprain, healthy) and limb (injured, uninjured). Separate dependent t tests were used to determine differences in MNPE between legs. Main Outcome Measure(s): The MNPE of the soleus, fibularis longus, and tibialis anterior was measured by the maximal Hoffmann reflex (Hmax) and maximal muscle response (Mmax) and was then normalized using the Hmax:Mmax ratio. Results: The soleus MNPE in the ankle-sprain group was higher in the injured limb (Hmax:Mmax = 0.63; 95% confidence interval [CI], 0.46, 0.80) than in the uninjured limb (Hmax:Mmax = 0.47; 95% CI, 0.08, 0.93) (t6 = 3.62, P = .01). In the acute ankle-sprain group, tibialis anterior MNPE tended to be lower in the injured ankle (Hmax:Mmax = 0.06; 95% CI, 0.01, 0.10) than in the uninjured ankle (Hmax:Mmax = 0.22; 95% CI, 0.09, 0.35), but this finding was not different (t9 = −2.01, P = .07). No differences were detected between injured (0.22; 95% CI, 0.14, 0.29) and uninjured (0.25; 95% CI, 0.12, 0.38) ankles for the fibularis longus in the ankle-sprain group (t9 = −0.739, P = .48). We found no side-to-side differences in

  19. The proinflammatory cytokine tumor necrosis factor-α excites subfornical organ neurons.

    PubMed

    Simpson, Nick J; Ferguson, Alastair V

    2017-09-01

    Tumor necrosis factor-α (TNF-α) is a proinflammatory cytokine implicated in cardiovascular and autonomic regulation via actions in the central nervous system. TNF-α(-/-) mice do not develop angiotensin II (ANG II)-induced hypertension, and administration of TNF-α into the bloodstream of rats increases blood pressure and sympathetic tone. Recent studies have shown that lesion of the subfornical organ (SFO) attenuates the hypertensive and autonomic effects of TNF-α, while direct administration of TNF-α into the SFO increases blood pressure, suggesting the SFO to be a key site for the actions of TNF-α. Therefore, we used patch-clamp techniques to examine both acute and long-term effects of TNF-α on the excitability of Sprague-Dawley rat SFO neurons. It was observed that acute bath application of TNF-α depolarized SFO neurons and subsequently increased action potential firing rate. Furthermore, the magnitude of depolarization and the proportion of depolarized SFO neurons were concentration dependent. Interestingly, following 24-h incubation with TNF-α, the basal firing rate of the SFO neurons was increased and the rheobase was decreased, suggesting that TNF-α elevates SFO neuron excitability. This effect was likely mediated by the transient sodium current, as TNF-α increased the magnitude of the current and lowered its threshold of activation. In contrast, TNF-α did not appear to modulate either the delayed rectifier potassium current or the transient potassium current. These data suggest that acute and long-term TNF-α exposure elevates SFO neuron activity, providing a basis for TNF-α hypertensive and sympathetic effects.NEW & NOTEWORTHY Considerable recent evidence has suggested important links between inflammation and the pathological mechanisms underlying hypertension. The present study describes cellular mechanisms through which acute and long-term exposure of tumor necrosis factor-α (TNF-α) influences the activity of subfornical organ neurons by

  20. Changes of the excitability of rat trigeminal root ganglion neurons evoked by alpha(2)-adrenoreceptors.

    PubMed

    Takeda, M; Ikeda, M; Tanimoto, T; Lipski, J; Matsumoto, S

    2002-01-01

    The aim of the study was to examine the effects of alpha(2)-adrenoreceptor agonists on the excitability of trigeminal root ganglion (TRG) neurons using the perforated patch-clamp technique, and to determine whether these neurons express mRNA for alpha(2)-adrenoreceptors. In current-clamp mode, the resting membrane potential was -57.4+/-1.2 mV (n=26). Most neurons (71%) were hyperpolarized by clonidine (5-50 microM) in a concentration-dependent manner. The response was associated with an increase of cell input resistance. In addition, clonidine reduced the repetitive firing evoked by depolarizing current pulses. An alpha(2)-adrenergic agonist, UK14,304, (10-20 microM) also hyperpolarized TRG neurons. The clonidine- and UK14,304-induced hyperpolarization was blocked by idazoxan (alpha(2)-adrenoreceptor antagonist). In voltage-clamp, clonidine (1-50 microM) reversibly reduced the hyperpolarization- and time-dependent cationic current. The effect was mimicked by UK14,304 (10-20 microM), and antagonized by idazoxan. Hyperpolarization-activated cationic current was blocked by extracellular Cs(+) (2 mM) or a specific blocker, ZD7288 (20 microM). Analysis of tail currents revealed that a reversal potential of the clonidine-sensitive component of hyperpolarization-activated cationic current was -46 mV. Single-cell reverse transcription-polymerase chain reaction analysis demonstrated the expression of mRNA for alpha(2A)- and alpha(2C)-adrenoreceptors. These results demonstrate that activation of alpha(2)-adrenoreceptors can hyperpolarize TRG neurons, and that the inhibitory effect is associated with inhibition of hyperpolarization-activated cationic current. Our results suggest that activation of alpha(2)-adrenoreceptors in the absence of nerve injury may have an inhibitory effect on nociceptive transmission in the trigeminal system at the level of both TRG neuronal cell bodies and primary afferent terminals.

  1. Skin impulse excitation of spinal sensory neurons in developing Xenopus laevis (Daudin) tadpoles.

    PubMed

    James, Lisa J; Soffe, Stephen R

    2011-10-15

    Responses to gentle touch in young Xenopus tadpoles are mediated by spinal cord sensory Rohon-Beard neurons. Tadpoles also respond to noxious stimuli that elicit 'skin impulses', which propagate between epithelial cells over the whole body surface, somehow entering the CNS to generate a response. After hatching (~48 h post-fertilization), skin impulse signals enter the CNS only via cranial nerves, but previous evidence suggested the possibility of direct entry to the spinal cord before this (~24 h). We have used behavioural and electrophysiological methods to explore the developmental pattern of skin impulse entry into the spinal cord and the involvement of Rohon-Beard neurons. Lesioning confirmed that skin impulse signals can directly enter the spinal cord in young embryos, but access decreases over ~12 h and disappears soon after hatching. Electrical recordings from central Rohon-Beard axons in young embryos showed firing in response to skin impulses. However, unit recordings from Rohon-Beard somata showed that individuals that responded to touch within a characteristic, localised receptive field did not fire to skin impulses, whereas others from similar locations responded reliably. Developmental loss of skin impulse access to the spinal cord mirrored the known spread of sensitivity to gentle touch as the peripheral mechanosensory endings of Rohon-Beard neurons mature. Together, these results suggest that Rohon-Beard neurons respond to skin impulses only while immature, providing a transitory route for skin impulses to excite the CNS. In this way, Rohon-Beard neurons would mediate responses first to noxious and then to localised, gentle touch stimuli as the neurons developed.

  2. Cyclic AMP stimulates neurite outgrowth of lamprey reticulospinal neurons without substantially altering their biophysical properties.

    PubMed

    Pale, T; Frisch, E B; McClellan, A D

    2013-08-15

    Reticulospinal (RS) neurons are critical for initiation of locomotor behavior, and following spinal cord injury (SCI) in the lamprey, the axons of these neurons regenerate and restore locomotor behavior within a few weeks. For lamprey RS neurons in culture, experimental induction of calcium influx, either in the growth cone or cell body, is inhibitory for neurite outgrowth. Following SCI, these neurons partially downregulate calcium channel expression, which would be expected to reduce calcium influx and possibly provide supportive conditions for axonal regeneration. In the present study, it was tested whether activation of second messenger signaling pathways stimulates neurite outgrowth of lamprey RS neurons without altering their electrical properties (e.g. spike broadening) so as to possibly increase calcium influx and compromise axonal growth. First, activation of cAMP pathways with forskolin or dbcAMP stimulated neurite outgrowth of RS neurons in culture in a PKA-dependent manner, while activation of cGMP signaling pathways with dbcGMP inhibited outgrowth. Second, neurophysiological recordings from uninjured RS neurons in isolated lamprey brain-spinal cord preparations indicated that dbcAMP or dbcGMP did not significantly affect any of the measured electrical properties. In contrast, for uninjured RS neurons, forskolin increased action potential duration, which might have increased calcium influx, but did not significantly affect most other electrical properties. Importantly, for injured RS neurons during the period of axonal regeneration, forskolin did not significantly alter their electrical properties. Taken together, these results suggest that activation of cAMP signaling by dbcAMP stimulates neurite outgrowth, but does not alter the electrical properties of lamprey RS neurons in such a way that would be expected to induce calcium influx. In conclusion, our results suggest that activation of cAMP pathways alone, without compensation for possible

  3. Cyclic AMP Stimulates Neurite Outgrowth of Lamprey Reticulospinal Neurons without Substantially Altering Their Biophysical Properties

    PubMed Central

    Pale, Timothée; Frisch, Emily B.; McClellan, Andrew D.

    2013-01-01

    Reticulospinal (RS) neurons are critical for initiation of locomotor behavior, and following spinal cord injury (SCI) in the lamprey, the axons of these neurons regenerate and restore locomotor behavior within a few weeks. For lamprey RS neurons in culture, experimental induction of calcium influx, either in the growth cone or cell body, is inhibitory for neurite outgrowth. Following SCI, these neurons partially downregulate calcium channel expression, which would be expected to reduce calcium influx and possibly provide supportive conditions for axonal regeneration. In the present study, it was tested whether activation of second messenger signaling pathways stimulates neurite outgrowth of lamprey RS neurons without altering their electrical properties (e.g. spike broadening) so as to possibly increase calcium influx and compromise axonal growth. First, activation of cAMP pathways with forskolin or dbcAMP stimulated neurite outgrowth of RS neurons in culture in a PKA-dependent manner, while activation of cGMP signaling pathways with dbcGMP inhibited outgrowth. Second, neurophysiological recordings from uninjured RS neurons in isolated lamprey brain-spinal cord preparations indicated that dbcAMP or dbcGMP did not significantly affect any of the measured electrical properties. In contrast, for uninjured RS neurons, forskolin increased action potential duration, which might have increased calcium influx, but did not significantly affect most other electrical properties. Importantly, for injured RS neurons during the period of axonal regeneration, forskolin did not significantly alter their electrical properties. Taken together, these results suggest that activation of cAMP signaling by dbcAMP stimulates neurite outgrowth, but does not alter the electrical properties of lamprey RS neurons in such a way that would be expected to induce calcium influx. In conclusion, our results suggest that activation of cAMP pathways alone, without compensation for possible

  4. Unique processing during a period of high excitation/inhibition balance in adult-born neurons.

    PubMed

    Marín-Burgin, Antonia; Mongiat, Lucas A; Pardi, M Belén; Schinder, Alejandro F

    2012-03-09

    The adult dentate gyrus generates new granule cells (GCs) that develop over several weeks and integrate into the preexisting network. Although adult hippocampal neurogenesis has been implicated in learning and memory, the specific role of new GCs remains unclear. We examined whether immature adult-born neurons contribute to information encoding. By combining calcium imaging and electrophysiology in acute slices, we found that weak afferent activity recruits few mature GCs while activating a substantial proportion of the immature neurons. These different activation thresholds are dictated by an enhanced excitation/inhibition balance transiently expressed in immature GCs. Immature GCs exhibit low input specificity that switches with time toward a highly specific responsiveness. Therefore, activity patterns entering the dentate gyrus can undergo differential decoding by a heterogeneous population of GCs originated at different times.

  5. Histamine potentiates neuronal excitation by blocking a calcium-dependent potassium conductance.

    PubMed

    Haas, H L

    1984-04-01

    Histaminergic neurones send their axons to the whole forebrain. The diffuse projection is consistent with a modulatory role of these pathways. In hippocampal slices from rats a mechanism for this modulation is described, on pyramidal neurones of the CA 1 area: Strong excitations induced by intracellular current injection, ionophoretic administration of glutamate or synaptic stimulation normally restrict themselves by the activation of the calcium-dependent potassium current (gK(Ca) ). This current causes a long lasting afterhyperpolarization and an accommodation of firing. Their block by histamine and impromidine (reversed by metiamide and cimetidine) leads to a profound potentiation of excitatory signals. It is suggested that HA, through H2 receptors, accelerates the removal of intracellular free Ca++ ions.

  6. The spread of excitation among neurons in the heart ganglion of the stomatopod, Squillia oratoria.

    PubMed

    WATANABE, A; TAKEDA, K

    1963-03-01

    Neurons in the heart ganglion of the mantis shrimp (a stomatopod crustacean) are functionally tightly linked together. The extracellular action potential from the whole trunk very often shows a complex form, but the response is all-or-none to the applied stimulus, indicating that the excitation in one neuron spreads very rapidly to all others. Application of isotonic MgCl(2) solution or repetitive stimulation sometimes separates the spike into its components. The resting potential of the soma membrane is 50 to 60 mv. External stimulation elicits a spike of 60 to 80 mv amplitude with a step on its rising phase. Hyperpolarization reveals one more inflection on the rising phase. These inflections divide the soma action potential into three parts, A(1), A(2), and B spikes in that order from the foot. The B spike disappears on increasing the hyperpolarization, but A(1) and A(2) remain, indicating that B originates from the soma membrane, whereas A(1) and A(2) originate from the two axons of the bipolar cell. Thus the impulse invades the soma from two directions, one from the stimulated side, the other from the other side via the "parallel axons" and the "side-connections;" the latter are presumed to interconnect the axons. When the parallel axons are cut, conduction takes place across the soma with a greatly reduced safety factor and a prolonged conduction time. Neuron-to-neuron transmission takes place in either direction.

  7. The Spread of Excitation among Neurons in the Heart Ganglion of the Stomatopod, Squilla oratoria

    PubMed Central

    Watanabe, Akira; Takeda, Kimihisa

    1963-01-01

    Neurons in the heart ganglion of the mantis shrimp (a stomatopod crustacean) are functionally tightly linked together. The extracellular action potential from the whole trunk very often shows a complex form, but the response is all-or-none to the applied stimulus, indicating that the excitation in one neuron spreads very rapidly to all others. Application of isotonic MgCl2 solution or repetitive stimulation sometimes separates the spike into its components. The resting potential of the soma membrane is 50 to 60 mv. External stimulation elicits a spike of 60 to 80 mv amplitude with a step on its rising phase. Hyperpolarization reveals one more inflection on the rising phase. These inflections divide the soma action potential into three parts, A1, A2, and B spikes in that order from the foot. The B spike disappears on increasing the hyperpolarization, but A1 and A2 remain, indicating that B originates from the soma membrane, whereas A1 and A2 originate from the two axons of the bipolar cell. Thus the impulse invades the soma from two directions, one from the stimulated side, the other from the other side via the "parallel axons" and the "side-connections;" the latter are presumed to interconnect the axons. When the parallel axons are cut, conduction takes place across the soma with a greatly reduced safety factor and a prolonged conduction time. Neuron-to-neuron transmission takes place in either direction. PMID:13999080

  8. Intrinsic excitability varies by sex in prepubertal striatal medium spiny neurons

    PubMed Central

    Dorris, David M.; Cao, Jinyan; Willett, Jaime A.; Hauser, Caitlin A.

    2014-01-01

    Sex differences in neuron electrophysiological properties were traditionally associated with brain regions directly involved in reproduction in adult, postpubertal animals. There is growing acknowledgement that sex differences can exist in other developmental periods and brain regions as well. This includes the dorsal striatum (caudate/putamen), which shows robust sex differences in gene expression, neuromodulator action (including dopamine and 17β-estradiol), and relevant sensorimotor behaviors and pathologies such as the responsiveness to drugs of abuse. Here we examine whether these sex differences extend to striatal neuron electrophysiology. We test the hypothesis that passive and active medium spiny neuron (MSN) electrophysiological properties in prepubertal rat dorsal striatum differ by sex. We made whole cell recordings from male and females MSNs from acute brain slices. The slope of the evoked firing rate to current injection curve was increased in MSNs recorded from females compared with males. The initial action potential firing rate was increased in MSNs recorded from females compared with males. Action potential after-hyperpolarization peak was decreased, and threshold was hyperpolarized in MSNs recorded from females compared with males. No sex differences in passive electrophysiological properties or miniature excitatory synaptic currents were detected. These findings indicate that MSN excitability is increased in prepubertal females compared with males, providing a new mechanism that potentially contributes to generating sex differences in striatal-mediated processes. Broadly, these findings demonstrate that sex differences in neuron electrophysiological properties can exist prepuberty in brain regions not directly related to reproduction. PMID:25376786

  9. Synaptic Symmetry Increases Coherence in a Pair of Excitable Electronic Neurons

    PubMed Central

    Medeiros, Bruno N. S.; Copelli, Mauro

    2013-01-01

    We study how the synaptic connections in a pair of excitable electronic neurons affect the coherence of their spike trains when the neurons are submitted to noise from independent sources. The coupling is provided by electronic circuits which mimic the dynamics of chemical AMPA synapses. In particular, we show that increasing the strength of an unidirectional synapse leads to a decrease of coherence in the post-synaptic neuron. More interestingly, we show that the decrease of coherence can be reverted if we add a synapse of sufficient strength in the reverse direction. Synaptic symmetry plays an important role in this process and, under the right choice of parameters, increases the network coherence beyond the value achieved at the resonance due to noise alone in uncoupled neurons. We also show that synapses with a longer time scale sharpen the dependency of the coherence on the synaptic symmetry. The results were reproduced by numerical simulations of a pair of synaptically coupled FitzHugh-Nagumo models. PMID:24312626

  10. Light at the end of the channel: optical manipulation of intrinsic neuronal excitability with chemical photoswitches

    PubMed Central

    Mourot, Alexandre; Tochitsky, Ivan; Kramer, Richard H.

    2013-01-01

    Ion channels are transmembrane proteins that control the movement of ions across the cell membrane. They are the molecular machines that make neurons excitable by enabling the initiation and propagation of action potentials (APs). Rapid signaling within and between neurons requires complex molecular processes that couple the sensing of membrane voltage or neurotransmitter release to the fast opening and closing of the ion channel gate. Malfunction of an ion channel's sensing or gating module can have disastrous pathological consequences. However, linking molecular changes to the modulation of neural circuits and ultimately to a physiological or pathological state is not a straightforward task. It requires precise and sophisticated methods of controlling the function of ion channels in their native environment. To address this issue we have developed new photochemical tools that enable the remote control of neuronal ion channels with light. Due to its optical nature, our approach permits the manipulation of the nervous system with high spatial, temporal and molecular precision that will help us understand the link between ion channel function and physiology. In addition, this strategy may also be used in the clinic for the direct treatment of some neuronal disorders. PMID:23518818

  11. A role for intracellular zinc in glioma alteration of neuronal chloride equilibrium

    PubMed Central

    Di Angelantonio, S; Murana, E; Cocco, S; Scala, F; Bertollini, C; Molinari, M G; Lauro, C; Bregestovski, P; Limatola, C; Ragozzino, D

    2014-01-01

    Glioma patients commonly suffer from epileptic seizures. However, the mechanisms of glioma-associated epilepsy are far to be completely understood. Using glioma-neurons co-cultures, we found that tumor cells are able to deeply influence neuronal chloride homeostasis, by depolarizing the reversal potential of γ-aminobutyric acid (GABA)-evoked currents (EGABA). EGABA depolarizing shift is due to zinc-dependent reduction of neuronal KCC2 activity and requires glutamate release from glioma cells. Consistently, intracellular zinc loading rapidly depolarizes EGABA in mouse hippocampal neurons, through the Src/Trk pathway and this effect is promptly reverted upon zinc chelation. This study provides a possible molecular mechanism linking glioma invasion to excitation/inhibition imbalance and epileptic seizures, through the zinc–mediated disruption of neuronal chloride homeostasis. PMID:25356870

  12. A role for intracellular zinc in glioma alteration of neuronal chloride equilibrium.

    PubMed

    Di Angelantonio, S; Murana, E; Cocco, S; Scala, F; Bertollini, C; Molinari, M G; Lauro, C; Bregestovski, P; Limatola, C; Ragozzino, D

    2014-10-30

    Glioma patients commonly suffer from epileptic seizures. However, the mechanisms of glioma-associated epilepsy are far to be completely understood. Using glioma-neurons co-cultures, we found that tumor cells are able to deeply influence neuronal chloride homeostasis, by depolarizing the reversal potential of γ-aminobutyric acid (GABA)-evoked currents (EGABA). EGABA depolarizing shift is due to zinc-dependent reduction of neuronal KCC2 activity and requires glutamate release from glioma cells. Consistently, intracellular zinc loading rapidly depolarizes EGABA in mouse hippocampal neurons, through the Src/Trk pathway and this effect is promptly reverted upon zinc chelation. This study provides a possible molecular mechanism linking glioma invasion to excitation/inhibition imbalance and epileptic seizures, through the zinc-mediated disruption of neuronal chloride homeostasis.

  13. Tannic acid modulates excitability of sensory neurons and nociceptive behavior and the Ionic mechanism.

    PubMed

    Zhang, Xuan; Zhang, Huiran; Zhou, Najing; Xu, Jiaxi; Si, Man; Jia, Zhanfeng; Du, Xiaona; Zhang, Hailin

    2015-10-05

    M/Kv7 K(+) channels, Ca(2+)-activated Cl(-) channels (CaCCs) and voltage gated Na(+) channels expressed in dorsal root ganglia (DRG) play an important role in nociception. Tannic acid has been proposed to be involved in multiple beneficial health effects; tannic acid has also been described to be analgesic. However the underlying mechanism is unknown. In this study, we investigated the effects of tannic acid on M/Kv7 K(+), Na(+) currents and CaCCs, and the effects on bradykinin-induced nociceptive behavior. A perforated patch technique was used. The bradykinin-induced rat pain model was used to assess the analgesic effect of tannic acid. We demonstrated that tannic acid enhanced M/Kv7 K(+) currents but inhibited bradykinin-induced activation of CaCC/TMEM16A currents in rat small DRG neurons. Tannic acid potentiated Kv7.2/7.3 and Kv7.2 currents expressed in HEK293B cells, with an EC50 of 7.38 and 5.40 µM, respectively. Tannic acid inhibited TTX-sensitive and TTX-insensitive currents of small DRG neurons with IC50 of 5.25 and 8.43 µM, respectively. Tannic acid also potently suppressed the excitability of small DRG neurons. Furthermore, tannic acid greatly reduced bradykinin-induced pain behavior of rats. This study thus demonstrates that tannic acid is an activator of M/Kv7 K(+) and an inhibitor of voltage-gated Na(+) channels and CaCC/TMEM16A, which may underlie its inhibitory effects on excitability of DRG neurons and its analgesic effect. Tannic acid could be a useful agent in treatment of inflammatory pain conditions such as osteoarthritis, rheumatic arthritis and burn pain.

  14. Assessment of motor neuron excitability in parkinsonian rigidity by the F wave.

    PubMed

    Abbruzzese, G; Vische, M; Ratto, S; Abbruzzese, M; Favale, E

    1985-01-01

    F-wave responses from abductor pollicis brevis muscle occurred more frequently, with a larger amplitude and longer duration in rigid parkinsonian patients than in age-matched normal controls. F-wave potentiation during voluntary contraction was impaired in parkinsonian patients. These findings suggest that spinal motor neuron excitability is enhanced in rigidity. F-wave amplitude was significantly correlated to the clinical evaluation of motor disability, so that the F wave may be regarded as a useful approach to quantitative evaluation of rigidity.

  15. Hypertension induced by angiotensin II and a high salt diet involves reduced SK current and increased excitability of RVLM projecting PVN neurons.

    PubMed

    Chen, Qing-Hui; Andrade, Mary Ann; Calderon, Alfredo S; Toney, Glenn M

    2010-11-01

    Although evidence indicates that activation of presympathetic paraventricular nucleus (PVN) neurons contributes to the pathogenesis of salt-sensitive hypertension, the underlying cellular mechanisms are not fully understood. Recent evidence indicates that small conductance Ca(2+)-activated K(+) (SK) channels play a significant role in regulating the excitability of a key group of sympathetic regulatory PVN neurons, those with axonal projections to the rostral ventrolateral medulla (RVLM; i.e., PVN-RVLM neurons). In the present study, rats consuming a high salt (2% NaCl) diet were made hypertensive by systemic infusion of angiotensin II (AngII), and whole cell patch-clamp recordings were made in brain slice from retrogradely labeled PVN-RVLM neurons. To determine if the amplitude of SK current was altered in neurons from hypertensive rats, voltage-clamp recordings were performed to isolate SK current. Results indicate that SK current amplitude (P < 0.05) and density (P < 0.01) were significantly smaller in the hypertensive group. To investigate the impact of this on intrinsic excitability, current-clamp recordings were performed in separate groups of PVN-RVLM neurons. Results indicate that the frequency of spikes evoked by current injection was significantly higher in the hypertensive group (P < 0.05-0.01). Whereas bath application of the SK channel blocker apamin significantly increased discharge of neurons from normotensive rats (P < 0.05-0.01), no effect was observed in the hypertensive group. In response to ramp current injections, subthreshold depolarizing input resistance was greater in the hypertensive group compared with the normotensive group (P < 0.05). Blockade of SK channels increased depolarizing input resistance in normotensive controls (P < 0.05) but had no effect in the hypertensive group. On termination of current pulses, a medium afterhyperpolarization potential (mAHP) was observed in most neurons of the normotensive group. In the hypertensive

  16. Multifaceted modulation of K+ channels by protein-tyrosine phosphatase ε tunes neuronal excitability.

    PubMed

    Ebner-Bennatan, Sharon; Patrich, Eti; Peretz, Asher; Kornilov, Polina; Tiran, Zohar; Elson, Ari; Attali, Bernard

    2012-08-10

    Non-receptor-tyrosine kinases (protein-tyrosine kinases) and non-receptor tyrosine phosphatases (PTPs) have been implicated in the regulation of ion channels, neuronal excitability, and synaptic plasticity. We previously showed that protein-tyrosine kinases such as Src kinase and PTPs such as PTPα and PTPε modulate the activity of delayed-rectifier K(+) channels (I(K)). Here we show cultured cortical neurons from PTPε knock-out (EKO) mice to exhibit increased excitability when compared with wild type (WT) mice, with larger spike discharge frequency, enhanced fast after-hyperpolarization, increased after-depolarization, and reduced spike width. A decrease in I(K) and a rise in large-conductance Ca(2+)-activated K(+) currents (mBK) were observed in EKO cortical neurons compared with WT. Parallel studies in transfected CHO cells indicate that Kv1.1, Kv1.2, Kv7.2/7.3, and mBK are plausible molecular correlates of this multifaceted modulation of K(+) channels by PTPε. In CHO cells, Kv1.1, Kv1.2, and Kv7.2/7.3 K(+) currents were up-regulated by PTPε, whereas mBK channel activity was reduced. The levels of tyrosine phosphorylation of Kv1.1, Kv1.2, Kv7.3, and mBK potassium channels were increased in the brain cortices of neonatal and adult EKO mice compared with WT, suggesting that PTPε in the brain modulates these channel proteins. Our data indicate that in EKO mice, the lack of PTPε-mediated dephosphorylation of Kv1.1, Kv1.2, and Kv7.3 leads to decreased I(K) density and enhanced after-depolarization. In addition, the deficient PTPε-mediated dephosphorylation of mBK channels likely contributes to enhanced mBK and fast after-hyperpolarization, spike shortening, and consequent increase in neuronal excitability observed in cortical neurons from EKO mice.

  17. Menthol Enhances Nicotine Reward-Related Behavior by Potentiating Nicotine-Induced Changes in nAChR Function, nAChR Upregulation, and DA Neuron Excitability.

    PubMed

    Henderson, Brandon J; Wall, Teagan R; Henley, Beverley M; Kim, Charlene H; McKinney, Sheri; Lester, Henry A

    2017-04-12

    Understanding why the quit rate among smokers of menthol cigarettes is lower than non-menthol smokers requires identifying the neurons that are altered by nicotine, menthol, and acetylcholine. Dopaminergic (DA) neurons in the ventral tegmental area (VTA) mediate the positive reinforcing effects of nicotine. Using mouse models, we show that menthol enhances nicotine-induced changes in nicotinic acetylcholine receptors (nAChRs) expressed on midbrain DA neurons. Menthol plus nicotine upregulates nAChR number and function on midbrain DA neurons more than nicotine alone. Menthol also enhances nicotine-induced changes in DA neuron excitability. In a conditioned place preference (CPP) assay, we observed that menthol plus nicotine produces greater reward-related behavior than nicotine alone. Our results connect changes in midbrain DA neurons to menthol-induced enhancements of nicotine reward-related behavior and may help explain how smokers of menthol cigarettes exhibit reduced cessation rates.Neuropsychopharmacology accepted article preview online, 12 April 2017. doi:10.1038/npp.2017.72.

  18. Excitation and modulation of TRPA1, TRPV1, and TRPM8 channel-expressing sensory neurons by the pruritogen chloroquine.

    PubMed

    Than, Jonathan Y-X L; Li, Lin; Hasan, Raquibul; Zhang, Xuming

    2013-05-03

    The sensations of pain, itch, and cold often interact with each other. Pain inhibits itch, whereas cold inhibits both pain and itch. TRPV1 and TRPA1 channels transduce pain and itch, whereas TRPM8 transduces cold. The pruritogen chloroquine (CQ) was reported to excite TRPA1, leading to the sensation of itch. It is unclear how CQ excites and modulates TRPA1(+), TRPV1(+), and TRPM8(+) neurons and thus affects the sensations of pain, itch, and cold. Here, we show that only 43% of CQ-excited dorsal root ganglion neurons expressed TRPA1; as expected, the responses of these neurons were completely prevented by the TRPA1 antagonist HC-030031. The remaining 57% of CQ-excited neurons did not express TRPA1, and excitation was not prevented by either a TRPA1 or TRPV1 antagonist but was prevented by the general transient receptor potential canonical (TRPC) channel blocker BTP2 and the selective TRPC3 inhibitor Pyr3. Furthermore, CQ caused potent sensitization of TRPV1 in 51.9% of TRPV1(+) neurons and concomitant inhibition of TRPM8 in 48.8% of TRPM8(+) dorsal root ganglion neurons. Sensitization of TRPV1 is caused mainly by activation of the phospholipase C-PKC pathway following activation of the CQ receptor MrgprA3. By contrast, inhibition of TRPM8 is caused by a direct action of activated Gαq independent of the phospholipase C pathway. Our data suggest the involvement of the TRPC3 channel acting together with TRPA1 to mediate CQ-induced itch. CQ not only elicits itch by directly exciting itch-encoding neurons but also exerts previously unappreciated widespread actions on pain-, itch-, and cold-sensing neurons, leading to enhanced pain and itch.

  19. [Effect of spontaneous firing of injured dorsal root ganglion neuron on excitability of wide dynamic range neuron in rat spinal dorsal horn].

    PubMed

    Song, Ying; Zhang, Yong-Mei; Xu, Jie; Wu, Jing-Ru; Qin, Xia; Hua, Rong

    2013-10-25

    The aim of the paper is to study the effect of spontaneous firing of injured dorsal root ganglion (DRG) neuron in chronic compression of DRG (CCD) model on excitability of wide dynamic range (WDR) neuron in rat spinal dorsal horn. In vivo intracellular recording was done in DRG neurons and in vivo extracellular recording was done in spinal WDR neurons. After CCD, incidence of spontaneous discharge and firing frequency enhanced to 59.46% and (4.30 ± 0.69) Hz respectively from 22.81% and (0.60 ± 0.08) Hz in normal control group (P < 0.05). Local administration of 50 nmol/L tetrodotoxin (TTX) on DRG neuron in CCD rats decreased the spontaneous activities of WDR neurons from (191.97 ± 45.20)/min to (92.50 ± 30.32)/min (P < 0.05). On the other side, local administration of 100 mmol/L KCl on DRG neuron evoked spontaneous firing in a reversible way (n = 5) in silent WDR neurons of normal rats. There was 36.36% (12/33) WDR neuron showing after-discharge in response to innocuous mechanical stimuli on cutaneous receptive field in CCD rats, while after-discharge was not seen in control rats. Local administration of TTX on DRG with a concentration of 50 nmol/L attenuated innocuous electric stimuli-evoked after-discharge of WDR neurons in CCD rats in a reversible manner, and the frequency was decreased from (263 ± 56.5) Hz to (117 ± 30) Hz (P < 0.05). The study suggests that the excitability of WDR neurons is influenced by spontaneous firings of DRG neurons after CCD.

  20. The dynamic regulation of cortical excitability is altered in episodic ataxia type 2.

    PubMed

    Helmich, Rick C; Siebner, Hartwig R; Giffin, Nicola; Bestmann, Sven; Rothwell, John C; Bloem, Bastiaan R

    2010-12-01

    Episodic ataxia type 2 and familial hemiplegic migraine are two rare hereditary disorders that are linked to dysfunctional ion channels and are characterized clinically by paroxysmal neurological symptoms. Impaired regulation of cerebral excitability is thought to play a role in the occurrence of these paroxysms, but the underlying mechanisms are poorly understood. Normal ion channels are crucial for coordinating neuronal firing in response to facilitatory input. Thus, we hypothesized that channel dysfunction in episodic ataxia type 2 and familial hemiplegic migraine may impair the ability to adjust cerebral excitability after facilitatory events. We tested this hypothesis in patients with episodic ataxia type 2 (n = 6), patients with familial hemiplegic migraine (n = 7) and healthy controls (n = 13). All subjects received a high-frequency burst (10 pulses at 20 Hz) of transcranial magnetic stimulation to transiently increase the excitability of the motor cortex. Acute burst-induced excitability changes were probed at 50, 250, 500 and 1000 ms after the end of the burst. This was done using single-pulse transcranial magnetic stimulation to assess corticospinal excitability, and paired-pulse transcranial magnetic stimulation at an interstimulus interval of 2 and 10 ms to assess intracortical inhibition and facilitation, respectively. The time course of burst-induced excitability changes differed between groups. Healthy controls showed a short-lived increase in excitability that was only present 50 ms after the burst. In contrast, patients with episodic ataxia type 2 showed an abnormally prolonged increase in corticospinal excitability that was still present 250 ms after the transcranial magnetic stimulation burst. Furthermore, while controls showed a decrease in intracortical facilitation during the 1 s period following the transcranial magnetic stimulation burst, patients with episodic ataxia type 2 had increased intracortical facilitation 1000 ms after the burst

  1. Increase in antidromic excitability in presumed serotonergic dorsal raphe neurons during paradoxical sleep in the cat.

    PubMed

    Sakai, K; Crochet, S

    2001-04-20

    Putative serotonergic dorsal raphe (DRN) neurons display a dramatic state-related change in behaviour, discharging regularly at a high rate during waking and at progressively slower rates during slow-wave sleep (SWS) and ceasing firing during paradoxical sleep (PS). Using the antidromic latency technique and extracellular recording, we have examined the change in neuronal excitability of presumed serotonergic DRN neurons during the wake-sleep cycle in freely moving cats. We found that, under normal conditions, suprathreshold stimulation of the main ascending serotonergic pathway resulted in a marked decrease in both the magnitude and variability of antidromic latency during PS, while subthreshold stimulation led to a marked increase in antidromic responsiveness during PS compared with during other behavioural states. The antidromic latency shift resulted from a change in the delay between the initial segment (IS) and soma-dendritic (SD) spikes, the antidromic latency being inversely related to the interval between the stimulus and the preceding spontaneous action potential. A marked decrease in the magnitude and variability of antidromic latency was also seen following suppression of the spontaneous discharge of DRN neurons by application of 5-HT autoreceptor agonists or muscimol, a potent GABA agonist. A marked IS-SD delay or blockage of SD spikes was, however, seen in association with the PS occurring during recovery from 5-HT autoreceptor agonist or during muscimol application. The present findings are discussed in the light of previous in vitro intracellular recording data and our recent findings of the disfacilitation mechanisms responsible for the cessation of discharge of DRN neurons during PS.

  2. Developmental regulation of membrane excitability in rat spinal lamina I projection neurons.

    PubMed

    Li, Jie; Baccei, Mark L

    2012-05-01

    It is now universally recognized that neonates can experience considerable pain. While spinal lamina I neurons projecting to the brain contribute to the generation of hyperalgesia, nothing is known about their electrophysiological properties during early life. Here we have used in vitro whole cell patch-clamp recordings in rat spinal cord slices to determine whether the intrinsic membrane properties of lamina I projection neurons, as well as their synaptic inputs, are developmentally regulated during the early postnatal period. Projection neurons were identified via retrograde transport of DiI injected into the parabrachial nucleus (PB) or periaqueductal gray (PAG) and characterized at postnatal days (P)2-5, P10-12, P19-23, and P30-32. Both spino-PB and spino-PAG neurons demonstrated an age-dependent reduction in spike threshold and duration at room temperature, which was accompanied by a developmental increase in the frequency of miniature excitatory and inhibitory postsynaptic currents. Notably, in both groups, age-dependent changes in the passive membrane properties or rheobase only occurred after the third postnatal week. However, spontaneous activity was significantly more prevalent within the developing spino-PB population and was dominated by an irregular pattern of discharge. In addition, while the instantaneous firing frequency remained unaltered in spino-PB neurons during the first weeks of life, spino-PAG cells fired at a higher rate at P19-23 compared with younger groups, suggesting that the gain of parallel ascending nociceptive pathways may be independently regulated during development. Overall, these results demonstrate that intrinsic membrane excitability is modulated in a cell type-specific manner within developing spinal nociceptive circuits.

  3. Increased excitability of medium-sized dorsal root ganglion neurons by prolonged interleukin-1β exposure is K+ channel dependent and reversible

    PubMed Central

    Stemkowski, Patrick L; Noh, Myung-chul; Chen, Yishen; Smith, Peter A

    2015-01-01

    Chronic constriction injury of rat sciatic nerve promotes signs of neuropathic pain. This is associated with an increase in the level of interleukin 1β (IL-1β) in primary afferents that peaks at 7 days. This initial cytokine exposure has been proposed to trigger an enduring alteration in neuronal phenotype that underlies chronic hyper-excitability in sensory nerves, which initiates and maintains chronic neuropathic pain. We have shown previously that 5–6 days of exposure of rat dorsal root ganglia (DRGs) to 100 pm IL-1β increases the excitability of medium-sized neurons. We have now found using whole-cell recording that this increased excitability reverts to control levels within 3–4 days of cytokine removal. The effects of IL-1β were dominated by changes in K+ currents. Thus, the amplitudes of A-current, delayed rectifier and Ca2+-sensitive K+ currents were reduced by ∼68%, ∼64% and ∼36%, respectively. Effects of IL-1β on other cation currents were modest by comparison. There was thus a slight decrease in availability of high voltage-activated Ca2+ channel current, a small increase in rates of activation of hyperpolarization-activated cyclic nucleotide-gated channel current (IH), and a shift in the voltage dependence of activation of tetrodotoxin-sensitive sodium current (TTX-S INa) to more negative potentials. It is unlikely, therefore, that direct interaction of IL-1β with DRG neurons initiates an enduring phenotypic shift in their electrophysiological properties following sciatic nerve injury. Persistent increases in primary afferent excitability following nerve injury may instead depend on altered K+ channel function and on the continued presence of slightly elevated levels IL-1β and other cytokines. PMID:26110238

  4. Intrinsic excitability changes induced by acute treatment of hippocampal CA1 pyramidal neurons with exogenous amyloid β peptide.

    PubMed

    Tamagnini, Francesco; Scullion, Sarah; Brown, Jon T; Randall, Andrew D

    2015-07-01

    Accumulation of beta-amyloid (Aβ) peptides in the human brain is a canonical pathological hallmark of Alzheimer's disease (AD). Recent work in Aβ-overexpressing transgenic mice indicates that increased brain Aβ levels can be associated with aberrant epileptiform activity. In line with this, such mice can also exhibit altered intrinsic excitability (IE) of cortical and hippocampal neurons: these observations may relate to the increased prevalence of seizures in AD patients. In this study, we examined what changes in IE are produced in hippocampal CA1 pyramidal cells after 2-5 h treatment with an oligomeric preparation of synthetic human Aβ 1-42 peptide. Whole cell current clamp recordings were compared between Aβ-(500 nM) and vehicle-(DMSO 0.05%) treated hippocampal slices obtained from mice. The soluble Aβ treatment did not produce alterations in sub-threshold intrinsic properties, including membrane potential, input resistance, and hyperpolarization activated "sag". Similarly, no changes were noted in the firing profile evoked by 500 ms square current supra-threshold stimuli. However, Aβ 500 nM treatment resulted in the hyperpolarization of the action potential (AP) threshold. In addition, treatment with Aβ at 500 nM depressed the after-hyperpolarization that followed both a single AP or 50 Hz trains of a number of APs between 5 and 25. These data suggest that acute exposure to soluble Aβ oligomers affects IE properties of CA1 pyramidal neurons differently from outcomes seen in transgenic models of amyloidopathy. However, in both chronic and acute models, the IE changes are toward hyperexcitability, reinforcing the idea that amyloidopathy and increased incidence in seizures might be causally related in AD patients.

  5. The cortical innate immune response increases local neuronal excitability leading to seizures

    PubMed Central

    Rodgers, Krista M.; Hutchinson, Mark R.; Northcutt, Alexis; Maier, Steven F.; Watkins, Linda R.

    2009-01-01

    Brain glial cells, five times more prevalent than neurons, have recently received attention for their potential involvement in epileptic seizures. Microglia and astrocytes, associated with inflammatory innate immune responses, are responsible for surveillance of brain damage that frequently results in seizures. Thus, an intriguing suggestion has been put forward that seizures may be facilitated and perhaps triggered by brain immune responses. Indeed, recent evidence strongly implicates innate immune responses in lowering seizure threshold in experimental models of epilepsy, yet, there is no proof that they can play an independent role in initiating seizures in vivo. Here, we show that cortical innate immune responses alone produce profound increases of brain excitability resulting in focal seizures. We found that cortical application of lipopolysaccharide, binding to toll-like receptor 4 (TLR4), triples evoked field potential amplitudes and produces focal epileptiform discharges. These effects are prevented by pre-application of interleukin-1 receptor antagonist. Our results demonstrate how the innate immune response may participate in acute seizures, increasing neuronal excitability through interleukin-1 release in response to TLR4 detection of the danger signals associated with infections of the central nervous system and with brain injury. These results suggest an important role of innate immunity in epileptogenesis and focus on glial inhibition, through pharmacological blockade of TLR4 and the pro-inflammatory mediators released by activated glia, in the study and treatment of seizure disorders in humans. PMID:19567702

  6. Motor imagery muscle contraction strength influences spinal motor neuron excitability and cardiac sympathetic nerve activity.

    PubMed

    Bunno, Yoshibumi; Suzuki, Toshiaki; Iwatsuki, Hiroyasu

    2015-12-01

    [Purpose] The aim of this study was to investigate the changes in spinal motor neuron excitability and autonomic nervous system activity during motor imagery of isometric thenar muscle activity at 10% and 50% maximal voluntary contraction (MVC). [Methods] The F-waves and low frequency/high frequency (LF/HF) ratio were recorded at rest, during motor imagery, and post-trial. For motor imagery trials, subjects were instructed to imagine thenar muscle activity at 10% and 50% MVC while holding the sensor of a pinch meter for 5 min. [Results] The F-waves and LF/HF ratio during motor imagery at 50% MVC were significantly increased compared with those at rest, whereas those during motor imagery at 10% MVC were not significantly different from those at rest. The relative values of the F/M amplitude ratio during motor imagery at 50% MVC were significantly higher than those at 10% MVC. The relative values of persistence and the LF/HF ratio during motor imagery were similar during motor imagery at the two muscle contraction strengths. [Conclusion] Motor imagery can increase the spinal motor neuron excitability and cardiac sympathetic nerve activity. Motor imagery at 50% MVC may be more effective than motor imagery at 10% MVC.

  7. Local excitation-inhibition ratio for synfire chain propagation in feed-forward neuronal networks

    NASA Astrophysics Data System (ADS)

    Guo, Xinmeng; Yu, Haitao; Wang, Jiang; Liu, Jing; Cao, Yibin; Deng, Bin

    2017-09-01

    A leading hypothesis holds that spiking activity propagates along neuronal sub-populations which are connected in a feed-forward manner, and the propagation efficiency would be affected by the dynamics of sub-populations. In this paper, how the interaction between local excitation and inhibition effects on synfire chain propagation in feed-forward network (FFN) is investigated. The simulation results show that there is an appropriate excitation-inhibition (EI) ratio maximizing the performance of synfire chain propagation. The optimal EI ratio can significantly enhance the selectivity of FFN to synchronous signals, which thereby increases the stability to background noise. Moreover, the effect of network topology on synfire chain propagation is also investigated. It is found that synfire chain propagation can be maximized by an optimal interlayer linking probability. We also find that external noise is detrimental to synchrony propagation by inducing spiking jitter. The results presented in this paper may provide insights into the effects of network dynamics on neuronal computations.

  8. Characterization of altered intrinsic excitability in hippocampal CA1 pyramidal cells of the Aβ-overproducing PDAPP mouse.

    PubMed

    Kerrigan, T L; Brown, J T; Randall, A D

    2014-04-01

    Transgenic mice that accumulate Aβ peptides in the CNS are commonly used to interrogate functional consequences of Alzheimer's disease-associated amyloidopathy. In addition to changes to synaptic function, there is also growing evidence that changes to intrinsic excitability of neurones can arise in these models of amyloidopathy. Furthermore, some of these alterations to intrinsic properties may occur relatively early within the age-related progression of experimental amyloidopathy. Here we report a detailed comparison between the intrinsic excitability properties of hippocampal CA1 pyramidal neurones in wild-type (WT) and PDAPP mice. The latter is a well-established model of Aβ accumulation which expresses human APP harbouring the Indiana (V717F) mutation. At the age employed in this study (9-10 months) CNS Abeta was elevated in PDAPP mice but significant plaque pathology was absent. PDAPP mice exhibited no differences in subthreshold intrinsic properties including resting potential, input resistance, membrane time constant and sag. When CA1 cells of PDAPP mice were given depolarizing stimuli of various amplitudes they initially fired at a higher frequency than WT cells. Commensurate with this, PDAPP cells exhibited a larger fast afterdepolarizing potential. PDAPP mice had narrower spikes but action potential threshold, rate of rise and peak were not different. Thus not all changes seen in our previous studies of amyloidopathy models were present in PDAPP mice; however, narrower spikes, larger ADPs and the propensity to fire at higher frequencies were consistent with our prior work and thus may represent robust, cross-model, indices of amyloidopathy. This article is part of a Special Issue entitled 'Neurodevelopment Disorder'.

  9. Increased intrinsic excitability of muscle vasoconstrictor preganglionic neurons may contribute to the elevated sympathetic activity in hypertensive rats.

    PubMed

    Briant, Linford J B; Stalbovskiy, Alexey O; Nolan, Matthew F; Champneys, Alan R; Pickering, Anthony E

    2014-12-01

    Hypertension is associated with pathologically increased sympathetic drive to the vasculature. This has been attributed to increased excitatory drive to sympathetic preganglionic neurons (SPN) from brainstem cardiovascular control centers. However, there is also evidence supporting increased intrinsic excitability of SPN. To test this hypothesis, we made whole cell recordings of muscle vasoconstrictor-like (MVClike) SPN in the working-heart brainstem preparation of spontaneously hypertensive (SH) and normotensive Wistar-Kyoto (WKY) rats. The MVClike SPN have a higher spontaneous firing frequency in the SH rat (3.85 ± 0.4 vs. 2.44 ± 0.4 Hz in WKY; P = 0.011) with greater respiratory modulation of their activity. The action potentials of SH SPN had smaller, shorter afterhyperpolarizations (AHPs) and showed diminished transient rectification indicating suppression of an A-type potassium conductance (IA). We developed mathematical models of the SPN to establish if changes in their intrinsic properties in SH rats could account for their altered firing. Reduction of the maximal conductance density of IA by 15-30% changed the excitability and output of the model from the WKY to a SH profile, with increased firing frequency, amplified respiratory modulation, and smaller AHPs. This change in output is predominantly a consequence of altered synaptic integration. Consistent with these in silico predictions, we found that intrathecal 4-aminopyridine (4-AP) increased sympathetic nerve activity, elevated perfusion pressure, and augmented Traube-Hering waves. Our findings indicate that IA acts as a powerful filter on incoming synaptic drive to SPN and that its diminution in the SH rat is potentially sufficient to account for the increased sympathetic output underlying hypertension. Copyright © 2014 the American Physiological Society.

  10. Increased intrinsic excitability of muscle vasoconstrictor preganglionic neurons may contribute to the elevated sympathetic activity in hypertensive rats

    PubMed Central

    Briant, Linford J. B.; Stalbovskiy, Alexey O.; Nolan, Matthew F.; Champneys, Alan R.

    2014-01-01

    Hypertension is associated with pathologically increased sympathetic drive to the vasculature. This has been attributed to increased excitatory drive to sympathetic preganglionic neurons (SPN) from brainstem cardiovascular control centers. However, there is also evidence supporting increased intrinsic excitability of SPN. To test this hypothesis, we made whole cell recordings of muscle vasoconstrictor-like (MVClike) SPN in the working-heart brainstem preparation of spontaneously hypertensive (SH) and normotensive Wistar-Kyoto (WKY) rats. The MVClike SPN have a higher spontaneous firing frequency in the SH rat (3.85 ± 0.4 vs. 2.44 ± 0.4 Hz in WKY; P = 0.011) with greater respiratory modulation of their activity. The action potentials of SH SPN had smaller, shorter afterhyperpolarizations (AHPs) and showed diminished transient rectification indicating suppression of an A-type potassium conductance (IA). We developed mathematical models of the SPN to establish if changes in their intrinsic properties in SH rats could account for their altered firing. Reduction of the maximal conductance density of IA by 15–30% changed the excitability and output of the model from the WKY to a SH profile, with increased firing frequency, amplified respiratory modulation, and smaller AHPs. This change in output is predominantly a consequence of altered synaptic integration. Consistent with these in silico predictions, we found that intrathecal 4-aminopyridine (4-AP) increased sympathetic nerve activity, elevated perfusion pressure, and augmented Traube-Hering waves. Our findings indicate that IA acts as a powerful filter on incoming synaptic drive to SPN and that its diminution in the SH rat is potentially sufficient to account for the increased sympathetic output underlying hypertension. PMID:25122704

  11. Imaging cell volume changes and neuronal excitation in the hippocampal slice.

    PubMed

    Andrew, R D; MacVicar, B A

    1994-09-01

    Brain cell swelling is a consequence of seizure, ischemia or excitotoxicity. Changes in light reflectance from cortical surface are now used to monitor brain activity but these intrinsic signals are poorly understood. The objectives of this study were first, to show that changes in light transmittance were correlated with cell volume and second, to image increases in light transmittance as they related to neuronal activation. Transverse hippocampal slices from the rat were used for the study. Brief exposure (4-6 min) to hypo-osmotic artificial cerebrospinal fluid (-40 mOsm) elevated light transmittance consistently and reversibly in most regions of the slice and particularly in CA1 dendritic regions. Neither zero-Ca2+ artificial cerebrospinal fluid nor tetrodotoxin altered the transmittance increase and its subsequent reversal, suggesting that it was dependent on osmolality but independent of synaptic transmission and neuronal firing. The amplitude of the CA1 population spike evoked from Schaffer collaterals increased concomitantly with the hypo-osmotic increase in light transmittance, providing evidence that the extracellular tissue resistance increased. Hyper-osmotic artificial cerebrospinal fluid (+40 mOsm) containing impermeant mannitol consistently lowered light transmittance and the amplitude of the population spike. Glycerol (+40 mOsm), which is cell permeant, did not have an affect. Taken together these observations indicate that osmotic challenge alters light transmittance by inducing changes in cell volume. Transmittance increases induced by hypo-osmotic artificial cerebrospinal fluid or 10 microM kainate were small in the CA1 cell body region compared to dendritic regions. Similarly, orthodromic stimulation of axons terminating in stratum oriens or in stratum radiatum evoked transmittance increases only in their respective postsynaptic areas. In contrast, the cell body region and its adjacent proximal-apical dendrites (both sites of action potential

  12. Chronic Intermittent Ethanol Exposure Enhances the Excitability and Synaptic Plasticity of Lateral Orbitofrontal Cortex Neurons and Induces a Tolerance to the Acute Inhibitory Actions of Ethanol

    PubMed Central

    Nimitvilai, Sudarat; Lopez, Marcelo F; Mulholland, Patrick J; Woodward, John J

    2016-01-01

    Alcoholism is associated with changes in brain reward and control systems, including the prefrontal cortex. In prefrontal areas, the orbitofrontal cortex (OFC) has been suggested to have an important role in the development of alcohol-abuse disorders and studies from this laboratory demonstrate that OFC-mediated behaviors are impaired in alcohol-dependent animals. However, it is not known whether chronic alcohol (ethanol) exposure alters the fundamental properties of OFC neurons. In this study, mice were exposed to repeated cycles of chronic intermittent ethanol (CIE) exposure to induce dependence and whole-cell patch-clamp electrophysiology was used to examine the effects of CIE treatment on lateral OFC (lOFC) neuron excitability, synaptic transmission, and plasticity. Repeated cycles of CIE exposure and withdrawal enhanced current-evoked action potential (AP) spiking and this was accompanied by a reduction in the after-hyperpolarization and a decrease in the functional activity of SK channels. CIE mice also showed an increase in the AMPA/NMDA ratio, and this was associated with an increase in GluA1/GluA2 AMPA receptor expression and a decrease in GluN2B NMDA receptor subunits. Following CIE treatment, lOFC neurons displayed a persistent long-term potentiation of glutamatergic synaptic transmission following a spike-timing-dependent protocol. Lastly, CIE treatment diminished the inhibitory effect of acute ethanol on AP spiking of lOFC neurons and reduced expression of the GlyT1 transporter. Taken together, these results suggest that chronic exposure to ethanol leads to enhanced intrinsic excitability and glutamatergic synaptic signaling of lOFC neurons. These alterations may contribute to the impairment of OFC-dependent behaviors in alcohol-dependent individuals. PMID:26286839

  13. Chronic Intermittent Ethanol Exposure Enhances the Excitability and Synaptic Plasticity of Lateral Orbitofrontal Cortex Neurons and Induces a Tolerance to the Acute Inhibitory Actions of Ethanol.

    PubMed

    Nimitvilai, Sudarat; Lopez, Marcelo F; Mulholland, Patrick J; Woodward, John J

    2016-03-01

    Alcoholism is associated with changes in brain reward and control systems, including the prefrontal cortex. In prefrontal areas, the orbitofrontal cortex (OFC) has been suggested to have an important role in the development of alcohol-abuse disorders and studies from this laboratory demonstrate that OFC-mediated behaviors are impaired in alcohol-dependent animals. However, it is not known whether chronic alcohol (ethanol) exposure alters the fundamental properties of OFC neurons. In this study, mice were exposed to repeated cycles of chronic intermittent ethanol (CIE) exposure to induce dependence and whole-cell patch-clamp electrophysiology was used to examine the effects of CIE treatment on lateral OFC (lOFC) neuron excitability, synaptic transmission, and plasticity. Repeated cycles of CIE exposure and withdrawal enhanced current-evoked action potential (AP) spiking and this was accompanied by a reduction in the after-hyperpolarization and a decrease in the functional activity of SK channels. CIE mice also showed an increase in the AMPA/NMDA ratio, and this was associated with an increase in GluA1/GluA2 AMPA receptor expression and a decrease in GluN2B NMDA receptor subunits. Following CIE treatment, lOFC neurons displayed a persistent long-term potentiation of glutamatergic synaptic transmission following a spike-timing-dependent protocol. Lastly, CIE treatment diminished the inhibitory effect of acute ethanol on AP spiking of lOFC neurons and reduced expression of the GlyT1 transporter. Taken together, these results suggest that chronic exposure to ethanol leads to enhanced intrinsic excitability and glutamatergic synaptic signaling of lOFC neurons. These alterations may contribute to the impairment of OFC-dependent behaviors in alcohol-dependent individuals.

  14. Imbalance between excitation and inhibition among synaptic connections of CA3 pyramidal neurons in cultured hippocampal slices.

    PubMed

    Cruz-Martín, Alberto; Schweizer, Felix E

    2008-03-01

    A fundamental property of small neuronal ensembles is their ability to be selectively activated by distinct stimuli. One cellular mechanism by which neurons achieve this input selectivity is by modulating the temporal dynamics of excitation and inhibition. We explored the interplay of excitation and inhibition in synapses between pyramidal neurons of cornu ammonis field 3 of the hippocampal formation (CA3) in cultured rat hippocampal slices, where activation of a single excitatory cell can readily recruit local interneurons. Simultaneous whole-cell recordings from pairs of CA3 pyramidal neurons revealed that the strength of connections was neither uniform nor balanced. Rather, stimulation of presynaptic neurons elicited distinct combinations of excitatory postsynaptic current-inhibitory postsynaptic current (EPSC-IPSC) amplitudes in the postsynaptic neurons. EPSC-IPSC sequences with small EPSCs had large IPSCs and sequences that contained large EPSCs had small IPSCs. In addition to differences in the amplitudes of the responses, the kinetics of the EPSCs were also different, creating distinct temporal dynamics of excitation and inhibition. Weaker EPSCs had significantly slower kinetics and were efficiently occluded by IPSCs, thereby further limiting their contribution to depolarizing the postsynaptic membrane. Our data suggest that hippocampal pyramidal cells may use an imbalance between excitation and inhibition as a filter to enhance selectivity toward preferential excitatory connections.

  15. Modulation by the BK accessory β4 subunit of phosphorylation-dependent changes in excitability of dentate gyrus granule neurons

    PubMed Central

    Petrik, David; Wang, Bin; Brenner, Robert

    2011-01-01

    BK channels are large conductance calcium- and voltage-activated potassium channels critical for neuronal excitability. Some neurons express so called fast-gated, type I BK channels. Other neurons express BK channels assembled with the accessory β4 subunit conferring slow-gating of type II BK channels. However, it is not clear how protein phosphorylation modulates these two distinct BK channel types. Using β4 knockout mice, we compared fast- or slow-gated BK channels in response to changes in phosphorylation status of hippocampus dentate gyrus granule neurons. We utilized the selective PP2A/PP4 phosphatase inhibitor, Fostriecin, to study changes in action potential shape and firing properties of the neurons. In β4 knockout neurons, Fostriecin increases BK current, speeds BK channel activation, and reduces action potential amplitudes. Fostriecin increases spiking during early components of an action potential train. In contrast, inhibition of BK channels through β4 in wild type neurons or by BK channel inhibitor Paxilline opposes Fostriecin effects. Voltage clamp recordings of neurons reveal that Fostriecin increases both calcium and BK currents. However, Fostriecin does not activate BK α alone channels in transfected HEK293 cells lacking calcium channels. In summary, these results suggest that the fast-gating, type I BK channels lacking β4 can increase neuronal excitability in response to reduced phosphatase activity and activation of calcium channels. By opposing BK channel activation; the β4 subunit plays an important role in moderating firing frequency regardless of changes in phosphorylation status. PMID:21848922

  16. Nalcn Is a “Leak” Sodium Channel That Regulates Excitability of Brainstem Chemosensory Neurons and Breathing

    PubMed Central

    Shi, Yingtang; Abe, Chikara; Holloway, Benjamin B.; Shu, Shaofang; Kumar, Natasha N.; Weaver, Janelle L.; Sen, Josh; Perez-Reyes, Edward; Stornetta, Ruth L.; Guyenet, Patrice G.

    2016-01-01

    The activity of background potassium and sodium channels determines neuronal excitability, but physiological roles for “leak” Na+ channels in specific mammalian neurons have not been established. Here, we show that a leak Na+ channel, Nalcn, is expressed in the CO2/H+-sensitive neurons of the mouse retrotrapezoid nucleus (RTN) that regulate breathing. In RTN neurons, Nalcn expression correlated with higher action potential discharge over a more alkalized range of activity; shRNA-mediated depletion of Nalcn hyperpolarized RTN neurons, and reduced leak Na+ current and firing rate. Nalcn depletion also decreased RTN neuron activation by the neuropeptide, substance P, without affecting pH-sensitive background K+ currents or activation by a cotransmitter, serotonin. In vivo, RTN-specific knockdown of Nalcn reduced CO2-evoked neuronal activation and breathing; hypoxic hyperventilation was unchanged. Thus, Nalcn regulates RTN neuronal excitability and stimulation by CO2, independent of direct pH sensing, potentially contributing to respiratory effects of Nalcn mutations; transmitter modulation of Nalcn may underlie state-dependent changes in breathing and respiratory chemosensitivity. SIGNIFICANCE STATEMENT Breathing is an essential, enduring rhythmic motor activity orchestrated by dedicated brainstem circuits that require tonic excitatory drive for their persistent function. A major source of drive is from a group of CO2/H+-sensitive neurons in the retrotrapezoid nucleus (RTN), whose ongoing activity is critical for breathing. The ionic mechanisms that support spontaneous activity of RTN neurons are unknown. We show here that Nalcn, a unique channel that generates “leak” sodium currents, regulates excitability and neuromodulation of RTN neurons and CO2-stimulated breathing. Thus, this work defines a specific function for this enigmatic channel in an important physiological context. PMID:27488637

  17. The effects of linalool on the excitability of central neurons of snail Caucasotachea atrolabiata.

    PubMed

    Vatanparast, Jafar; Bazleh, Sara; Janahmadi, Mahyar

    2017-02-01

    Linalool is a major constituent of the essential oil of several plant species and possesses several biological activities. In this work, we studied the effects of linalool on excitability of central neurons of land snail Caucasotachea atrolabiata and tried to elucidate the underlying mechanisms. The lower concentration of linalool (0.1mM) showed suppressive action on spontaneous activity and pentylenetetrazole-induced epileptiform activity. These effects were associated with elevation of the action potential threshold and reduction of action potential rising phase, supporting the inhibitory action of linalool on Na(+) channels. At this concentration it also prolonged the post stimulus inhibitory period that can take part in its antiepileptic effect and apparently results from increased action potential duration and indirect augmentation of Ca(2+)-activated K(+) currents. At higher concentration, however, linalool (0.4mM) increased the neuronal excitability and induced epileptiform activity. The modulatory effects on action potential waveform during preconvulsive period suggest that the recent effect is mainly dependent on the suppression of outward potassium currents underlying repolarization phase and afterhyperpolarization. The linalool-induced epileptiform activity was abolished by Ca2(+) channel blockers, nifedipine and nickel chloride, and selective inhibitor of protein kinase C, chelerythrine, suggesting that Ca2(+) inward currents and protein kinase C (PKC) activity are required for linalool-induced epileptiform activity. Our results support the antiepileptic activity of linalool at lower dose, but it shows epileptogenic activity when applied directly on snail neurons at higher dose. Linalool may also be a potential therapeutic agent for activating PKC.

  18. Differential alterations of intracellular [Ca2+] dynamics induced by cocaine and methylphenidate in thalamocortical ventrobasal neurons

    PubMed Central

    Rozas, José L.; Goitia, Belén; Bisagno, Verónica; Urbano, Francisco J.

    2017-01-01

    The ventrobasal (VB) thalamus relay nucleus processes information from rodents’ whiskers, projecting to somatosensory cortex. Cocaine and methylphenidate (MPH) have been described to differentially alter intrinsic properties of, and spontaneous GABAergic input to, VB neurons. Here we studied using bis-fura 2 ratiometric fluorescence the effects of cocaine and MPH on intracellular [Ca2+] dynamics at the soma and dendrites of VB neurons. Cocaine increased baseline fluorescence in VB somatic and dendritic compartments. Peak and areas of fluorescence amplitudes were reduced by cocaine binge treatment in somas and dendrites at different holding potentials. MPH binge treatment did not alter ratiometric fluorescence at either somatic or dendritic levels. These novel cocaine-mediated blunting effects on intracellular [Ca2+] might account for alterations in the capacity of thalamocortical neurons to maintain gamma band oscillations, as well as their ability to integrate synaptic afferents. PMID:28920083

  19. Low Concentrations of the Solvent Dimethyl Sulphoxide Alter Intrinsic Excitability Properties of Cortical and Hippocampal Pyramidal Cells

    PubMed Central

    Brown, Jonathan T.; Randall, Andrew D.

    2014-01-01

    Dimethylsulfoxide (DMSO) is a widely used solvent in biology. It has many applications perhaps the most common of which is in aiding the preparation of drug solutions from hydrophobic chemical entities. Recent studies have suggested that this molecule may be able to induce apoptosis in neural tissues urging caution regarding its introduction into humans, for example as part of stem cell transplants. Here we have used in vitro electrophysiological methods applied to murine brain slices to examine whether a few hours treatment with 0.05% DMSO (a concentration regarded by many as innocuous) alters intrinsic excitability properties of neurones. We investigated pyramidal neurones in two distinct brain regions, namely area CA1 of the hippocampus and layer 2 of perirhinal cortex. In the former there was no effect on resting potential but input resistance was decreased by DMSO pre-treatment. In line with this action potential count for any level of depolarizing current stimulus was reduced by ∼25% following DMSO treatment. Ih-mediated “sag” was also increased in CA1 pyramids and action potential waveform analysis demonstrated that DMSO treatment moved action potential threshold towards resting potential. In perirhinal cortex a decreased action potential output for various depolarizing current stimuli was also seen. In these cells action potential threshold was unaltered by DMSO but a significant increase in action potential width was apparent. These data indicate that pre-treatment with this widely employed solvent can elicit multifaceted neurophysiological changes in mammalian neurones at concentrations below those frequently encountered in the published literature. PMID:24647720

  20. Recovery of neuronal and network excitability after spinal cord injury and implications for spasticity

    PubMed Central

    D'Amico, Jessica M.; Condliffe, Elizabeth G.; Martins, Karen J. B.; Bennett, David J.; Gorassini, Monica A.

    2014-01-01

    The state of areflexia and muscle weakness that immediately follows a spinal cord injury (SCI) is gradually replaced by the recovery of neuronal and network excitability, leading to both improvements in residual motor function and the development of spasticity. In this review we summarize recent animal and human studies that describe how motoneurons and their activation by sensory pathways become hyperexcitable to compensate for the reduction of functional activation of the spinal cord and the eventual impact on the muscle. Specifically, decreases in the inhibitory control of sensory transmission and increases in intrinsic motoneuron excitability are described. We present the idea that replacing lost patterned activation of the spinal cord by activating synaptic inputs via assisted movements, pharmacology or electrical stimulation may help to recover lost spinal inhibition. This may lead to a reduction of uncontrolled activation of the spinal cord and thus, improve its controlled activation by synaptic inputs to ultimately normalize circuit function. Increasing the excitation of the spinal cord with spared descending and/or peripheral inputs by facilitating movement, instead of suppressing it pharmacologically, may provide the best avenue to improve residual motor function and manage spasticity after SCI. PMID:24860447

  1. Synchronized excitability in a network enables generation of internal neuronal sequences

    PubMed Central

    Wang, Yingxue; Roth, Zachary; Pastalkova, Eva

    2016-01-01

    Hippocampal place field sequences are supported by sensory cues and network internal mechanisms. In contrast, sharp-wave (SPW) sequences, theta sequences, and episode field sequences are internally generated. The relationship of these sequences to memory is unclear. SPW sequences have been shown to support learning and have been assumed to also support episodic memory. Conversely, we demonstrate these SPW sequences were present in trained rats even after episodic memory was impaired and after other internal sequences – episode field and theta sequences – were eliminated. SPW sequences did not support memory despite continuing to ‘replay’ all task-related sequences – place- field and episode field sequences. Sequence replay occurred selectively during synchronous increases of population excitability -- SPWs. Similarly, theta sequences depended on the presence of repeated synchronized waves of excitability – theta oscillations. Thus, we suggest that either intermittent or rhythmic synchronized changes of excitability trigger sequential firing of neurons, which in turn supports learning and/or memory. DOI: http://dx.doi.org/10.7554/eLife.20697.001 PMID:27677848

  2. Receptor Subtype Alterations: Bases of Neuronal Plasticity and Learning

    DTIC Science & Technology

    1991-12-03

    thalamus and cingulate cortex increased during the course of discriminative avoidance conditioning (DAC). Since there was no change in pirenzepine ...binding protocols included the following: ml, m3 and m4, 3H- pirenzepine ; m2, 3H-oxotremorine-M in thc presence of unlabeled pirenzepine ; GABAa, 3H...led us to alter our goals in a number of important ways. First, the increase in pirenzepine binding in the pilot study could not be confirmed and so

  3. A not cytotoxic nickel concentration alters the expression of neuronal differentiation markers in NT2 cells.

    PubMed

    Ceci, Claudia; Barbaccia, Maria Luisa; Pistritto, Giuseppa

    2015-03-01

    Nickel, a known occupational/environmental hazard, may cross the placenta and reach appreciable concentrations in various fetal organs, including the brain. The aim of this study was to investigate whether nickel interferes with the process of neuronal differentiation. Following a 4 week treatment with retinoic acid (10μM), the human teratocarcinoma-derived NTera2/D1 cell line (NT2 cells) terminally differentiate into neurons which recapitulate many features of human fetal neurons. The continuous exposure of the differentiating NT2 cells to a not cytotoxic nickel concentration (10μM) increased the expression of specific neuronal differentiation markers such as neural cell adhesion molecule (NCAM) and microtubule associated protein 2 (MAP2). Furthermore, nickel exposure increased the expression of hypoxia-inducible-factor-1α (HIF-1α) and induced the activation of the AKT/PKB kinase pathway, as shown by the increase of P(Ser-9)-GSK-3β, the inactive form of glycogen synthase kinase-3β (GSK-3β). Intriguingly, by the end of the fourth week the expression of tyrosine hydroxylase (TH) protein, a marker of dopaminergic neurons, was lower in nickel-treated than in control cultures. Thus, likely by partially mimicking hypoxic conditions, a not-cytotoxic nickel concentration appears to alter the process of neuronal differentiation and hinder the expression of the dopaminergic neuronal phenotype. Taken together, these results suggest that nickel, by altering normal brain development, may increase susceptibility to neuro-psychopathology later in life.

  4. Cell-Specific Cholinergic Modulation of Excitability of Layer 5B Principal Neurons in Mouse Auditory Cortex

    PubMed Central

    Joshi, Ankur; Kalappa, Bopanna I.; Anderson, Charles T.

    2016-01-01

    The neuromodulator acetylcholine (ACh) is crucial for several cognitive functions, such as perception, attention, and learning and memory. Whereas, in most cases, the cellular circuits or the specific neurons via which ACh exerts its cognitive effects remain unknown, it is known that auditory cortex (AC) neurons projecting from layer 5B (L5B) to the inferior colliculus, corticocollicular neurons, are required for cholinergic-mediated relearning of sound localization after occlusion of one ear. Therefore, elucidation of the effects of ACh on the excitability of corticocollicular neurons will bridge the cell-specific and cognitive properties of ACh. Because AC L5B contains another class of neurons that project to the contralateral cortex, corticocallosal neurons, to identify the cell-specific mechanisms that enable corticocollicular neurons to participate in sound localization relearning, we investigated the effects of ACh release on both L5B corticocallosal and corticocollicular neurons. Using in vitro electrophysiology and optogenetics in mouse brain slices, we found that ACh generated nicotinic ACh receptor (nAChR)-mediated depolarizing potentials and muscarinic ACh receptor (mAChR)-mediated hyperpolarizing potentials in AC L5B corticocallosal neurons. In corticocollicular neurons, ACh release also generated nAChR-mediated depolarizing potentials. However, in contrast to the mAChR-mediated hyperpolarizing potentials in corticocallosal neurons, ACh generated prolonged mAChR-mediated depolarizing potentials in corticocollicular neurons. These prolonged depolarizing potentials generated persistent firing in corticocollicular neurons, whereas corticocallosal neurons lacking mAChR-mediated depolarizing potentials did not show persistent firing. We propose that ACh-mediated persistent firing in corticocollicular neurons may represent a critical mechanism required for learning-induced plasticity in AC. SIGNIFICANCE STATEMENT Acetylcholine (ACh) is crucial for cognitive

  5. Recovery of motor neuron excitability after facial nerve impairment in rats.

    PubMed

    Ohki, Masafumi; Takeuchi, Naonobu

    2014-05-07

    Multiple studies have demonstrated alterations in excitability in the central nervous system after peripheral nerve injury. However, there are few reports on changes in the central nervous system after peripheral facial nerve injury. Our objective was to determine the excitability changes that occur in the facial nucleus after facial nerve impairment. The excitability changes in the facial nucleus were investigated by assessing two types of compound muscle action potentials (M and F waves) in the orbicularis oculi muscles, evoked by electrical stimulation of the zygomatic branch of the facial nerve. In rats, M and F waves were measured in the orbicularis oculi muscles before and every week up to 8 weeks after the application of nerve compression under anesthesia. M and F waves disappeared after nerve compression, only to reappear 2 weeks later, although M-wave amplitude was decreased and the latencies of both waves were delayed. Thereafter, these waves recovered gradually. During the recovery period, the F/M wave amplitude ratio, which is an indicator of facial nucleus excitability, significantly increased on the impaired side but not on the intact side. This increase was most prominent within 3 weeks; thereafter, the ratio gradually decreased and reached the levels recorded before facial nerve impairment by 7 weeks. Facial nerve impairment leads to hyperexcitability of the facial nucleus during the recovery period.

  6. Label-free distinguishing between neurons and glial cells based on two-photon excited fluorescence signal of neuron perinuclear granules

    NASA Astrophysics Data System (ADS)

    Du, Huiping; Jiang, Liwei; Wang, Xingfu; Liu, Gaoqiang; Wang, Shu; Zheng, Liqin; Li, Lianhuang; Zhuo, Shuangmu; Zhu, Xiaoqin; Chen, Jianxin

    2016-08-01

    Neurons and glial cells are two critical cell types of brain tissue. Their accurate identification is important for the diagnosis of psychiatric disorders such as depression and schizophrenia. In this paper, distinguishing between neurons and glial cells by using the two-photon excited fluorescence (TPEF) signals of intracellular intrinsic sources was performed. TPEF microscopy combined with TUJ-1 and GFAP immunostaining and quantitative image analysis demonstrated that the perinuclear granules of neurons in the TPEF images of brain tissue and the primary cultured cortical cells were a unique characteristic of neurons compared to glial cells which can become a quantitative feature to distinguish neurons from glial cells. With the development of miniaturized TPEF microscope (‘two-photon fiberscopes’) imaging devices, TPEF microscopy can be developed into an effective diagnostic and monitoring tool for psychiatric disorders such as depression and schizophrenia.

  7. Direct muscarinic and nicotinic receptor-mediated excitation of rat medial vestibular nucleus neurons in vitro

    NASA Technical Reports Server (NTRS)

    Phelan, K. D.; Gallagher, J. P.

    1992-01-01

    We have utilized intracellular recording techniques to investigate the cholinoceptivity of rat medial vestibular nucleus (MVN) neurons in a submerged brain slice preparation. Exogenous application of the mixed cholinergic agonists, acetylcholine (ACh) or carbachol (CCh), produced predominantly membrane depolarization, induction of action potential firing, and decreased input resistance. Application of the selective muscarinic receptor agonist muscarine (MUSC), or the selective nicotinic receptor agonists nicotine (NIC) or 1,1-dimethyl-4-phenylpiperazinium (DMPP) also produced membrane depolarizations. The MUSC-induced depolarization was accompanied by decreased conductance, while an increase in conductance appeared to underlie the NIC- and DMPP-induced depolarizations. The muscarinic and nicotinic receptor mediated depolarizations persisted in tetrodotoxin and/or low Ca2+/high Mg2+ containing media, suggesting direct postsynaptic receptor activation. The MUSC-induced depolarization could be reversibly blocked by the selective muscarinic-receptor antagonist, atropine, while the DMPP-induced depolarization could be reversibly suppressed by the selective ganglionic nicotinic-receptor antagonist, mecamylamine. Some neurons exhibited a transient membrane hyperpolarization during the depolarizing response to CCh or MUSC application. This transient inhibition could be reversibly blocked by the gamma-aminobutyric acid (GABA) antagonist, bicuculline, suggesting that the underlying hyperpolarization results indirectly from the endogenous release of GABA acting at GABA receptors. This study confirms the cholinoceptivity of MVN neurons and establishes that individual MVN cells possess muscarinic as well as nicotinic receptors. The data provide support for a prominent role of cholinergic mechanisms in the direct and indirect regulation of the excitability of MVN neurons.

  8. A tingling sanshool derivative excites primary sensory neurons and elicits nocifensive behavior in rats

    PubMed Central

    Klein, Amanda H.; Sawyer, Carolyn M.; Zanotto, Karen L.; Ivanov, Margaret A.; Cheung, Susan; Carstens, Mirela Iodi; Furrer, Stephan; Simons, Christopher T.; Slack, Jay P.

    2011-01-01

    Szechuan peppers contain hydroxy-α-sanshool that imparts desirable tingling, cooling, and numbing sensations. Hydroxy-α-sanshool activates a subset of sensory dorsal root ganglion (DRG) neurons by inhibiting two-pore potassium channels. We presently investigated if a tingle-evoking sanshool analog, isobutylalkenyl amide (IBA), excites rat DRG neurons and, if so, if these neurons are also activated by agonists of TRPM8, TRPA1, and/or TRPV1. Thirty-four percent of DRG neurons tested responded to IBA, with 29% of them also responding to menthol, 29% to cinnamic aldehyde, 66% to capsaicin, and subsets responding to two or more transient receptor potential (TRP) agonists. IBA-responsive cells had similar size distributions regardless of whether they responded to capsaicin or not; cells only responsive to IBA were larger. Responses to repeated application of IBA at a 5-min interstimulus interval exhibited self-desensitization (tachyphylaxis). Capsaicin did not cross-desensitize responses to IBA to any greater extent than the tachyphylaxis observed with repeated IBA applications. These findings are consistent with psychophysical observations that IBA elicits tingle sensation accompanied by pungency and cooling, with self-desensitization but little cross-desensitization by capsaicin. Intraplantar injection of IBA elicited nocifensive responses (paw licking, shaking-flinching, and guarding) in a dose-related manner similar to the effects of intraplantar capsaicin and serotonin. IBA had no effect on thermal sensitivity but enhanced mechanical sensitivity at the highest dose tested. These observations suggest that IBA elicits an unfamiliar aversive sensation that is expressed behaviorally by the limited response repertoire available to the animal. PMID:21273322

  9. Direct muscarinic and nicotinic receptor-mediated excitation of rat medial vestibular nucleus neurons in vitro

    NASA Technical Reports Server (NTRS)

    Phelan, K. D.; Gallagher, J. P.

    1992-01-01

    We have utilized intracellular recording techniques to investigate the cholinoceptivity of rat medial vestibular nucleus (MVN) neurons in a submerged brain slice preparation. Exogenous application of the mixed cholinergic agonists, acetylcholine (ACh) or carbachol (CCh), produced predominantly membrane depolarization, induction of action potential firing, and decreased input resistance. Application of the selective muscarinic receptor agonist muscarine (MUSC), or the selective nicotinic receptor agonists nicotine (NIC) or 1,1-dimethyl-4-phenylpiperazinium (DMPP) also produced membrane depolarizations. The MUSC-induced depolarization was accompanied by decreased conductance, while an increase in conductance appeared to underlie the NIC- and DMPP-induced depolarizations. The muscarinic and nicotinic receptor mediated depolarizations persisted in tetrodotoxin and/or low Ca2+/high Mg2+ containing media, suggesting direct postsynaptic receptor activation. The MUSC-induced depolarization could be reversibly blocked by the selective muscarinic-receptor antagonist, atropine, while the DMPP-induced depolarization could be reversibly suppressed by the selective ganglionic nicotinic-receptor antagonist, mecamylamine. Some neurons exhibited a transient membrane hyperpolarization during the depolarizing response to CCh or MUSC application. This transient inhibition could be reversibly blocked by the gamma-aminobutyric acid (GABA) antagonist, bicuculline, suggesting that the underlying hyperpolarization results indirectly from the endogenous release of GABA acting at GABA receptors. This study confirms the cholinoceptivity of MVN neurons and establishes that individual MVN cells possess muscarinic as well as nicotinic receptors. The data provide support for a prominent role of cholinergic mechanisms in the direct and indirect regulation of the excitability of MVN neurons.

  10. 17β-Estradiol increases persistent Na(+) current and excitability of AVPV/PeN Kiss1 neurons in female mice.

    PubMed

    Zhang, Chunguang; Bosch, Martha A; Qiu, Jian; Rønnekleiv, Oline K; Kelly, Martin J

    2015-04-01

    In vitro slice studies have revealed that there are significant differences in the spontaneous firing activity between anteroventral periventricular/periventricular preoptic nucleus (AVPV/PeN) and arcuate nucleus (ARC) kisspeptin (Kiss1) neurons in females. Although both populations express similar endogenous conductances, we have discovered that AVPV/PeN Kiss1 neurons express a subthreshold, persistent sodium current (INaP) that dramatically alters their firing activity. Based on whole-cell recording of Kiss1-Cre-green fluorescent protein (GFP) neurons, INaP was 4-fold greater in AVPV/PeN vs ARC Kiss1 neurons. An LH surge-producing dose of 17β-estradiol (E2) that increased Kiss1 mRNA expression in the AVPV/PeN, also augmented INaP in AVPV/PeN neurons by 2-fold. Because the activation threshold for INaP was close to the resting membrane potential (RMP) of AVPV/PeN Kiss1 neurons (-54 mV), it rendered them much more excitable and spontaneously active vs ARC Kiss1 neurons (RMP = -66 mV). Single-cell RT-PCR revealed that AVPV/PeN Kiss1 neurons expressed the requisite sodium channel α-subunit transcripts, NaV1.1, NaV1.2, and NaV1.6 and β subunits, β2 and β4. Importantly, NaV1.1α and -β2 transcripts in AVPV/PeN, but not ARC, were up-regulated 2- to 3-fold by a surge-producing dose of E2, similar to the transient calcium current channel subunit Cav3.1. The transient calcium current collaborates with INaP to generate burst firing, and selective blockade of INaP by riluzole significantly attenuated rebound burst firing and spontaneous activity. Therefore, INaP appears to play a prominent role in AVPV/PeN Kiss1 neurons to generate spontaneous, repetitive burst firing, which is required for the high-frequency-stimulated release of kisspeptin for exciting GnRH neurons and potentially generating the GnRH surge.

  11. 17β-Estradiol Increases Persistent Na+ Current and Excitability of AVPV/PeN Kiss1 Neurons in Female Mice

    PubMed Central

    Zhang, Chunguang; Bosch, Martha A.; Qiu, Jian

    2015-01-01

    In vitro slice studies have revealed that there are significant differences in the spontaneous firing activity between anteroventral periventricular/periventricular preoptic nucleus (AVPV/PeN) and arcuate nucleus (ARC) kisspeptin (Kiss1) neurons in females. Although both populations express similar endogenous conductances, we have discovered that AVPV/PeN Kiss1 neurons express a subthreshold, persistent sodium current (INaP) that dramatically alters their firing activity. Based on whole-cell recording of Kiss1-Cre-green fluorescent protein (GFP) neurons, INaP was 4-fold greater in AVPV/PeN vs ARC Kiss1 neurons. An LH surge-producing dose of 17β-estradiol (E2) that increased Kiss1 mRNA expression in the AVPV/PeN, also augmented INaP in AVPV/PeN neurons by 2-fold. Because the activation threshold for INaP was close to the resting membrane potential (RMP) of AVPV/PeN Kiss1 neurons (−54 mV), it rendered them much more excitable and spontaneously active vs ARC Kiss1 neurons (RMP = −66 mV). Single-cell RT-PCR revealed that AVPV/PeN Kiss1 neurons expressed the requisite sodium channel α-subunit transcripts, NaV1.1, NaV1.2, and NaV1.6 and β subunits, β2 and β4. Importantly, NaV1.1α and -β2 transcripts in AVPV/PeN, but not ARC, were up-regulated 2- to 3-fold by a surge-producing dose of E2, similar to the transient calcium current channel subunit Cav3.1. The transient calcium current collaborates with INaP to generate burst firing, and selective blockade of INaP by riluzole significantly attenuated rebound burst firing and spontaneous activity. Therefore, INaP appears to play a prominent role in AVPV/PeN Kiss1 neurons to generate spontaneous, repetitive burst firing, which is required for the high-frequency-stimulated release of kisspeptin for exciting GnRH neurons and potentially generating the GnRH surge. PMID:25734516

  12. Muscarinic Receptor Subtypes Differentially Control Synaptic Input and Excitability of Cerebellum-Projecting Medial Vestibular Nucleus Neurons

    PubMed Central

    Zhu, Yun; Chen, Shao-Rui; Pan, Hui-Lin

    2016-01-01

    Neurons in the vestibular nuclei have a vital function in balance maintenance, gaze stabilization, and posture. Although muscarinic acetylcholine receptors (mAChRs) are expressed and involved in regulating vestibular function, it is unclear how individual mAChR subtypes regulate vestibular neuronal activity. In this study, we determined which specific subtypes of mAChRs control synaptic input and excitability of medial vestibular nucleus (MVN) neurons that project to the cerebellum. Cerebellum-projecting MVN neurons were labeled by a fluorescent retrograde tracer and then identified in rat brainstem slices. Quantitative PCR analysis suggested that M2 and M3 were the possible major mAChR subtypes expressed in the MVN. The mAChR agonist oxotremorine-M significantly reduced the amplitude of glutamatergic excitatory postsynaptic currents evoked by stimulation of vestibular primary afferents, and this effect was abolished by the M2-preferring antagonist AF-DX 116. However, oxotremorine-M had no effect on GABA-mediated spontaneous inhibitory postsynaptic currents of labeled MVN neurons. Furthermore, oxotremorine-M significantly increased the firing activity of labeled MVN neurons, and this effect was blocked by the M3-preferring antagonist J104129 in most neurons tested. In addition, AF-DX 116 reduced the onset latency and prolonged the excitatory effect of oxotremorine-M on the firing activity of labeled MVN neurons. Our findings suggest that M3 is the predominant postsynaptic mAChR involved in muscarinic excitation of cerebellum-projecting MVN neurons. Presynaptic M2 mAChR regulates excitatory glutamatergic input from vestibular primary afferents, which in turn influences the excitability of cerebellum-projecting MVN neurons. This new information has important therapeutic implications for treating vestibular disorders with mAChR subtype-selective agents. PMID:26823384

  13. Resveratrol attenuates early pyramidal neuron excitability impairment and death in acute rat hippocampal slices caused by oxygen-glucose deprivation

    PubMed Central

    Zhang, Huaqiu; Schools, Gary P.; Lei, Ting; Wang, Wei; Kimelberg, Harold; Zhou, Min

    2008-01-01

    Accumulating evidence indicates that the polyphenol resveratrol (trans-3, 5, 4′-trihydroxystibene, RVT) potently protects against cerebral ischemia neuronal damage due to its oxygen free radicals scavenging and antioxidant properties. However, it is unknown whether RVT can attenuate ischemia-induced early impairment of neuronal excitability. To address this question, we simulated ischemic conditions by applying oxygen-glucose deprivation (OGD) to acute rat hippocampal slices and examined the effect of RVT on OGD-induced pyramidal neuron excitability impairment using whole-cell patch clamp recording. 100 μM RVT largely inhibited the 15 min OGD-induced progressive membrane potential (Vm) depolarization and the reduction in evoked action potential frequency and amplitude in pyramidal neurons. In the parallel neuronal viability study using TO-PRO-3 iodide staining, 20 min OGD induced irreversible CA1 pyramidal neuronal death which was significantly reduced by 100 μM RVT. No similar effects were found with PQQ treatment, an antioxidant also showing potent neuroprotection in the rat rMCAO ischemia model. This suggests that antioxidant action per se, is unlikely accounting for the observed early effects of RVT. RVT also markedly reduced the frequency and amplitude of AMPA mediated spontaneous excitatory postsynaptic currents (sEPSCs) in pyramidal neurons, which is also an early consequence of OGD. RVT effects on neuronal excitability were inhibited by the large conductance potassium channel (BK channel) inhibitor paxilline. Together, these studies demonstrate that RVT attenuates OGD induced neuronal impairment occurring early in the simulated ischemia slice model by enhancing the activation of BK channel and reducing the OGD-enhanced AMPA/NMDA receptor mediated neuronal EPSCs. PMID:18495119

  14. Corticospinal excitation of presumed cervical propriospinal neurones and its reversal to inhibition in humans

    PubMed Central

    Nicolas, Guillaume; Marchand-Pauvert, Véronique; Burke, David; Pierrot-Deseilligny, Emmanuel

    2001-01-01

    This study addresses whether in human subjects indirect corticospinal excitation of upper limb motoneurones (MNs) relayed through presumed cervical propriospinal neurones (PNs) is paralleled by corticospinal activation of inhibitory projections to these premotoneurones. The responses to transcranial magnetic stimulation (TMS), whether assessed as the compound motor-evoked potential (MEP) or the peak of corticospinal excitation elicited in the post-stimulus time histograms (PSTHs) of single motor units, were conditioned by weak volleys to musculo-cutaneous, ulnar and superficial radial nerves. Afferent volleys, which hardly modified the H reflex, significantly facilitated the corticospinal response produced by weak TMS. In PSTHs, the central delay of the peripheral facilitation of the peak of corticospinal excitation in MNs located at either end of the cervical enlargement was longer the more caudal the MN pool, suggesting an interaction in premotoneurones located rostral to the tested MNs. Small increases in the strength of TMS (≈2-5 % of the maximal stimulator output) caused the facilitation to disappear and then to be reversed to inhibition. The facilitatory and inhibitory effects had the same latencies and spared the initial 0.5-1 ms of the corticospinal excitatory response. Both effects were more readily demonstrable when there was a co-contraction of the target muscle and the muscle innervated by nerve used for the conditioning stimulus. The above features suggest that the inhibition resulted from disfacilitation due to suppression of corticospinal excitation passing through the presumed premotoneuronal relay. The reversal of the facilitation to inhibition by stronger corticospinal volleys is consistent with a well-developed system of ‘feedback inhibitory interneurones’ activated by corticospinal and afferent inputs inhibiting the presumed propriospinal excitatory premotoneurones. It is argued that these findings might explain why simply stimulating the

  15. Excitation of lateral habenula neurons as a neural mechanism underlying ethanol-induced conditioned taste aversion.

    PubMed

    Tandon, Shashank; Keefe, Kristen A; Taha, Sharif A

    2017-02-15

    The lateral habenula (LHb) has been implicated in regulation of drug-seeking behaviours through aversion-mediated learning. In this study, we recorded neuronal activity in the LHb of rats during an operant task before and after ethanol-induced conditioned taste aversion (CTA) to saccharin. Ethanol-induced CTA caused significantly higher baseline firing rates in LHb neurons, as well as elevated firing rates in response to cue presentation, lever press and saccharin taste. In a separate cohort of rats, we found that bilateral LHb lesions blocked ethanol-induced CTA. Our results strongly suggest that excitation of LHb neurons is required for ethanol-induced CTA, and point towards a mechanism through which LHb firing may regulate voluntary ethanol consumption. Ethanol, like other drugs of abuse, has both rewarding and aversive properties. Previous work suggests that sensitivity to ethanol's aversive effects negatively modulates voluntary alcohol intake and thus may be important in vulnerability to developing alcohol use disorders. We previously found that rats with lesions of the lateral habenula (LHb), which is implicated in aversion-mediated learning, show accelerated escalation of voluntary ethanol consumption. To understand neural encoding in the LHb contributing to ethanol-induced aversion, we recorded neural firing in the LHb of freely behaving, water-deprived rats before and after an ethanol-induced (1.5 g kg(-1) 20% ethanol, i.p.) conditioned taste aversion (CTA) to saccharin taste. Ethanol-induced CTA strongly decreased motivation for saccharin in an operant task to obtain the tastant. Comparison of LHb neural firing before and after CTA induction revealed four main differences in firing properties. First, baseline firing after CTA induction was significantly higher. Second, firing evoked by cues signalling saccharin availability shifted from a pattern of primarily inhibition before CTA to primarily excitation after CTA induction. Third, CTA induction

  16. Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism

    PubMed Central

    Ferris, Heather A.; Perry, Rachel J.; Moreira, Gabriela V.; Shulman, Gerald I.; Horton, Jay D.; Kahn, C. Ronald

    2017-01-01

    Cholesterol is important for normal brain function. The brain synthesizes its own cholesterol, presumably in astrocytes. We have previously shown that diabetes results in decreased brain cholesterol synthesis by a reduction in sterol regulatory element-binding protein 2 (SREBP2)-regulated transcription. Here we show that coculture of control astrocytes with neurons enhances neurite outgrowth, and this is reduced with SREBP2 knockdown astrocytes. In vivo, mice with knockout of SREBP2 in astrocytes have impaired brain development and behavioral and motor defects. These mice also have altered energy balance, altered body composition, and a shift in metabolism toward carbohydrate oxidation driven by increased glucose oxidation by the brain. Thus, SREBP2-mediated cholesterol synthesis in astrocytes plays an important role in brain and neuronal development and function, and altered brain cholesterol synthesis may contribute to the interaction between metabolic diseases, such as diabetes and altered brain function. PMID:28096339

  17. Understanding mirror neurons: evidence for enhanced corticospinal excitability during the observation of transitive but not intransitive hand gestures.

    PubMed

    Enticott, Peter G; Kennedy, Hayley A; Bradshaw, John L; Rinehart, Nicole J; Fitzgerald, Paul B

    2010-07-01

    Putative measures of mirror neuron activity suggest that mirror neurons respond preferentially to biological motion, but it remains unclear whether enhanced cortical activity occurs during the observation of any behaviour, or whether that behaviour needs to be associated with a particular object or goal. Forty-three healthy adults completed a transcranial magnetic stimulation (TMS) experiment that assessed corticospinal excitability while viewing intransitive and transitive hand gestures (compared with the presentation of a static hand). Visual presentations were designed to control for motoric and stimulus properties. A significant increase in corticospinal excitability (putatively reflecting mirror neuron activation) was seen only during the observation of transitive behaviour. These findings are consistent with the notion that human hand-related mirror neurons are sensitive to object- and goal-directed behaviour, rather than biological motion per se. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

  18. Phasic excitation of ventral tegmental dopamine neurons potentiates the initiation of conditioned approach behavior: parametric and reinforcement-schedule analyses.

    PubMed

    Ilango, Anton; Kesner, Andrew J; Broker, Carl J; Wang, Dong V; Ikemoto, Satoshi

    2014-01-01

    Midbrain dopamine neurons are implicated in motivation and learning. However, it is unclear how phasic excitation of dopamine neurons, which is implicated in learning, is involved in motivation. Here we used a self-stimulation procedure to examine how mice seek for optogenetically-induced phasic excitation of dopamine neurons, with an emphasis on the temporal dimension. TH-Cre transgenic mice received adeno-associated viral vectors encoding channelrhodopsin-2 into the ventral tegmental area, resulting in selective expression of the opsin in dopamine neurons. These mice were trained to press on a lever for photo-pulse trains that phasically excited dopamine neurons. They learned to self-stimulate in a fast, constant manner, and rapidly reduced pressing during extinction. We first determined effective parameters of photo-pulse trains in self-stimulation. Lever-press rates changed as a function of the manipulation of pulse number, duration, intensity, and frequency. We then examined effects of interval and ratio schedules of reinforcement on photo-pulse train reinforcement, which was contrasted with food reinforcement. Reinforcement with food inhibited lever pressing for a few seconds, after which pressing was robustly regulated in a goal-directed manner. In contrast, phasic excitation of dopamine neurons robustly potentiated the initiation of lever pressing; however, this effect did not last more than 1 s and quickly diminished. Indeed, response rates markedly decreased when lever pressing was reinforced with inter-reinforcement interval schedules of 3 or 10 s or ratio schedules requiring multiple responses per reinforcement. Thus, phasic excitation of dopamine neurons briefly potentiates the initiation of approach behavior with apparent lack of long-term motivational regulation.

  19. Neuronal redox imbalance results in altered energy homeostasis and early postnatal lethality.

    PubMed

    Maity-Kumar, Gandhari; Thal, Dietmar R; Baumann, Bernd; Scharffetter-Kochanek, Karin; Wirth, Thomas

    2015-07-01

    Redox imbalance is believed to contribute to the development and progression of several neurodegenerative disorders. Our aim was to develop an animal model that exhibits neuron-specific oxidative stress in the CNS to study the consequences and eventually find clues regarding the pathomechanisms of oxidative insults in neuronal homeostasis. We therefore generated a novel neuron-specific superoxide dismutase 2 (SOD2)-deficient mouse by deleting exon 3 of the SOD2 gene using CamKIIα promoter-driven Cre expression. These neuron-specific SOD2 knockout (SOD2(nko)) mice, although born at normal frequencies, died at the age of 4 weeks with critical growth retardation, severe energy failure, and several neurologic phenotypes. In addition, SOD2(nko) mice exhibited severe neuronal alterations such as reactive astrogliosis, neuronal cell cycle inhibition, and induction of apoptosis. JNK activation and stabilization of p53, as a result of reactive oxygen species accumulation, are most likely the inducers of neuronal apoptosis in SOD2(nko) mice. It is remarkable that hypothalamic regulation of glucose metabolism was affected, which in turn induced necrotic brain lesions in SOD2(nko) mice. Taken together, our findings suggest that exclusive deficiency of SOD2 in neurons results in an impaired central regulation of energy homeostasis that leads to persistent hypoglycemia, hypoglycemia-related neuropathology, and an early lethality of the mutant mice. © FASEB.

  20. Chronic intermittent nicotine treatment dose-dependently alters serotonergic neurons response to citalopram in the rat.

    PubMed

    Touiki, Khalid; Rat, Pascal; Arib, Ouafa; Molimard, Robert; Chait, Abderrahman; de Beaurepaire, Renaud

    2008-05-01

    Acetylcholine nicotinic systems and serotonergic systems are known to interact. In rodents, acute and chronic nicotine treatments have consequences on several aspects of the activity of dorsal raphe serotonin (DRN 5-HT) neurons. One hypothesis is that states of functioning of DRN 5-HT neurons (firing rate and sensitivity) vary as a function of nicotine dose and mode of administration during chronic nicotine treatment. In the present study, the firing rate and sensitivity of DRN 5-HT neurons were investigated using single (0.5 and 1 mg/kg) or multiple (3 injections of 0.7 mg/kg) daily injections of nicotine over 10 days. The sensitivity of neurons was tested by the cumulative dose of the selective serotonin reuptake inhibitor citalopram necessary to inhibit their firing. The activity of neurons was tested during treatment, and then 24 and 48 h after nicotine withdrawal. The results show that, on day 10, DRN 5-HT neurons were desensitized (reduced response to citalopram) after chronic single daily injection treatments with the high dose of nicotine (1 mg/kg), while their sensitivity remained unaltered after single daily injections with the low dose (0.5 mg/kg), and after the multiple daily injection paradigm. None of the treatments altered the firing rate of DRN 5-HT neurons. The dose-dependent and time-dependent alterations of serotonergic neurons sensitivity after chronic nicotine treatments are likely the consequences of long-term adaptations of nicotinic receptors. The desensitization of DRN 5-HT neurons after chronic single daily injections of 1 mg/kg of nicotine suggests an antidepressant-like effect of chronic nicotine.

  1. A novel subtype of astrocytes expressing TRPV4 (transient receptor potential vanilloid 4) regulates neuronal excitability via release of gliotransmitters.

    PubMed

    Shibasaki, Koji; Ikenaka, Kazuhiro; Tamalu, Fuminobu; Tominaga, Makoto; Ishizaki, Yasuki

    2014-05-23

    Astrocytes play active roles in the regulation of synaptic transmission. Neuronal excitation can evoke Ca(2+) transients in astrocytes, and these Ca(2+) transients can modulate neuronal excitability. Although only a subset of astrocytes appears to communicate with neurons, the types of astrocytes that can regulate neuronal excitability are poorly characterized. We found that ∼30% of astrocytes in the brain express transient receptor potential vanilloid 4 (TRPV4), indicating that astrocytic subtypes can be classified on the basis of their expression patterns. When TRPV4(+) astrocytes are activated by ligands such as arachidonic acid, the activation propagates to neighboring astrocytes through gap junctions and by ATP release from the TRPV4(+) astrocytes. After activation, both TRPV4(+) and TRPV4(-) astrocytes release glutamate, which acts as an excitatory gliotransmitter to increase synaptic transmission through type 1 metabotropic glutamate receptor (mGluR). Our results indicate that TRPV4(+) astrocytes constitute a novel subtype of the population and are solely responsible for initiating excitatory gliotransmitter release to enhance synaptic transmission. We propose that TRPV4(+) astrocytes form a core of excitatory glial assembly in the brain and function to efficiently increase neuronal excitation in response to endogenous TRPV4 ligands. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  2. Contribution of TRPV1 to the bradykinin-evoked nociceptive behavior and excitation of cutaneous sensory neurons.

    PubMed

    Katanosaka, Kimiaki; Banik, Ratan Kumar; Giron, Rocio; Higashi, Tomohiro; Tominaga, Makoto; Mizumura, Kazue

    2008-11-01

    Bradykinin (BK), a major inflammatory mediator, excites and sensitizes nociceptor neurons/fibers, thus evoking pain and hyperalgesia. The cellular signaling mechanisms underlying these actions have remained unsolved, especially in regard to the identity of channels that mediate acute excitation. Here, to clarify the contribution of transient receptor potential vanilloid 1 (TRPV1), a heat-sensitive ion channel, to the BK-evoked nociceptor excitation and pain, we examined the behavioral and physiological BK-responses in TRPV1-deficient (KO) mice. A nocifencive behavior after BK injection (100 pmol/site) into mouse sole was reduced in TRPV1-KO mice compared with wild-type (WT). A higher dose of BK (1 nmol/site), however, induced the response in TRPV1-KO mice indistinguishable from that in the WT. BK-evoked excitation of cutaneous C-fibers in TRPV1-KO mice was comparable to that in WT. BK clearly increased intracellular calcium in cultured dorsal root ganglion (DRG) neurons of TRPV1-KO mice, although the incidence of BK-sensitive neurons was reduced. BK has been reported to activate TRPA1 indirectly, yet a considerable part of BK-sensitive DRG neurons did not respond to a TRPA1 agonist, mustard oil. These results suggest that BK-evoked nociception/nociceptor response would not be simply explained by activation of TRPV1 and A1, and that BK-evoked nociceptor excitation would be mediated by several ionic mechanisms.

  3. Alterations in Cortical Network Oscillations and Parvalbumin Neurons in Schizophrenia

    PubMed Central

    Gonzalez-Burgos, Guillermo; Cho, Raymond Y; Lewis, David A

    2015-01-01

    Cognitive deficits are a core clinical feature of schizophrenia but respond poorly to available medications. Thus, understanding the neural basis of these deficits is crucial for the development of new therapeutic interventions. The types of cognitive processes affected in schizophrenia are thought to depend on the precisely timed transmission of information in cortical regions via synchronous oscillations at gamma band frequency. Here, we review 1) data from clinical studies suggesting that induction of frontal cortex gamma oscillations during tasks that engage cognitive or complex perceptual functions is attenuated in schizophrenia, 2) findings from basic neuroscience studies highlighting the features of parvalbumin-positive (PV) interneurons that are critical for gamma oscillation production and 3) results from recent postmortem human brain studies providing additional molecular bases for PV interneuron alterations in prefrontal cortical circuitry in schizophrenia. PMID:25863358

  4. Alterations in cortical network oscillations and parvalbumin neurons in schizophrenia.

    PubMed

    Gonzalez-Burgos, Guillermo; Cho, Raymond Y; Lewis, David A

    2015-06-15

    Cognitive deficits are a core clinical feature of schizophrenia but respond poorly to available medications. Thus, understanding the neural basis of these deficits is crucial for the development of new therapeutic interventions. The types of cognitive processes affected in schizophrenia are thought to depend on the precisely timed transmission of information in cortical regions via synchronous oscillations at gamma band frequency. Here, we review 1) data from clinical studies suggesting that induction of frontal cortex gamma oscillations during tasks that engage cognitive or complex perceptual functions is attenuated in schizophrenia; 2) findings from basic neuroscience studies highlighting the features of parvalbumin-positive interneurons that are critical for gamma oscillation production; and 3) results from recent postmortem human brain studies providing additional molecular bases for parvalbumin-positive interneuron alterations in prefrontal cortical circuitry in schizophrenia. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  5. Multisensory plasticity in adulthood: cross-modal experience enhances neuronal excitability and exposes silent inputs.

    PubMed

    Yu, Liping; Rowland, Benjamin A; Xu, Jinghong; Stein, Barry E

    2013-01-01

    Multisensory superior colliculus neurons in cats were found to retain substantial plasticity to short-term, site-specific experience with cross-modal stimuli well into adulthood. Following cross-modal exposure trials, these neurons substantially increased their sensitivity to the cross-modal stimulus configuration as well as to its individual component stimuli. In many cases, the exposure experience also revealed a previously ineffective or "silent" input channel, rendering it overtly responsive. These experience-induced changes required relatively few exposure trials and could be retained for more than 1 h. However, their induction was generally restricted to experience with cross-modal stimuli. Only rarely were they induced by exposure to a modality-specific stimulus and were never induced by stimulating a previously ineffective input channel. This short-term plasticity likely provides substantial benefits to the organism in dealing with ongoing and sequential events that take place at a given location in space and may reflect the ability of multisensory superior colliculus neurons to rapidly alter their response properties to accommodate to changes in environmental challenges and event probabilities.

  6. Multisensory plasticity in adulthood: cross-modal experience enhances neuronal excitability and exposes silent inputs

    PubMed Central

    Yu, Liping; Rowland, Benjamin A.; Xu, Jinghong

    2013-01-01

    Multisensory superior colliculus neurons in cats were found to retain substantial plasticity to short-term, site-specific experience with cross-modal stimuli well into adulthood. Following cross-modal exposure trials, these neurons substantially increased their sensitivity to the cross-modal stimulus configuration as well as to its individual component stimuli. In many cases, the exposure experience also revealed a previously ineffective or “silent” input channel, rendering it overtly responsive. These experience-induced changes required relatively few exposure trials and could be retained for more than 1 h. However, their induction was generally restricted to experience with cross-modal stimuli. Only rarely were they induced by exposure to a modality-specific stimulus and were never induced by stimulating a previously ineffective input channel. This short-term plasticity likely provides substantial benefits to the organism in dealing with ongoing and sequential events that take place at a given location in space and may reflect the ability of multisensory superior colliculus neurons to rapidly alter their response properties to accommodate to changes in environmental challenges and event probabilities. PMID:23114212

  7. Reduced Hyperpolarization-Activated Current Contributes to Enhanced Intrinsic Excitability in Cultured Hippocampal Neurons from PrP−/− Mice

    PubMed Central

    Fan, Jing; Stemkowski, Patrick L.; Gandini, Maria A.; Black, Stefanie A.; Zhang, Zizhen; Souza, Ivana A.; Chen, Lina; Zamponi, Gerald W.

    2016-01-01

    Genetic ablation of cellular prion protein (PrPC) has been linked to increased neuronal excitability and synaptic activity in the hippocampus. We have previously shown that synaptic activity in hippocampi of PrP-null mice is increased due to enhanced N-methyl-D-aspartate receptor (NMDAR) function. Here, we focused on the effect of PRNP gene knock-out (KO) on intrinsic neuronal excitability, and in particular, the underlying ionic mechanism in hippocampal neurons cultured from P0 mouse pups. We found that the absence of PrPC profoundly affected the firing properties of cultured hippocampal neurons in the presence of synaptic blockers. The membrane impedance was greater in PrP-null neurons, and this difference was abolished by the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blocker ZD7288 (100 μM). HCN channel activity appeared to be functionally regulated by PrPC. The amplitude of voltage sag, a characteristic of activating HCN channel current (Ih), was decreased in null mice. Moreover, Ih peak current was reduced, along with a hyperpolarizing shift in activation gating and slower kinetics. However, neither HCN1 nor HCN2 formed a biochemical complex with PrPC. These results suggest that the absence of PrP downregulates the activity of HCN channels through activation of a cell signaling pathway rather than through direct interactions. This in turn contributes to an increase in membrane impedance to potentiate neuronal excitability. PMID:27047338

  8. Ionic Mechanisms of Neuronal Excitation by Inhibitory GABA_A Receptors

    NASA Astrophysics Data System (ADS)

    Staley, Kevin J.; Soldo, Brandi L.; Proctor, William R.

    1995-08-01

    Gamma-aminobutyric acid A (GABA_A) receptors are the principal mediators of synaptic inhibition, and yet when intensely activated, dendritic GABA_A receptors excite rather than inhibit neurons. The membrane depolarization mediated by GABA_A receptors is a result of the differential, activity-dependent collapse of the opposing concentration gradients of chloride and bicarbonate, the anions that permeate the GABA_A ionophore. Because this depolarization diminishes the voltage-dependent block of the N-methyl-D-aspartate (NMDA) receptor by magnesium, the activity-dependent depolarization mediated by GABA is sufficient to account for frequency modulation of synaptic NMDA receptor activation. Anionic gradient shifts may represent a mechanism whereby the rate and coherence of synaptic activity determine whether dendritic GABA_A receptor activation is excitatory or inhibitory.

  9. Dynamic response of ensemble neurons to pulsed optical and electrical excitation in vivo and in vitro

    NASA Astrophysics Data System (ADS)

    Akchurin, Garif G.; Seleverstov, George A.; Kamenskih, Tatyana G.; Akchurin, George G.; Bondarenko, Olga A.

    2002-07-01

    The nonlinear response of the Hodgkin-Huxley model neuron with external electrical pulsed was investigated. Dynamic response of somatic frog nerve on electrical pulsed duration was study in vitro. Transcutaneous millisecond of excitation of the ganglion cell of the human retina by electric uses is used for diagnosis, determination of the extent of optic nerve damage, and also partial restoration of visual function in patients with glaucoma, myopia and different types of optic nerve atrophy. Correlation between the threshold of phosphen formation and duration of the stimulating electric pulses was determined experimentally in normal eyes and in eyes with various pathologies. Comparison of optical and electrical scintillating frequency gives information about the dynamic processes in the normal and pathological retina.

  10. Alterations in Cortical Excitation and Inhibition in Genetic Mouse Models of Huntington’s Disease

    PubMed Central

    Cummings, Damian M.; André, Véronique M.; Uzgil, Besim O.; Gee, Steven M.; Fisher, Yvette E.; Cepeda, Carlos; Levine, Michael S.

    2009-01-01

    Previously, we identified progressive alterations in spontaneous excitatory (EPSCs) and inhibitory (IPSCs) postsynaptic currents in the striatum of the R6/2 mouse model of Huntington’s disease (HD). Medium-sized spiny neurons (MSNs) from these mice displayed a lower frequency of EPSCs and a population of cells exhibited an increased frequency of IPSCs beginning at about 40 days, a time point when the overt behavioral phenotype begins. The cortex provides the major excitatory drive to the striatum and is affected during disease progression. We examined spontaneous EPSCs and IPSCs of somatosensory cortical pyramidal neurons in layers II/III in slices from three different mouse models of HD, the R6/2, the YAC128 and the CAG140 knock-in. Results revealed that spontaneous EPSCs occurred at a higher frequency and evoked EPSCs were larger in behaviorally phenotypic mice while spontaneous IPSCs were initially increased in frequency in all models and subsequently decreased in R6/2 mice after they displayed the typical R6/2 overt behavioral phenotype. Changes in miniature IPSCs and evoked IPSC paired-pulse ratios suggested altered probability of GABA release. Also, in R6/2 mice, blockade of GABAA receptors induced complex discharges in slices and seizures in vivo at all ages. In conclusion, altered excitatory and inhibitory inputs to pyramidal neurons in the cortex in HD appear to be a prevailing deficit throughout the development of the disease. Furthermore, the differences between synaptic phenotypes in cortex and striatum are important for the development of future therapeutic approaches, which may need to be targeted early in the development of the phenotype. PMID:19692612

  11. Effects of acute and chronic administration of neurosteroid dehydroepiandrosterone sulfate on neuronal excitability in mice.

    PubMed

    Svob Strac, Dubravka; Vlainic, Josipa; Samardzic, Janko; Erhardt, Julija; Krsnik, Zeljka

    2016-01-01

    Neurosteroid dehydroepiandrosterone sulfate (DHEAS) has been associated with important brain functions, including neuronal survival, memory, and behavior, showing therapeutic potential in various neuropsychiatric and cognitive disorders. However, the antagonistic effects of DHEAS on γ-amino-butyric acidA receptors and its facilitatory action on glutamatergic neurotransmission might lead to enhanced brain excitability and seizures and thus limit DHEAS therapeutic applications. The aim of this study was to investigate possible age and sex differences in the neuronal excitability of the mice following acute and chronic DHEAS administration. DHEAS was administered intraperitoneally in male and female adult and old mice either acutely or repeatedly once daily for 4 weeks in a 10 mg/kg dose. To investigate the potential proconvulsant properties of DHEAS, we studied the effects of acute and chronic DHEAS treatment on picrotoxin-, pentylentetrazole-, and N-methyl-D-aspartate-induced seizures in mice. The effects of acute and chronic DHEAS administration on the locomotor activity, motor coordination, and body weight of the mice were also studied. We also investigated the effects of DHEAS treatment on [(3)H]flunitrazepam binding to the mouse brain membranes. DHEAS did not modify the locomotor activity, motor coordination, body weight, and brain [(3)H]flunitrazepam binding of male and female mice. The results failed to demonstrate significant effects of single- and long-term DHEAS treatment on the convulsive susceptibility in both adult and aged mice of both sexes. However, small but significant changes regarding sex differences in the susceptibility to seizures were observed following DHEAS administration to mice. Although our findings suggest that DHEAS treatment might be safe for various potential therapeutic applications in adult as well as in old age, they also support subtle interaction of DHEAS with male and female hormonal status, which may underline observed sex

  12. MAPT Genetic Variation and Neuronal Maturity Alter Isoform Expression Affecting Axonal Transport in iPSC-Derived Dopamine Neurons.

    PubMed

    Beevers, Joel E; Lai, Mang Ching; Collins, Emma; Booth, Heather D E; Zambon, Federico; Parkkinen, Laura; Vowles, Jane; Cowley, Sally A; Wade-Martins, Richard; Caffrey, Tara M

    2017-08-08

    The H1 haplotype of the microtubule-associated protein tau (MAPT) locus is genetically associated with neurodegenerative diseases, including Parkinson's disease (PD), and affects gene expression and splicing. However, the functional impact on neurons of such expression differences has yet to be fully elucidated. Here, we employ extended maturation phases during differentiation of induced pluripotent stem cells (iPSCs) into mature dopaminergic neuronal cultures to obtain cultures expressing all six adult tau protein isoforms. After 6 months of maturation, levels of exon 3+ and exon 10+ transcripts approach those of adult brain. Mature dopaminergic neuronal cultures display haplotype differences in expression, with H1 expressing 22% higher levels of MAPT transcripts than H2 and H2 expressing 2-fold greater exon 3+ transcripts than H1. Furthermore, knocking down adult tau protein variants alters axonal transport velocities in mature iPSC-derived dopaminergic neuronal cultures. This work links haplotype-specific MAPT expression with a biologically functional outcome relevant for PD. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  13. Autaptic muscarinic self-excitation and nitrergic self-inhibition in neurons initiating Aplysia feeding are revealed when the neurons are cultured in isolation.

    PubMed

    Saada-Madar, Ravit; Miller, Nimrod; Susswein, Abraham J

    2012-08-01

    Properties of a neuron may arise via endogenous mechanisms, or via interactions with other neurons. Culturing a neuron in isolation is a useful tool to distinguish between endogenous and circuit-derived properties. We identified two remarkable functional features of pattern initiator neurons B31/B32 in Aplysia when these neurons were cultured in isolation. These features were also present in situ, but were less prominent, and would have been missed had they not been observed first in the isolated cultured neurons. The properties are likely to be present in neurons of higher animals, but have not yet been observed. One feature was autaptic muscarinic self-excitation that contributes to the neuron's plateau potential, by which it initiates behavior. The other feature was the release of nitric oxide (NO) in the absence of spiking, which causes self-inhibition at rest. The nitrergic modulation of B31/B32 is likely to contribute to the control of feeding by dietary changes in the concentration of L: -arginine, the precursor from which NO is synthesized.

  14. Mechanisms regulating neuronal excitability and seizure development following mTOR pathway hyperactivation

    PubMed Central

    LaSarge, Candi L.; Danzer, Steve C.

    2014-01-01

    The phosphatidylinositol-3-kinase/phosphatase and tensin homolog (PTEN)-mammalian target of rapamycin (mTOR) pathway regulates a variety of neuronal functions, including cell proliferation, survival, growth, and plasticity. Dysregulation of the pathway is implicated in the development of both genetic and acquired epilepsies. Indeed, several causal mutations have been identified in patients with epilepsy, the most prominent of these being mutations in PTEN and tuberous sclerosis complexes 1 and 2 (TSC1, TSC2). These genes act as negative regulators of mTOR signaling, and mutations lead to hyperactivation of the pathway. Animal models deleting PTEN, TSC1, and TSC2 consistently produce epilepsy phenotypes, demonstrating that increased mTOR signaling can provoke neuronal hyperexcitability. Given the broad range of changes induced by altered mTOR signaling, however, the mechanisms underlying seizure development in these animals remain uncertain. In transgenic mice, cell populations with hyperactive mTOR have many structural abnormalities that support recurrent circuit formation, including somatic and dendritic hypertrophy, aberrant basal dendrites, and enlargement of axon tracts. At the functional level, mTOR hyperactivation is commonly, but not always, associated with enhanced synaptic transmission and plasticity. Moreover, these populations of abnormal neurons can affect the larger network, inducing secondary changes that may explain paradoxical findings reported between cell and network functioning in different models or at different developmental time points. Here, we review the animal literature examining the link between mTOR hyperactivation and epileptogenesis, emphasizing the impact of enhanced mTOR signaling on neuronal form and function. PMID:24672426

  15. Altered Astrocyte-Neuron Interactions and Epileptogenesis in Tuberous Sclerosis Complex Disorder

    DTIC Science & Technology

    2014-06-01

    pathogenesis of epilepsy in TS by producing neuronal over-excitability, and that this is in part due to loss of astrocyte’s normal role in normal GABA...indicates an elevanted presynaptic release probability. 7 An alternative mechanism that may explain how epilepsy develops in our...mossy fiber sprouting in the knockout mice, which has been reported to be correlated with epilepsy (Figure7). These data suggest that granule cells may

  16. Degeneration of Dopaminergic Neurons Due to Metabolic Alterations and Parkinson’s Disease

    PubMed Central

    Song, Juhyun; Kim, Jongpil

    2016-01-01

    The rates of metabolic diseases, such as type 2 diabetes mellitus (T2DM), obesity, and cardiovascular disease (CVD), markedly increase with age. In recent years, studies have reported an association between metabolic changes and various pathophysiological mechanisms in the central nervous system (CNS) in patients with metabolic diseases. Oxidative stress and hyperglycemia in metabolic diseases lead to adverse neurophysiological phenomena, including neuronal loss, synaptic dysfunction, and improper insulin signaling, resulting in Parkinson’s disease (PD). In addition, several lines of evidence suggest that alterations of CNS environments by metabolic changes influence the dopamine neuronal loss, eventually affecting the pathogenesis of PD. Thus, we reviewed recent findings relating to degeneration of dopaminergic neurons during metabolic diseases. We highlight the fact that using a metabolic approach to manipulate degeneration of dopaminergic neurons can serve as a therapeutic strategy to attenuate pathology of PD. PMID:27065205

  17. Corticotropin releasing factor excites neurons of posterior hypothalamic nucleus to produce tachycardia in rats.

    PubMed

    Gao, He-Ren; Zhuang, Qian-Xing; Li, Bin; Li, Hong-Zhao; Chen, Zhang-Peng; Wang, Jian-Jun; Zhu, Jing-Ning

    2016-02-01

    Corticotropin releasing factor (CRF), a peptide hormone involved in the stress response, holds a key position in cardiovascular regulation. Here, we report that the central effect of CRF on cardiovascular activities is mediated by the posterior hypothalamic nucleus (PH), an important structure responsible for stress-induced cardiovascular changes. Our present results demonstrate that CRF directly excites PH neurons via two CRF receptors, CRFR1 and CRFR2, and consequently increases heart rate (HR) rather than the mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA). Bilateral vagotomy does not influence the tachycardia response to microinjection of CRF into the PH, while β adrenergic receptor antagonist propranolol almost totally abolishes the tachycardia. Furthermore, microinjecting CRF into the PH primarily increases neuronal activity of the rostral ventrolateral medulla (RVLM) and rostral ventromedial medulla (RVMM), but does not influence that of the dorsal motor nucleus of the vagus nerve (DMNV). These findings suggest that the PH is a critical target for central CRF system in regulation of cardiac activity and the PH-RVLM/RVMM-cardiac sympathetic nerve pathways, rather than PH-DMNV-vagus pathway, may contribute to the CRF-induced tachycardia.

  18. Corticotropin releasing factor excites neurons of posterior hypothalamic nucleus to produce tachycardia in rats

    PubMed Central

    Gao, He-Ren; Zhuang, Qian-Xing; Li, Bin; Li, Hong-Zhao; Chen, Zhang-Peng; Wang, Jian-Jun; Zhu, Jing-Ning

    2016-01-01

    Corticotropin releasing factor (CRF), a peptide hormone involved in the stress response, holds a key position in cardiovascular regulation. Here, we report that the central effect of CRF on cardiovascular activities is mediated by the posterior hypothalamic nucleus (PH), an important structure responsible for stress-induced cardiovascular changes. Our present results demonstrate that CRF directly excites PH neurons via two CRF receptors, CRFR1 and CRFR2, and consequently increases heart rate (HR) rather than the mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA). Bilateral vagotomy does not influence the tachycardia response to microinjection of CRF into the PH, while β adrenergic receptor antagonist propranolol almost totally abolishes the tachycardia. Furthermore, microinjecting CRF into the PH primarily increases neuronal activity of the rostral ventrolateral medulla (RVLM) and rostral ventromedial medulla (RVMM), but does not influence that of the dorsal motor nucleus of the vagus nerve (DMNV). These findings suggest that the PH is a critical target for central CRF system in regulation of cardiac activity and the PH-RVLM/RVMM-cardiac sympathetic nerve pathways, rather than PH-DMNV-vagus pathway, may contribute to the CRF-induced tachycardia. PMID:26831220

  19. Adiponectin regulates contextual fear extinction and intrinsic excitability of dentate gyrus granule neurons through AdipoR2 receptors

    PubMed Central

    Zhang, D; Wang, X; Wang, B; Garza, J C; Fang, X; Wang, J; Scherer, P E; Brenner, R; Zhang, W; Lu, X-Y

    2017-01-01

    Post-traumatic stress disorder (PTSD) is characterized by exaggerated fear expression and impaired fear extinction. The underlying molecular and cellular mechanisms of PTSD are largely unknown. The current pharmacological and non-pharmacological treatments for PTSD are either ineffective or temporary with high relapse rates. Here we report that adiponectin-deficient mice exhibited normal contextual fear conditioning but displayed slower extinction learning. Infusions of adiponectin into the dentate gyrus (DG) of the hippocampus in fear-conditioned mice facilitated extinction of contextual fear. Whole-cell patch-clamp recordings in brain slices revealed that intrinsic excitability of DG granule neurons was enhanced by adiponectin deficiency and suppressed after treatment with the adiponectin mimetic AdipoRon, which were associated with increased input resistance and hyperpolarized resting membrane potential, respectively. Moreover, deletion of AdipoR2, but not AdipoR1 in the DG, resulted in augmented fear expression and reduced extinction, accompanied by intrinsic hyperexcitability of DG granule neurons. Adiponectin and AdipoRon failed to induce facilitation of fear extinction and elicit inhibition of intrinsic excitability of DG neurons in AdipoR2 knockout mice. These results indicated that adiponectin action via AdipoR2 was both necessary and sufficient for extinction of contextual fear and intrinsic excitability of DG granule neurons, implying that enhancing or dampening DG neuronal excitability may cause resistance to or facilitation of extinction. Therefore, our findings provide a functional link between adiponectin/AdipoR2 activation, DG neuronal excitability and contextual fear extinction, and suggest that targeting adiponectin/AdipoR2 may be used to strengthen extinction-based exposure therapies for PTSD. PMID:27137743

  20. Alterations of motor cortical excitability and anatomy in Unverricht-Lundborg disease.

    PubMed

    Danner, Nils; Julkunen, Petro; Hyppönen, Jelena; Niskanen, Eini; Säisänen, Laura; Könönen, Mervi; Koskenkorva, Päivi; Vanninen, Ritva; Kälviäinen, Reetta; Mervaala, Esa

    2013-11-01

    Unverricht-Lundborg disease is the most common form of progressive myoclonus epilepsies. In addition to generalized seizures, it is characterized by myoclonus, which usually is the most disabling feature of the disease. Classically, the myoclonus has been attributed to increased excitability of the primary motor cortex. However, inhibitory cortical phenomena have also been described along with anatomical alterations. We aimed to characterize the relationship between the excitability and anatomy of the motor cortex and their association with the severity of the clinical symptoms. Seventy genetically verified patients were compared with forty healthy controls. The symptoms were evaluated with the Unified Myoclonus Rating Scale. Navigated transcranial magnetic stimulation was applied to characterize the excitability of the primary motor cortex by determining the motor thresholds and cortical silent periods. In addition, the induced cortical electric fields were estimated using individual scalp-to-cortex distances measured from MRIs. A cortical thickness analysis was performed to elucidate possible disease-related anatomical alterations. The motor thresholds, cortical electric fields, and silent periods were significantly increased in the patients (P < 0.01). The silent periods correlated with the myoclonus scores (r = 0.48 to r = 0.49, P < 0.001). The scalp-to-cortex distance increased significantly with disease duration (r = 0.56, P < 0.001) and correlated inversely with cortical thickness. The results may reflect the refractory nature of the myoclonus and indicate a possible reactive cortical inhibitory mechanism to the underlying disease process. This is the largest clinical series on Unverricht-Lundborg disease and the first study describing parallel pathophysiological and structural alterations associated with the severity of the symptoms.

  1. Nanotechnologies for stimulating and recording excitable events in neurons and cardiomyocytes.

    PubMed

    Silva, Gabriel A; Khraiche, Massoud L

    2013-06-01

    Nanotechnologies are engineered materials and devices that have a functional organization in at least one dimension on the nanometer scale, ranging from a few to about 100 nanometers. Functionally, nanotechnologies can display physical, chemical, and engineering properties that go beyond the component building block molecules or structures that make them up. Given such properties and the physical scale involved, these technologies are capable of interacting and interfacing with target cells and tissues in unique ways. One particular emerging application of wide spread interest is the development of nanotechnologies for stimulating and recording excitable cells such as neurons and cardiomyocytes. Such approaches offer the possibility of achieving high density stimulation and recording at sub-cellular resolutions in large populations of cells. This would provide a scale of electrophysiological interactions with excitable cells beyond anything achievable by current existing methods. In this review we introduce the reader to the key concepts and methods associated with nanotechnology and nanoengineering, and discuss the work of some of the key groups developing nanoscale stimulation and recording technologies.

  2. Diabetic polyneuropathy, sensory neurons, nuclear structure and spliceosome alterations: a role for CWC22.

    PubMed

    Kobayashi, Masaki; Chandrasekhar, Ambika; Cheng, Chu; Martinez, Jose A; Ng, Hilarie; de la Hoz, Cristiane; Zochodne, Douglas W

    2017-03-01

    Unique deficits in the function of adult sensory neurons as part of their early neurodegeneration might account for progressive polyneuropathy during chronic diabetes mellitus. Here, we provide structural and functional evidence for aberrant pre-mRNA splicing in a chronic type 1 model of experimental diabetic polyneuropathy (DPN). Cajal bodies (CBs), unique nuclear substructures involved in RNA splicing, increased in number in diabetic sensory neurons, but their expected colocalization with survival motor neuron (SMN) proteins was reduced - a mislocalization described in motor neurons of spinal muscular atrophy. Small nuclear ribonucleoprotein particles (snRNPs), also participants in the spliceosome, had abnormal multiple nuclear foci unassociated with CBs, and their associated snRNAs were reduced. CWC22, a key spliceosome protein, was aberrantly upregulated in diabetic dorsal root ganglia (DRG), and impaired neuronal function. CWC22 attenuated sensory neuron plasticity, with knockdown in vitro enhancing their neurite outgrowth. Further, axonal delivery of CWC22 siRNA unilaterally to locally knock down the aberrant protein in diabetic nerves improved aspects of sensory function in diabetic mice. Collectively, our findings identify subtle but significant alterations in spliceosome structure and function, including dysregulated CBs and CWC22 overexpression, in diabetic sensory neurons that offer new ideas regarding diabetic sensory neurodegeneration in polyneuropathy.

  3. Diabetic polyneuropathy, sensory neurons, nuclear structure and spliceosome alterations: a role for CWC22

    PubMed Central

    Kobayashi, Masaki; Chandrasekhar, Ambika; Cheng, Chu; Martinez, Jose A.; Ng, Hilarie; de la Hoz, Cristiane

    2017-01-01

    ABSTRACT Unique deficits in the function of adult sensory neurons as part of their early neurodegeneration might account for progressive polyneuropathy during chronic diabetes mellitus. Here, we provide structural and functional evidence for aberrant pre-mRNA splicing in a chronic type 1 model of experimental diabetic polyneuropathy (DPN). Cajal bodies (CBs), unique nuclear substructures involved in RNA splicing, increased in number in diabetic sensory neurons, but their expected colocalization with survival motor neuron (SMN) proteins was reduced – a mislocalization described in motor neurons of spinal muscular atrophy. Small nuclear ribonucleoprotein particles (snRNPs), also participants in the spliceosome, had abnormal multiple nuclear foci unassociated with CBs, and their associated snRNAs were reduced. CWC22, a key spliceosome protein, was aberrantly upregulated in diabetic dorsal root ganglia (DRG), and impaired neuronal function. CWC22 attenuated sensory neuron plasticity, with knockdown in vitro enhancing their neurite outgrowth. Further, axonal delivery of CWC22 siRNA unilaterally to locally knock down the aberrant protein in diabetic nerves improved aspects of sensory function in diabetic mice. Collectively, our findings identify subtle but significant alterations in spliceosome structure and function, including dysregulated CBs and CWC22 overexpression, in diabetic sensory neurons that offer new ideas regarding diabetic sensory neurodegeneration in polyneuropathy. PMID:28250049

  4. Nicotine Enhances Excitability of Medial Habenular Neurons via Facilitation of Neurokinin Signaling

    PubMed Central

    Dao, Dang Q.; Perez, Erika E.; Teng, Yanfen; Dani, John A.

    2014-01-01

    The medial habenula (MHb) densely expresses nicotinic acetylcholine receptors (nAChRs) and participates in nicotine-related behaviors such as nicotine withdrawal and regulating nicotine intake. Although specific nAChR subunits are identified as being involved in withdrawal behavior, the cellular mechanisms through which nicotine acts to cause this aversive experience is unclear. Here, we demonstrate an interaction between the nicotinic and neurokinin signaling systems that may form the basis for some symptoms experienced during nicotine withdrawal. Using patch-clamp electrophysiology in mouse brain slices, we show that nicotine (1 μm) increases intrinsic excitability in MHb neurons. This nicotine-induced phenomenon requires α5-containing nAChRs and depends on intact neurokinin signaling. The effect is blocked by preincubation with neurokinin 1 (NK1; L-732138, 10 μm) and NK3 (SB222200, 2 μm) antagonists and mimicked by NK1 (substance P, 100 nm) and NK3 (neurokinin B [NKB], 100 nm) agonists. Microinjections (1 μl) of L-732138 (50 nm) and SB222200 (100 nm) into the MHb induces withdrawal behavior in chronic nicotine-treated (8.4 mg/kg/d, 2 weeks) mice. Conversely, withdrawal behavior is absent with analogous microinjections into the lateral habenula of nicotine-treated mice or in mice chronically treated with a vehicle solution. Further, chronic nicotine reduces nicotine's acute modulation of intrinsic excitability while sparing modulation by NKB. Our work elucidates the interplay between two neuromodulatory signaling systems in the brain through which nicotine acts to influence intrinsic excitability. More importantly, we document a neuroadaptation of this mechanism to chronic nicotine exposure and implicate these mechanisms collectively in the emergence of nicotine withdrawal behavior. PMID:24647947

  5. Hypocretin/Orexin excites hypocretin neurons via a local glutamate neuron-A potential mechanism for orchestrating the hypothalamic arousal system.

    PubMed

    Li, Ying; Gao, Xiao Bing; Sakurai, Takeshi; van den Pol, Anthony N

    2002-12-19

    Neurons that release hypocretin/orexin modulate sleep, arousal, and energy homeostasis; the absence of hypocretin results in narcolepsy. Here we present data on the physiological characteristics of these cells, identified with GFP in transgenic mouse brain slices. Hypocretin-1 and -2 depolarized hypocretin neurons by 15mV and evoked an increase in spike frequency (+366% from a 1-3 Hz baseline). The mechanism for this appears to be hypocretin-mediated excitation of local glutamatergic neurons that regulate hypocretin neuron activity, in part by presynaptic facilitation of glutamate release. This represents a possible mechanism for orchestrating the output of the diffuse hypothalamic arousal system. No direct effect of hypocretin on membrane properties of hypocretin cells was detected. Norepinephrine and serotonin, transmitters of other arousal systems, decreased spike frequency and evoked outward currents, whereas acetylcholine and histamine had little effect.

  6. Regulation of intrinsic excitability in hippocampal neurons by activity-dependent modulation of the Kv2.1 potassium channel

    PubMed Central

    Mohapatra, Durga P.; Misonou, Hiroaki; Pan, Sheng-Jun; Held, Joshua E.; Surmeier, D. James; Trimmer, James S.

    2009-01-01

    Kv2.1 is the prominent somatodendritic sustained or delayed rectifier voltage-gated potassium (Kv) channel in mammalian central neurons, and is a target for activity-dependent modulation via calcineurin-dependent dephosphorylation. Using hanatoxin-mediated block of Kv2.1 we show that, in cultured rat hippocampal neurons, glutamate stimulation leads to significant hyperpolarizing shifts in the voltage-dependent activation and inactivation gating properties of the Kv2.1-component of delayed rectifier K+ (IK) currents. In computer models of hippocampal neurons, these glutamate-stimulated shifts in the gating of the Kv2.1-component of IK lead to a dramatic suppression of action potential firing frequency. Current-clamp experiments in cultured rat hippocampal neurons showed glutamate-stimulation induced a similar suppression of neuronal firing frequency. Membrane depolarization also resulted in similar hyperpolarizing shifts in the voltage-dependent gating properties of neuronal IK currents, and suppression of neuronal firing. The glutamate-induced effects on neuronal firing were eliminated by hanatoxin, but not by dendrotoxin-K, a blocker of Kv1.1-containing channels. These studies together demonstrate a specific contribution of modulation of Kv2.1 channels in the activity-dependent regulation of intrinsic neuronal excitability. PMID:19276663

  7. Imbalanced K+ and Ca2+ subthreshold interactions contribute to increased hypothalamic presympathetic neuronal excitability in hypertensive rats

    PubMed Central

    Sonner, P M; Lee, S; Ryu, P D; Lee, S Y; Stern, J E

    2011-01-01

    We investigated here whether an opposing interplay between the subthreshold currents A-type potassium (IA) and T-type calcium (IT) influences membrane excitability in presympathetic neurones of the hypothalamic paraventricular nucleus (PVN) that innervate the rostral ventrolateral medulla (RVLM). Moreover, we assessed whether a shift in the balance between these two subthreshold currents contributed to increased neuronal activity in hypertension. To this end, we obtained simultaneous electrophysiological recordings, confocal Ca2+ imaging, and single-cell RT-PCR samples from identified PVN-RVLM neurones in sham and renovascular hypertensive rats. Our results indicate that IA and IT, displaying overlapping voltage-dependent and kinetic properties, are present in PVN-RVLM neurones. We found that the relative predominance of each current at hyperpolarized membrane potentials dictates whether PVN-RVLN neurones express a low-threshold spike (LTS) or a transient outward rectification (TOR). Moreover, we report the IA/IT balance to be correlated with the relative expression of Kv4.3 and Cav3.1 subunit mRNA within individual neurones. Pharmacological blockade of IA resulted in an enhanced IT-mediated LTS, as well as LTS-mediated somatodendritic Ca2+ transients. In hypertensive rats, we found a shift in the IT/IA balance, towards an IT predominance, due in part to a diminished Kv4.3 and enhanced Cav3.1 mRNA subunits expression. The imbalanced IT/IA relationship resulted in enhanced LTS, LTS-mediated somatodendritic Ca2+ transients, and increased firing activity in hypertensive rats. Taken together, our results support that a balanced IT/IA interaction influences membrane excitability and Ca2+ dynamics in PVN-RVLM neurones. Moreover, an imbalanced relationship favouring IT results in enhanced neuronal excitability and firing discharge in hypertensive rats, constituting thus a likely mechanism contributing to the characteristic sympathoexcitation observed in this disease. PMID

  8. Severely impaired learning and altered neuronal morphology in mice lacking NMDA receptors in medium spiny neurons.

    PubMed

    Beutler, Lisa R; Eldred, Kiara C; Quintana, Albert; Keene, C Dirk; Rose, Shannon E; Postupna, Nadia; Montine, Thomas J; Palmiter, Richard D

    2011-01-01

    The striatum is composed predominantly of medium spiny neurons (MSNs) that integrate excitatory, glutamatergic inputs from the cortex and thalamus, and modulatory dopaminergic inputs from the ventral midbrain to influence behavior. Glutamatergic activation of AMPA, NMDA, and metabotropic receptors on MSNs is important for striatal development and function, but the roles of each of these receptor classes remain incompletely understood. Signaling through NMDA-type glutamate receptors (NMDARs) in the striatum has been implicated in various motor and appetitive learning paradigms. In addition, signaling through NMDARs influences neuronal morphology, which could underlie their role in mediating learned behaviors. To study the role of NMDARs on MSNs in learning and in morphological development, we generated mice lacking the essential NR1 subunit, encoded by the Grin1 gene, selectively in MSNs. Although these knockout mice appear normal and display normal 24-hour locomotion, they have severe deficits in motor learning, operant conditioning and active avoidance. In addition, the MSNs from these knockout mice have smaller cell bodies and decreased dendritic length compared to littermate controls. We conclude that NMDAR signaling in MSNs is critical for normal MSN morphology and many forms of learning.

  9. Resveratrol Attenuates Aβ-Induced Early Hippocampal Neuron Excitability Impairment via Recovery of Function of Potassium Channels.

    PubMed

    Yin, Hongqiang; Wang, Hui; Zhang, Hui; Gao, Na; Zhang, Tao; Yang, Zhuo

    2017-03-30

    Alzheimer's disease (AD) is an age-related neurodegenerative disease. Amyloid-β (Aβ) is not only the morphological hallmark but also the initiator of the pathology process of AD. As a natural compound found in grapes, resveratrol shows a protective effect on the pathophysiology of AD, but the underlying mechanism is not very clear. This study was to investigate whether resveratrol could attenuate Aβ-induced early impairment in hippocampal neuron excitability and the underlying mechanism. The excitability and voltage-gated potassium currents were examined in rat hippocampal CA1 pyramidal neurons by using whole-cell patch-clamp technique. It was found that Aβ25-35 increased the excitability of neurons. Resveratrol could reverse the Aβ25-35-induced increase in the frequency of repetitive firing and the spike half-width of action potential (AP). Moreover, resveratrol can attenuate Aβ25-35-induced decreases in transient potassium channel (I A ) and delay rectifier potassium channel (I K(DR)) of neurons. It was also found that resveratrol could decline the increase of protein kinase A (PKA) and inhibit the activation of PI3K/Akt signaling pathway induced by Aβ25-35. The results suggest that resveratrol alleviates Aβ25-35-induced dysfunction in hippocampal CA1 pyramidal neurons via recovery of the function of I A and I K(DR) by inhibiting the increase of PKA and the activation of PI3K/Akt signaling pathway.

  10. ACTH TREATMENT OF INFANTILE SPASMS: MECHANISMS OF ITS EFFECTS IN MODULATION OF NEURONAL EXCITABILITY

    PubMed Central

    Brunson, K. L.; Avishai-Eliner, S.; Baram, T. Z.

    2011-01-01

    receptors in the mechanisms by which ACTH exerts this effect. Thus, ACTH may reduce neuronal excitability in IS by two mechanisms of action: (1) by inducing steroid release and (2) by a direct, steroid-independent action on melanocortin receptors. These combined effects may explain the robust established clinical effects of ACTH in the therapy of IS. PMID:12040892

  11. Alterations of orexinergic and melanin-concentrating hormone neurons in experimental sleeping sickness.

    PubMed

    Palomba, M; Seke-Etet, P F; Laperchia, C; Tiberio, L; Xu, Y-Z; Colavito, V; Grassi-Zucconi, G; Bentivoglio, M

    2015-04-02

    neurons in the pathogenesis of sleep/wake alterations in the disease and to their vulnerability to inflammatory signaling.

  12. Alterations in neuronal activity in basal ganglia-thalamocortical circuits in the parkinsonian state

    PubMed Central

    Galvan, Adriana; Devergnas, Annaelle; Wichmann, Thomas

    2015-01-01

    In patients with Parkinson’s disease and in animal models of this disorder, neurons in the basal ganglia and related regions in thalamus and cortex show changes that can be recorded by using electrophysiologic single-cell recording techniques, including altered firing rates and patterns, pathologic oscillatory activity and increased inter-neuronal synchronization. In addition, changes in synaptic potentials or in the joint spiking activities of populations of neurons can be monitored as alterations in local field potentials (LFPs), electroencephalograms (EEGs) or electrocorticograms (ECoGs). Most of the mentioned electrophysiologic changes are probably related to the degeneration of diencephalic dopaminergic neurons, leading to dopamine loss in the striatum and other basal ganglia nuclei, although degeneration of non-dopaminergic cell groups may also have a role. The altered electrical activity of the basal ganglia and associated nuclei may contribute to some of the motor signs of the disease. We here review the current knowledge of the electrophysiologic changes at the single cell level, the level of local populations of neural elements, and the level of the entire basal ganglia-thalamocortical network in parkinsonism, and discuss the possible use of this information to optimize treatment approaches to Parkinson’s disease, such as deep brain stimulation (DBS) therapy. PMID:25698937

  13. Activation of CRH receptor type 1 expressed on glutamatergic neurons increases excitability of CA1 pyramidal neurons by the modulation of voltage-gated ion channels.

    PubMed

    Kratzer, Stephan; Mattusch, Corinna; Metzger, Michael W; Dedic, Nina; Noll-Hussong, Michael; Kafitz, Karl W; Eder, Matthias; Deussing, Jan M; Holsboer, Florian; Kochs, Eberhard; Rammes, Gerhard

    2013-01-01

    Corticotropin-releasing hormone (CRH) plays an important role in a substantial number of patients with stress-related mental disorders, such as anxiety disorders and depression. CRH has been shown to increase neuronal excitability in the hippocampus, but the underlying mechanisms are poorly understood. The effects of CRH on neuronal excitability were investigated in acute hippocampal brain slices. Population spikes (PS) and field excitatory postsynaptic potentials (fEPSP) were evoked by stimulating Schaffer-collaterals and recorded simultaneously from the somatic and dendritic region of CA1 pyramidal neurons. CRH was found to increase PS amplitudes (mean ± Standard error of the mean; 231.8 ± 31.2% of control; n = 10) while neither affecting fEPSPs (104.3 ± 4.2%; n = 10) nor long-term potentiation (LTP). However, when Schaffer-collaterals were excited via action potentials (APs) generated by stimulation of CA3 pyramidal neurons, CRH increased fEPSP amplitudes (119.8 ± 3.6%; n = 8) and the magnitude of LTP in the CA1 region. Experiments in slices from transgenic mice revealed that the effect on PS amplitude is mediated exclusively by CRH receptor 1 (CRHR1) expressed on glutamatergic neurons. The effects of CRH on PS were dependent on phosphatase-2B, L- and T-type calcium channels and voltage-gated potassium channels but independent on intracellular Ca(2+)-elevation. In patch-clamp experiments, CRH increased the frequency and decay times of APs and decreased currents through A-type and delayed-rectifier potassium channels. These results suggest that CRH does not affect synaptic transmission per se, but modulates voltage-gated ion currents important for the generation of APs and hence elevates by this route overall neuronal activity.

  14. Activation of CRH receptor type 1 expressed on glutamatergic neurons increases excitability of CA1 pyramidal neurons by the modulation of voltage-gated ion channels

    PubMed Central

    Kratzer, Stephan; Mattusch, Corinna; Metzger, Michael W.; Dedic, Nina; Noll-Hussong, Michael; Kafitz, Karl W.; Eder, Matthias; Deussing, Jan M.; Holsboer, Florian; Kochs, Eberhard; Rammes, Gerhard

    2013-01-01

    Corticotropin-releasing hormone (CRH) plays an important role in a substantial number of patients with stress-related mental disorders, such as anxiety disorders and depression. CRH has been shown to increase neuronal excitability in the hippocampus, but the underlying mechanisms are poorly understood. The effects of CRH on neuronal excitability were investigated in acute hippocampal brain slices. Population spikes (PS) and field excitatory postsynaptic potentials (fEPSP) were evoked by stimulating Schaffer-collaterals and recorded simultaneously from the somatic and dendritic region of CA1 pyramidal neurons. CRH was found to increase PS amplitudes (mean ± Standard error of the mean; 231.8 ± 31.2% of control; n = 10) while neither affecting fEPSPs (104.3 ± 4.2%; n = 10) nor long-term potentiation (LTP). However, when Schaffer-collaterals were excited via action potentials (APs) generated by stimulation of CA3 pyramidal neurons, CRH increased fEPSP amplitudes (119.8 ± 3.6%; n = 8) and the magnitude of LTP in the CA1 region. Experiments in slices from transgenic mice revealed that the effect on PS amplitude is mediated exclusively by CRH receptor 1 (CRHR1) expressed on glutamatergic neurons. The effects of CRH on PS were dependent on phosphatase-2B, L- and T-type calcium channels and voltage-gated potassium channels but independent on intracellular Ca2+-elevation. In patch-clamp experiments, CRH increased the frequency and decay times of APs and decreased currents through A-type and delayed-rectifier potassium channels. These results suggest that CRH does not affect synaptic transmission per se, but modulates voltage-gated ion currents important for the generation of APs and hence elevates by this route overall neuronal activity. PMID:23882180

  15. Muscarinic receptor subtypes differentially control synaptic input and excitability of cerebellum-projecting medial vestibular nucleus neurons.

    PubMed

    Zhu, Yun; Chen, Shao-Rui; Pan, Hui-Lin

    2016-04-01

    Neurons in the vestibular nuclei have a vital function in balance maintenance, gaze stabilization, and posture. Although muscarinic acetylcholine receptors (mAChRs) are expressed and involved in regulating vestibular function, it remains unclear how individual mAChR subtypes regulate vestibular neuronal activity. In this study, we determined which specific subtypes of mAChRs control synaptic input and excitability of medial vestibular nucleus (MVN) neurons that project to the cerebellum. Cerebellum-projecting MVN neurons were labeled by a fluorescent retrograde tracer and then identified in rat brainstem slices. Quantitative PCR analysis suggested that M2 and M3 were the possible major mAChR subtypes expressed in the MVN. The mAChR agonist oxotremorine-M significantly reduced the amplitude of glutamatergic excitatory post-synaptic currents evoked by stimulation of vestibular primary afferents, and this effect was abolished by the M2-preferring antagonist AF-DX 116. However, oxotremorine-M had no effect on GABA-mediated spontaneous inhibitory post-synaptic currents of labeled MVN neurons. Furthermore, oxotremorine-M significantly increased the firing activity of labeled MVN neurons, and this effect was blocked by the M3-preferring antagonist J104129 in most neurons tested. In addition, AF-DX 116 reduced the onset latency and prolonged the excitatory effect of oxotremorine-M on the firing activity of labeled MVN neurons. Our findings suggest that M3 is the predominant post-synaptic mAChR involved in muscarinic excitation of cerebellum-projecting MVN neurons. Pre-synaptic M2 mAChR regulates excitatory glutamatergic input from vestibular primary afferents, which in turn influences the excitability of cerebellum-projecting MVN neurons. This new information has important therapeutic implications for treating vestibular disorders with mAChR subtype-selective agents. Medial vestibular nucleus (MVN) neurons projecting to the cerebellum are involved in balance control. We

  16. Exposure to a high fat diet during the perinatal period alters vagal motoneurone excitability, even in the absence of obesity

    PubMed Central

    Bhagat, Ruchi; Fortna, Samuel R; Browning, Kirsteen N

    2015-01-01

    The perinatal period is critically important to the development of autonomic neural circuits responsible for energy homeostasis. Vagal neurocircuits are vital to the regulation of upper gastrointestinal functions, including satiety. Diet-induced obesity modulates the excitability and responsiveness of both peripheral vagal afferents and central vagal efferents but less information is available regarding the effects of diet per se on vagal neurocircuit functions. The aims of this study were to investigate whether perinatal exposure to a high fat diet (HFD) dysregulated dorsal motor nucleus of the vagus (DMV) neurones, prior to the development of obesity. Whole cell patch clamp recordings were made from gastric-projecting DMV neurones in thin brainstem slices from rats that were exposed to either a control diet or HFD from pregnancy day 13. Our data demonstrate that following perinatal HFD: (i) DMV neurones had decreased excitability and input resistance with a reduced ability to fire action potentials; (ii) the proportion of DMV neurones excited by cholecystokinin (CCK) was unaltered but the proportion of neurones in which CCK increased excitatory glutamatergic synaptic inputs was reduced; (iii) the tonic activation of presynaptic group II metabotropic glutamate receptors on inhibitory nerve terminals was attenuated, allowing modulation of GABAergic synaptic transmission; and (iv) the size and dendritic arborization of gastric-projecting DMV neurones was increased. These results suggest that perinatal HFD exposure compromises the excitability and responsiveness of gastric-projecting DMV neurones, even in the absence of obesity, suggesting that attenuation of vago-vagal reflex signalling may precede the development of obesity. PMID:25556801

  17. Hypocretin/Orexin Peptides Alter Spike Encoding by Serotonergic Dorsal Raphe Neurons through Two Distinct Mechanisms That Increase the Late Afterhyperpolarization

    PubMed Central

    Ishibashi, Masaru; Gumenchuk, Iryna; Miyazaki, Kenichi; Inoue, Takafumi; Ross, William N.

    2016-01-01

    Orexins (hypocretins) are neuropeptides that regulate multiple homeostatic processes, including reward and arousal, in part by exciting serotonergic dorsal raphe neurons, the major source of forebrain serotonin. Here, using mouse brain slices, we found that, instead of simply depolarizing these neurons, orexin-A altered the spike encoding process by increasing the postspike afterhyperpolarization (AHP) via two distinct mechanisms. This orexin-enhanced AHP (oeAHP) was mediated by both OX1 and OX2 receptors, required Ca2+ influx, reversed near EK, and decayed with two components, the faster of which resulted from enhanced SK channel activation, whereas the slower component decayed like a slow AHP (sAHP), but was not blocked by UCL2077, an antagonist of sAHPs in some neurons. Intracellular phospholipase C inhibition (U73122) blocked the entire oeAHP, but neither component was sensitive to PKC inhibition or altered PKA signaling, unlike classical sAHPs. The enhanced SK current did not depend on IP3-mediated Ca2+ release but resulted from A-current inhibition and the resultant spike broadening, which increased Ca2+ influx and Ca2+-induced-Ca2+ release, whereas the slower component was insensitive to these factors. Functionally, the oeAHP slowed and stabilized orexin-induced firing compared with firing produced by a virtual orexin conductance lacking the oeAHP. The oeAHP also reduced steady-state firing rate and firing fidelity in response to stimulation, without affecting the initial rate or fidelity. Collectively, these findings reveal a new orexin action in serotonergic raphe neurons and suggest that, when orexin is released during arousal and reward, it enhances the spike encoding of phasic over tonic inputs, such as those related to sensory, motor, and reward events. SIGNIFICANCE STATEMENT Orexin peptides are known to excite neurons via slow postsynaptic depolarizations. Here we elucidate a significant new orexin action that increases and prolongs the postspike

  18. Spike-Timing Dependent Plasticity Beyond Synapse – Pre- and Post-Synaptic Plasticity of Intrinsic Neuronal Excitability

    PubMed Central

    Debanne, Dominique; Poo, Mu-Ming

    2010-01-01

    Long-lasting plasticity of synaptic transmission is classically thought to be the cellular substrate for information storage in the brain. Recent data indicate however that it is not the whole story and persistent changes in the intrinsic neuronal excitability have been shown to occur in parallel to the induction of long-term synaptic modifications. This form of plasticity depends on the regulation of voltage-gated ion channels. Here we review the experimental evidence for plasticity of neuronal excitability induced at pre- or postsynaptic sites when long-term plasticity of synaptic transmission is induced with Spike-Timing Dependent Plasticity (STDP) protocols. We describe the induction and expression mechanisms of the induced changes in excitability. Finally, the functional synergy between synaptic and non-synaptic plasticity and their spatial extent are discussed. PMID:21423507

  19. [The study of role of membrane-bound Ca2+ in the regulation of relationship between neuron and glia during rhythmic excitation].

    PubMed

    Maksimov, G V; Turovetskiĭ, V B; Chaterjy, Ch; Andreev, A I; Mironova, Iu E; Brindikova, T A; Rubin, A B

    2000-01-01

    The role of membrane-bound Ca2+ in the regulation of Ca2+ transport through voltage-gated Ca2+ channel, and NMDA-glutamate and n-acetylcholine receptors upon interaction of a neuron with glia during rhythmic excitation was studied. It was found that the redistribution and transport of Ca2+ play a crucial role in the conductance of rhythmic excitation in both a "neuron-neuron" system and the processes providing the maintenance of a stationary level of rhythmic excitation in the system "neuron-glia".

  20. The pharmacological control of neuronal excitability in the retinal spreading depression model of migraine.

    PubMed

    Wiedemann, M; Lyhs, B; Bartels, J-P; Sieber, M

    2012-01-01

    Spreading Depression is the underlying patho physiological mechanism for the neurological symptoms of migraine aura and is thought to play a major role in triggering migraine. Therefore it seems reasonable to use the Spreading Depression as a pharmacological tool for anti migraine drugs. Drugs that are able to alter parameters of Spreading Depression should also influence appearance and course of migraine attacks. Concerning the classification on the different mechanisms of drug action, especially the retinal Spreading Depression is useful, due to the separation of vascular and neuronal effects. In this study we investigated substances from different classes of common anti migraine drugs on different parameters of the retinal spreading depression. The results are discussed according to the classification of the drug.

  1. Leptin modulates the intrinsic excitability of AgRP/NPY neurons in the arcuate nucleus of the hypothalamus.

    PubMed

    Baver, Scott B; Hope, Kevin; Guyot, Shannon; Bjørbaek, Christian; Kaczorowski, Catherine; O'Connell, Kristen M S

    2014-04-16

    The hypothalamic arcuate nucleus (ARH) is a brain region critical for regulation of food intake and a primary area for the action of leptin in the CNS. In lean mice, the adipokine leptin inhibits neuropeptide Y (NPY) and agouti-related peptide (AgRP) neuronal activity, resulting in decreased food intake. Here we show that diet-induced obesity in mice is associated with persistent activation of NPY neurons and a failure of leptin to reduce the firing rate or hyperpolarize the resting membrane potential. However, the molecular mechanism whereby diet uncouples leptin's effect on neuronal excitability remains to be fully elucidated. In NPY neurons from lean mice, the Kv channel blocker 4-aminopyridine inhibited leptin-induced changes in input resistance and spike rate. Consistent with this, we found that ARH NPY neurons have a large, leptin-sensitive delayed rectifier K(+) current and that leptin sensitivity of this current is blunted in neurons from diet-induced obese mice. This current is primarily carried by Kv2-containing channels, as the Kv2 channel inhibitor stromatoxin-1 significantly increased the spontaneous firing rate in NPY neurons from lean mice. In HEK cells, leptin induced a significant hyperpolarizing shift in the voltage dependence of Kv2.1 but had no effect on the function of the closely related channel Kv2.2 when these channels were coexpressed with the long isoform of the leptin receptor LepRb. Our results suggest that dynamic modulation of somatic Kv2.1 channels regulates the intrinsic excitability of NPY neurons to modulate the spontaneous activity and the integration of synaptic input onto these neurons in the ARH.

  2. Excitability of jcBNST neurons is reduced in alcohol-dependent animals during protracted alcohol withdrawal.

    PubMed

    Szücs, Attila; Berton, Fulvia; Sanna, Pietro Paolo; Francesconi, Walter

    2012-01-01

    Alcohol dependence and withdrawal has been shown to cause neuroadaptive changes at multiple levels of the nervous system. At the neuron level, adaptations of synaptic connections have been extensively studied in a number of brain areas and accumulating evidence also shows the importance of alcohol dependence-related changes in the intrinsic cellular properties of neurons. At the same time, it is still largely unknown how such neural adaptations impact the firing and integrative properties of neurons. To address these problems, here, we analyze physiological properties of neurons in the bed nucleus of stria terminalis (jcBNST) in animals with a history of alcohol dependence. As a comprehensive approach, first we measure passive and active membrane properties of neurons using conventional current clamp protocols and then analyze their firing responses under the action of simulated synaptic bombardment via dynamic clamp. We find that most physiological properties as measured by DC current injection are barely affected during protracted withdrawal. However, neuronal excitability as measured from firing responses under simulated synaptic inputs with the dynamic clamp is markedly reduced in all 3 types of jcBNST neurons. These results support the importance of studying the effects of alcohol and drugs of abuse on the firing properties of neurons with dynamic clamp protocols designed to bring the neurons into a high conductance state. Since the jcBNST integrates excitatory inputs from the basolateral amygdala (BLA) and cortical inputs from the infralimbic and the insular cortices and in turn is believed to contribute to the inhibitory input to the central nucleus of the amygdala (CeA) the reduced excitability of the jcBNST during protracted withdrawal in alcohol-dependent animals will likely affect ability of the jcBNST to shape the activity and output of the CeA.

  3. Leptin Modulates the Intrinsic Excitability of AgRP/NPY Neurons in the Arcuate Nucleus of the Hypothalamus

    PubMed Central

    Baver, Scott B.; Hope, Kevin; Guyot, Shannon; Bjørbaek, Christian; Kaczorowski, Catherine

    2014-01-01

    The hypothalamic arcuate nucleus (ARH) is a brain region critical for regulation of food intake and a primary area for the action of leptin in the CNS. In lean mice, the adipokine leptin inhibits neuropeptide Y (NPY) and agouti-related peptide (AgRP) neuronal activity, resulting in decreased food intake. Here we show that diet-induced obesity in mice is associated with persistent activation of NPY neurons and a failure of leptin to reduce the firing rate or hyperpolarize the resting membrane potential. However, the molecular mechanism whereby diet uncouples leptin's effect on neuronal excitability remains to be fully elucidated. In NPY neurons from lean mice, the Kv channel blocker 4-aminopyridine inhibited leptin-induced changes in input resistance and spike rate. Consistent with this, we found that ARH NPY neurons have a large, leptin-sensitive delayed rectifier K+ current and that leptin sensitivity of this current is blunted in neurons from diet-induced obese mice. This current is primarily carried by Kv2-containing channels, as the Kv2 channel inhibitor stromatoxin-1 significantly increased the spontaneous firing rate in NPY neurons from lean mice. In HEK cells, leptin induced a significant hyperpolarizing shift in the voltage dependence of Kv2.1 but had no effect on the function of the closely related channel Kv2.2 when these channels were coexpressed with the long isoform of the leptin receptor LepRb. Our results suggest that dynamic modulation of somatic Kv2.1 channels regulates the intrinsic excitability of NPY neurons to modulate the spontaneous activity and the integration of synaptic input onto these neurons in the ARH. PMID:24741039

  4. Primary motor cortex of the parkinsonian monkey: altered neuronal responses to muscle stretch

    PubMed Central

    Pasquereau, Benjamin; Turner, Robert S.

    2013-01-01

    Exaggeration of the long-latency stretch reflex (LLSR) is a characteristic neurophysiologic feature of Parkinson's disease (PD) that contributes to parkinsonian rigidity. To explore one frequently-hypothesized mechanism, we studied the effects of fast muscle stretches on neuronal activity in the macaque primary motor cortex (M1) before and after the induction of parkinsonism by unilateral administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We compared results from the general population of M1 neurons and two antidromically-identified subpopulations: distant-projecting pyramidal-tract type neurons (PTNs) and intra-telecenphalic-type corticostriatal neurons (CSNs). Rapid rotations of elbow or wrist joints evoked short-latency responses in 62% of arm-related M1 neurons. As in PD, the late electromyographic responses that constitute the LLSR were enhanced following MPTP. This was accompanied by a shortening of M1 neuronal response latencies and a degradation of directional selectivity, but surprisingly, no increase in single unit response magnitudes. The results suggest that parkinsonism alters the timing and specificity of M1 responses to muscle stretch. Observation of an exaggerated LLSR with no change in the magnitude of proprioceptive responses in M1 is consistent with the idea that the increase in LLSR gain that contributes to parkinsonian rigidity is localized to the spinal cord. PMID:24324412

  5. Effects of cold temperatures on the excitability of rat trigeminal ganglion neurons that are not for cold sensing.

    PubMed

    Kanda, Hirosato; Gu, Jianguo G

    2015-12-28

    Aside from a small population of primary afferent neurons for sensing cold, which generate sensations of innocuous and noxious cold, it is generally believed that cold temperatures suppress the excitability of primary afferent neurons not responsible for cold sensing. These not-for-cold-sensing neurons include the majority of non-nociceptive and nociceptive afferent neurons. In this study we have found that the not-for-cold-sensing neurons of rat trigeminal ganglia (TG) change their excitability in several ways at cooling temperatures. In nearly 70% of not-for-cold-sensing TG neurons, a cooling temperature of 15°C increases their membrane excitability. We regard these neurons as cold-active neurons. For the remaining 30% of not-for-cold-sensing TG neurons, the cooling temperature of 15°C either has no effect (cold-ineffective neurons) or suppress their membrane excitability (cold-suppressive neurons). For cold-active neurons, the cold temperature of 15°C increases their excitability as is evidenced by increases in action potential (AP) firing numbers and/or the reduction in AP rheobase when these neurons are depolarized electrically. The cold temperature of 15°C significantly inhibits M-currents and increases membrane input resistance of cold-active neurons. Retigabine, an M-current activator, abolishes the effect of cold temperatures on AP firing, but not the effect of cold temperature on AP rheobase levels. The inhibition of M-currents and the increases of membrane input resistance are likely two mechanisms by which cooling temperatures increase the excitability of not-for-cold-sensing TG neurons. This article is part of the special article series "Pain".

  6. Orexin excites rat inferior vestibular nuclear neurons via co-activation of OX1 and OX 2 receptors.

    PubMed

    Yu, Lei; Zhang, Xiao-Yang; Chen, Zhang-Peng; Zhuang, Qian-Xing; Zhu, Jing-Ning; Wang, Jian-Jun

    2015-06-01

    Orexin deficiency results in cataplexy, a motor deficit characterized by sudden loss of muscle tone, strongly indicating an active role of central orexinergic system in motor control. However, effects of orexin on neurons in central motor structures are still largely unknown. Our previous studies have revealed that orexin excites neurons in the cerebellar nuclei and lateral vestibular nucleus, two important subcortical motor centers for control of muscle tone. Here, we report that both orexin-A and orexin-B depolarizes and increases the firing rate of neurons in the inferior vestibular nucleus (IVN), the largest nucleus in the vestibular nuclear complex and holding an important position in integration of information signals in the control of body posture. TTX does not block orexin-induced excitation on IVN neurons, suggesting a direct postsynaptic action of the neuropeptide. Furthermore, bath application of orexin induces an inward current on IVN neurons in a concentration-dependent manner. SB334867 and TCS-OX2-29, specific OX1 and OX2 receptor antagonists, blocked the excitatory effect of orexin, and [Ala(11), D-Leu(15)]-orexin B, a selective OX2 receptor agonist, mimics the orexin-induced inward current on IVN neurons. qPCR and immunofluorescence results show that both OX1 and OX2 receptor mRNAs and proteins are expressed and localized in the rat IVN. These results demonstrate that orexin excites the IVN neurons by co-activation of both OX1 and OX2 receptors, suggesting that via the direct modulation on the IVN, the central orexinergic system may actively participate in the central vestibular-mediated postural and motor control.

  7. Alterations in striatal dopamine catabolism precede loss of substantia nigra neurons in a mouse model of Juvenile Neuronal Ceroid Lipofuscinosis

    PubMed Central

    Weimer, Jill M.; Benedict, Jared W.; Elshatory, Yasser M.; Short, Douglas W.; Ramirez-Montealegre, Denia; Ryan, Deborah A.; Alexander, Noreen A.; Federoff, Howard J.; Cooper, Jonathan D.; Pearce, David A.

    2016-01-01

    Batten disease, or juvenile neuronal ceroid lipofuscinosis (JNCL), results from mutations in the CLN3 gene. This disorder presents clinically around the age of five years with visual deficits progressing to include seizures, cognitive impairment, motor deterioration, hallucinations, and premature death by the third to forth decade of life. The motor deficits include coordination and gait abnormalities, myoclonic jerks, inability to initiate movements, and spasticity. Previous work from our laboratory has identified an early reduction in catechol-O-methyltransferase (COMT), an enzyme responsible for the efficient degradation of dopamine. Alterations in the kinetics of dopamine metabolism could cause the accumulation of undegraded or unsequestered dopamine leading to the formation of toxic dopamine intermediates. We report an imbalance in the catabolism of dopamine in three month Cln3-/- mice persisting through nine months of age that may be causal to oxidative damage within the striatum at nine months of age. Combined with the previously reported inflammatory changes and loss of post-synaptic D1α receptors, this could facilitate cell loss in striatal projection regions and underlie a general locomotion deficit that becomes apparent at twelve months of age in Cln3-/- mice. This study provides evidence for early changes in the kinetics of COMT in the Cln3-/- mouse striatum, affecting the turnover of dopamine, likely leading to neuron loss and motor deficits. These data provide novel insights into the basis of motor deficits in JNCL and how alterations in dopamine catabolism may result in oxidative damage and localized neuronal loss in this disorder. PMID:17617387

  8. Optogenetic excitation of preBötzinger complex neurons potently drives inspiratory activity in vivo

    PubMed Central

    Alsahafi, Zaki; Dickson, Clayton T; Pagliardini, Silvia

    2015-01-01

    Understanding the sites and mechanisms underlying respiratory rhythmogenesis is of fundamental interest in the field of respiratory neurophysiology. Previous studies demonstrated the necessary and sufficient role of preBötzinger complex (preBötC) in generating inspiratory rhythms in vitro and in vivo. However, the influence of timed activation of the preBötC network in vivo is as yet unknown given the experimental approaches previously used. By unilaterally infecting preBötC neurons using an adeno-associated virus expressing channelrhodopsin we photo-activated the network in order to assess how excitation delivered in a spatially and temporally precise manner to the inspiratory oscillator influences ongoing breathing rhythms and related muscular activity in urethane-anaesthetized rats. We hypothesized that if an excitatory drive is necessary for rhythmogenesis and burst initiation, photo-activation of preBötC not only will increase respiratory rate, but also entrain it over a wide range of frequencies with fast onset, and have little effect on ongoing respiratory rhythm if a stimulus is delivered during inspiration. Stimulation of preBötC neurons consistently increased respiratory rate and entrained respiration up to fourfold baseline conditions. Furthermore, brief pulses of photostimulation delivered at random phases between inspiratory events robustly and consistently induced phase-independent (Type 0) respiratory reset and recruited inspiratory muscle activity at very short delays (∼100 ms). A 200 ms refractory period following inspiration was also identified. These data provide strong evidence for a fine control of inspiratory activity in the preBötC and provide further evidence that the preBötC network constitutes the fundamental oscillator of inspiratory rhythms. PMID:26010654

  9. Hydrogen Sulfide Regulates Cardiovascular Function by Influencing the Excitability of Subfornical Organ Neurons

    PubMed Central

    Kuksis, Markus; Smith, Pauline M.; Ferguson, Alastair V.

    2014-01-01

    Hydrogen sulfide (H2S), a gasotransmitter endogenously found in the central nervous system, has recently been suggested to act as a signalling molecule in the brain having beneficial effects on cardiovascular function. This study was thus undertaken to investigate the effect of NaHS (an H2S donor) in the subfornical organ (SFO), a central nervous system site important to blood pressure regulation. We used male Sprague-Dawley rats for both in vivo and in vitro experiments. We first used RT-PCR to confirm our previous microarray analyses showing that mRNAs for the enzymes required to produce H2S are expressed in the SFO. We then used microinjection techniques to investigate the physiological effects of NaHS in SFO, and found that NaHS microinjection (5 nmol) significantly increased blood pressure (mean AUC = 853.5±105.7 mmHg*s, n = 5). Further, we used patch-clamp electrophysiology and found that 97.8% (88 of 90) of neurons depolarized in response to NaHS. This response was found to be concentration dependent with an EC50 of 35.6 µM. Coupled with the depolarized membrane potential, we observed an overall increase in neuronal excitability using an analysis of rheobase and action potential firing patterns. This study has provided the first evidence of NaHS and thus H2S actions and their cellular correlates in SFO, implicating this brain area as a site where H2S may act to control blood pressure. PMID:25144759

  10. Mouse spinal cord neurons in serum-free culture media: suitability for patch clamp studies on chemical and electrical excitability.

    PubMed

    Salamanca, M C; Mathers, D A

    1987-01-01

    Methods were devised for the serum-free culture of spinal cord neurons derived from 12- to 13-day mouse embryos. Neurons exhibited good attachment if plated for 24 h on poly-d-lysine-coated dishes in the presence of serum. Cultures were subsequently fed with a serum-free medium consisting of minimum essential medium, Earle's salts and the N1 supplement, i.e. insulin, putrescine, transferrin, progesterone and selenium. After 3 weeks in vitro, growth and survival of neurons in this medium were comparable to results obtained using serum-supplemented medium. The presence of putrescine was not essential for the beneficial effects of N1, while insulin was required for long-term survival in serum-free media. Neurons maintained in serum-free media for 3 weeks retained aspects of electrical and chemical excitability characteristic of serum-grown cells.

  11. Long-term potentiation in rat hippocampal neurons is accompanied by spatially widespread changes in intrinsic oscillatory dynamics and excitability.

    PubMed

    Narayanan, Rishikesh; Johnston, Daniel

    2007-12-20

    Oscillations in neural activity are a prominent feature of many brain states. Individual hippocampal neurons exhibit intrinsic membrane potential oscillations and intrinsic resonance in the theta frequency range. We found that the subthreshold resonance frequency of CA1 pyramidal neurons was location dependent, varying more than 3-fold between the soma and the distal dendrites. Furthermore, activity- and NMDA-receptor-dependent long-term plasticity increased this resonance frequency through changes in h channel properties. The increase in resonance frequency and an associated reduction in excitability were nearly identical in the soma and the first 300 mum of the apical dendrites. These spatially widespread changes accompanying long-term synaptic potentiation also reduced the neuron's ability to elicit spikes evoked through a nonpotentiated synaptic pathway. Our results suggest that the frequency response of these neurons depends on the dendritic location of their inputs and that activity can regulate their response dynamics within an oscillating neural network.

  12. Expression of Carbonic Anhydrase I in Motor Neurons and Alterations in ALS

    PubMed Central

    Liu, Xiaochen; Lu, Deyi; Bowser, Robert; Liu, Jian

    2016-01-01

    Carbonic anhydrase I (CA1) is the cytosolic isoform of mammalian α-CA family members which are responsible for maintaining pH homeostasis in the physiology and pathology of organisms. A subset of CA isoforms are known to be expressed and function in the central nervous system (CNS). CA1 has not been extensively characterized in the CNS. In this study, we demonstrate that CA1 is expressed in the motor neurons in human spinal cord. Unexpectedly, a subpopulation of CA1 appears to be associated with endoplasmic reticulum (ER) membranes. In addition, the membrane-associated CA1s are preferentially upregulated in amyotrophic lateral sclerosis (ALS) and exhibit altered distribution in motor neurons. Furthermore, long-term expression of CA1 in mammalian cells activates apoptosis. Our results suggest a previously unknown role for CA1 function in the CNS and its potential involvement in motor neuron degeneration in ALS. PMID:27809276

  13. Impaired Long-term Potentiation and Enhanced Neuronal Excitability in the Amygdala of CaV1.3 Knockout Mice

    PubMed Central

    McKinney, Brandon C.; Sze, Wilson; Lee, Benjamin; Murphy, Geoffrey G.

    2009-01-01

    Previously, we demonstrated that mice in which the gene for the L-type voltage-gated calcium channel CaV1.3 is deleted (CaV1.3 knockout mice) exhibit an impaired ability to consolidate contextually-conditioned fear. Given that this form of Pavlovian fear conditioning is critically dependent on the basolateral complex of the amygdala (BLA), we were interested in the mechanisms by which CaV1.3 contributes to BLA neurophysiology. In the present study, we used in vitro amygdala slices prepared from CaV1.3 knockout mice and wild-type littermates to explore the role of CaV1.3 in long-term potentiation (LTP) and intrinsic neuronal excitability in the BLA. We found that LTP in the lateral nucleus (LA) of the BLA, induced by high-frequency stimulation of the external capsule, was significantly reduced in CaV1.3 knockout mice. Additionally, we found that BLA principal neurons from CaV1.3 knockout mice were hyperexcitable, exhibiting significant increases in firing rates and decreased interspike intervals in response to prolonged somatic depolarization. This aberrant increase in neuronal excitability appears to be at least in part due to a concomitant reduction in the slow component of the post-burst afterhyperpolarization. Together, these results demonstrate altered neuronal function in the BLA of CaV1.3 knockout mice which may account for the impaired ability of these mice to consolidate contextually-conditioned fear. PMID:19595780

  14. Dopamine Inhibition Differentially Controls Excitability of Substantia Nigra Dopamine Neuron Subpopulations through T-Type Calcium Channels.

    PubMed

    Evans, Rebekah C; Zhu, Manhua; Khaliq, Zayd M

    2017-03-29

    While there is growing appreciation for diversity among ventral tegmental area dopamine neurons, much less is known regarding functional heterogeneity among the substantia nigra pars compacta (SNc) neurons. Here, we show that calbindin-positive dorsal tier and calbindin-negative ventral tier SNc dopaminergic neurons in mice comprise functionally distinct subpopulations distinguished by their dendritic calcium signaling, rebound excitation, and physiological responses to dopamine D2-receptor (D2) autoinhibition. While dopamine is known to inhibit action potential backpropagation, our experiments revealed an unexpected enhancement of excitatory responses and dendritic calcium signals in the presence of D2-receptor inhibition. Specifically, dopamine inhibition and direct hyperpolarization enabled the generation of low-threshold depolarizations that occurred in an all-or-none or graded manner, due to recruitment of T-type calcium channels. Interestingly, these effects occurred selectively in calbindin-negative dopaminergic neurons within the SNc. Thus, calbindin-positive and calbindin-negative SNc neurons differ substantially in their calcium channel composition and efficacy of excitatory inputs in the presence of dopamine inhibition.SIGNIFICANCE STATEMENT Substantia nigra dopaminergic neurons can be divided into two populations: the calbindin-negative ventral tier, which is vulnerable to neurodegeneration in Parkinson's disease, and the calbindin-positive dorsal tier, which is relatively resilient. Although tonic firing is similar in these subpopulations, we find that their responses to dopamine-mediated inhibition are strikingly different. During inhibition, calbindin-negative neurons exhibit increased sensitivity to excitatory inputs, which can then trigger large dendritic calcium transients due to strong expression of T-type calcium channels. Therefore, SNc neurons differ substantially in their calcium channel composition, which may contribute to their differential

  15. L-Phosphinothricin modulation of inwardly rectifying K(+) channels increased excitability in striatal medium-sized spiny neurons.

    PubMed

    Domingos, Laetitia; Desrus, Agnès; Même, Sandra; Même, William

    2016-07-01

    Phosphinotricin (L-PPT) is the active compound of a broad-spectrum herbicide. Acute poisoning with L-PPT has various clinical manifestations, including seizures and convulsions. However, the exact mechanism of L-PPT toxicity remains unclear. The present study addressed the role of L-PPT, in the excitability of striatal medium-sized spiny neurons (MSNs). In whole-cell current-clamp experiments, L-PPT increased the input resistance (Ri), decreased the rheobase and increased the firing frequency of action potentials. In voltage-clamp experiments, L-PPT inhibited the inward-rectifying potassium (Kir) currents. Finally, the effects of L-PPT mimicked the inhibition of Kir channels with Ba(2+) on neuronal excitability. Altogether, these results suggest that the herbicide L-PPT is a modulator of Kir channels in MSNs. Thereby, Kir channels are potent regulators of the excitability of MSNs and reduced open probability of these channels would generate a powerful upregulation of neuronal output. This effect may represent a possible mechanism for L-PPT dependent neuronal toxicity.

  16. Neuronal expression of a thyroid hormone receptor α mutation alters mouse behaviour.

    PubMed

    Richard, S; Aguilera, N; Thévenet, M; Dkhissi-Benyahya, O; Flamant, F

    2017-03-15

    In humans, alterations in thyroid hormone signalling are associated with mood and anxiety disorders, but the neural mechanisms underlying such association are poorly understood. The present study investigates the involvement of neuronal thyroid hormone receptor α (TRα) in anxiety, using mouse genetics and Cre/loxP technology to specifically alter TRα signalling in neurons. We evaluated the behaviour of mice expressing a dominant negative, neuron-specific mutation of TRα (TRα(AMI)/Cre3 mice), using the elevated-plus maze, light-dark box and open-field tests. In a first experiment, mice were housed individually, and the behaviour of TRα(AMI)/Cre3 mice differed significantly from that of control littermates in these 3 tests, suggesting heightened anxiety. In a second experiment, designed to evaluate the robustness of the results with the same 3 tests, mice were housed in groups. In these conditions, the behaviour of TRα(AMI)/Cre3 mice differed from that of control littermates only in the light-dark box. Thus, TRα(AMI)/Cre3 mice appear to be more likely to develop anxiety under stressful housing conditions than control mice. These results suggest that in adult mice, thyroid hormone signalling in neurons, via TRα, is involved in the control of anxiety behaviour.

  17. Altered neuronal network and rescue in a human MECP2 duplication model

    PubMed Central

    Nageshappa, Savitha; Carromeu, Cassiano; Trujillo, Cleber A.; Mesci, Pinar; Espuny-Camacho, Ira; Pasciuto, Emanuela; Vanderhaeghen, Pierre; Verfaillie, Catherine; Raitano, Susanna; Kumar, Anujith; Carvalho, Claudia M.B.; Bagni, Claudia; Ramocki, Melissa B.; Araujo, Bruno H. S.; Torres, Laila B.; Lupski, James R.; Van Esch, Hilde; Muotri, Alysson R.

    2015-01-01

    Increased dosage of MeCP2 results in a dramatic neurodevelopmental phenotype with onset at birth. We generated induced pluripotent stem cells (iPSC) from patients with the MECP2 duplication syndrome (MECP2dup), carrying different duplication sizes, to study the impact of increased MeCP2 dosage in human neurons. We show that cortical neurons derived from these different MECP2dup iPSC lines have increase synaptogenesis and dendritic complexity. Additionally, using multi-electrodes arrays, we show that neuronal network synchronization was altered in MECP2dup-derived neurons. Given MeCP2 function at the epigenetic level, we tested if these alterations were reversible using a library of compounds with defined activity on epigenetic pathways. One histone deacetylase inhibitor, NCH-51, was validated as a potential clinical candidate. Interestingly, this compound has never been considered before as a therapeutic alternative for neurological disorders. Our model recapitulates early stages of the human MECP2 duplication syndrome and represents a promising cellular tool to facilitate therapeutic drug screening for severe neurodevelopmental disorders. PMID:26347316

  18. Dendritic remodeling of hippocampal neurons is associated with altered NMDA receptor expression in alcohol dependent rats.

    PubMed

    Staples, Miranda C; Kim, Airee; Mandyam, Chitra D

    2015-03-01

    Prolonged alcohol exposure has been previously shown to impair the structure and function of the hippocampus, although the underlying structural and biochemical alterations contributing to these deleterious effects are unclear. Also unclear is whether these changes persist into prolonged periods of abstinence. Previous work from our lab utilizing a clinically relevant rodent model of alcohol consumption demonstrated that alcohol dependence (induced by chronic intermittent ethanol vapor exposure or CIE) decreases proliferation and survival of neural stem cells in the hippocampal subgranular zone and hippocampal neurogenesis in the dentate gyrus, implicating this region of the cortex as particularly sensitive to the toxic effects of prolonged ethanol exposure. For this study, we investigated seven weeks of CIE-induced morphological changes (dendritic complexity and dendritic spine density) of dentate gyrus (DG) granule cell neurons, CA3, and CA1 pyramidal neurons and the associated alterations in biochemical markers of synaptic plasticity and toxicity (NMDA receptors and PSD-95) in the hippocampus in ethanol-experienced Wistar rats 3h (CIE) and 21days (protracted abstinence) after the last ethanol vapor exposure. CIE reduced dendritic arborization of DG neurons and this effect persisted into protracted abstinence. CIE enhanced dendritic arborization of pyramidal neurons and this effect did not persist into protracted abstinence. The architectural changes in dendrites did not correlate with alterations in dendritic spine density, however, they were associated with increases in the expression of pNR2B, total NR2B, and total NR2A immediately following CIE with expression levels returning to control levels in prolonged abstinence. Overall, these data provide the evidence that CIE produces profound changes in hippocampal structural plasticity and in molecular tools that maintain hippocampal structural plasticity, and these alterations may underlie cognitive dysfunction

  19. Dendritic remodeling of hippocampal neurons is associated with altered NMDA receptor expression in alcohol dependent rats

    PubMed Central

    Staples, Miranda C.; Kim, Airee; Mandyam, Chitra D.

    2015-01-01

    Prolonged alcohol exposure has been previously shown to impair the structure and function of the hippocampus, although the underlying structural and biochemical alterations contributing to these deleterious effects are unclear. Also unclear is whether these changes persist into prolonged periods of abstinence. Previous work from our lab utilizing a clinically relevant rodent model of alcohol consumption demonstrated that alcohol dependence (induced by chronic intermittent ethanol vapor exposure or CIE) decreases proliferation and survival of neural stem cells in the hippocampal subgranular zone and hippocampal neurogenesis in the dentate gyrus, implicating this region of the cortex as particularly sensitive to the toxic effects of prolonged ethanol exposure. For this study, we investigated seven weeks of CIE-induced morphological changes (dendritic complexity and dendritic spine density) of dentate gyrus (DG) granule cell neurons, CA3, and CA1 pyramidal neurons and the associated alterations in biochemical markers of synaptic plasticity and toxicity (NMDA receptors and PSD-95) in the hippocampus in ethanol-experienced Wistar rats 3h (CIE) and 21 days (protracted abstinence) after the last ethanol vapor exposure. CIE reduced dendritic arborization of DG neurons and this effect persisted into protracted abstinence. CIE enhanced dendritic arborization of pyramidal neurons and this effect did not persist into protracted abstinence. The architectural changes in dendrites did not correlate with alterations in dendritic spine density, however, they were associated with increases in the expression of pNR2B, total NR2B, and total NR2A immediately following CIE with expression levels returning to control levels in prolonged abstinence. Overall, these data provide the evidence that CIE produces profound changes in hippocampal structural plasticity and in molecular tools that maintain hippocampal structural plasticity, and these alterations may underlie cognitive dysfunction

  20. Transcranial magnetic stimulation with the maximum voluntary muscle contraction facilitates motor neuron excitability and muscle force.

    PubMed

    Touge, Tetsuo; Urai, Yoshiteru; Ikeda, Kazuyo; Kume, Kodai; Deguchi, Kazushi

    2012-01-01

    Three trials of transcranial magnetic stimulation (TMS) during the maximum voluntary muscle contraction (MVC) were repeated at 15-minute intervals for 1 hour to examine the effects on motor evoked potentials (MEPs) in the digital muscles and pinching muscle force before and after 4 high-intensity TMSs (test 1 condition) or sham TMS (test 2 condition) with MVC. Under the placebo condition, real TMS with MVC was administered only before and 1 hour after the sham TMS with MVC. Magnetic stimulation at the foramen magnum level (FMS) with MVC was performed by the same protocol as that for the test 2 condition. As a result, MEP sizes in the digital muscles significantly increased after TMS with MVC under test conditions compared with the placebo conditions (P < 0.05). Pinching muscle force was significantly larger 45 minutes and 1 hour after TMS with MVC under the test conditions than under the placebo condition (P < 0.05). FMS significantly decreased MEP amplitudes 60 minutes after the sham TMS with MVC (P < 0.005). The present results suggest that intermittently repeated TMS with MVC facilitates motor neuron excitabilities and muscle force. However, further studies are needed to confirm the effects of TMS with MVC and its mechanism.

  1. Ionic Mechanism Underlying Optimal Stimuli for Neuronal Excitation: Role of Na+ Channel Inactivation

    PubMed Central

    Clay, John R.; Forger, Daniel B.; Paydarfar, David

    2012-01-01

    The ionic mechanism underlying optimal stimulus shapes that induce a neuron to fire an action potential, or spike, is relevant to understanding optimal information transmission and therapeutic stimulation in the nervous system. Here we analyze for the first time the ionic basis for stimulus optimality in the Hodgkin and Huxley model and for eliciting a spike in squid giant axons, the preparation for which the model was devised. The experimentally determined stimulus is a smoothly varying biphasic current waveform having a relatively long and shallow hyperpolarizing phase followed by a depolarizing phase of briefer duration. The hyperpolarizing phase removes a small degree of the resting level of Na+ channel inactivation. This result together with the subsequent depolarizing phase provides a signal that is energetically more efficient for eliciting spikes than rectangular current pulses. Sodium channel inactivation is the only variable that is changed during the stimulus waveform, other than the membrane potential, V. The activation variables for Na+ and K+ channels are unchanged throughout the stimulus. This result demonstrates how an optimal stimulus waveform relates to ionic dynamics and may have implications for energy efficiency of neural excitation in many systems including the mammalian brain. PMID:23049913

  2. Ionic mechanism underlying optimal stimuli for neuronal excitation: role of Na+ channel inactivation.

    PubMed

    Clay, John R; Forger, Daniel B; Paydarfar, David

    2012-01-01

    The ionic mechanism underlying optimal stimulus shapes that induce a neuron to fire an action potential, or spike, is relevant to understanding optimal information transmission and therapeutic stimulation in the nervous system. Here we analyze for the first time the ionic basis for stimulus optimality in the Hodgkin and Huxley model and for eliciting a spike in squid giant axons, the preparation for which the model was devised. The experimentally determined stimulus is a smoothly varying biphasic current waveform having a relatively long and shallow hyperpolarizing phase followed by a depolarizing phase of briefer duration. The hyperpolarizing phase removes a small degree of the resting level of Na(+) channel inactivation. This result together with the subsequent depolarizing phase provides a signal that is energetically more efficient for eliciting spikes than rectangular current pulses. Sodium channel inactivation is the only variable that is changed during the stimulus waveform, other than the membrane potential, V. The activation variables for Na(+) and K(+) channels are unchanged throughout the stimulus. This result demonstrates how an optimal stimulus waveform relates to ionic dynamics and may have implications for energy efficiency of neural excitation in many systems including the mammalian brain.

  3. Saccade-Related Modulations of Neuronal Excitability Support Synchrony of Visually Elicited Spikes

    PubMed Central

    Maldonado, Pedro; Singer, Wolf; Grün, Sonja

    2011-01-01

    During natural vision, primates perform frequent saccadic eye movements, allowing only a narrow time window for processing the visual information at each location. Individual neurons may contribute only with a few spikes to the visual processing during each fixation, suggesting precise spike timing as a relevant mechanism for information processing. We recently found in V1 of monkeys freely viewing natural images, that fixation-related spike synchronization occurs at the early phase of the rate response after fixation-onset, suggesting a specific role of the first response spikes in V1. Here, we show that there are strong local field potential (LFP) modulations locked to the onset of saccades, which continue into the successive fixation periods. Visually induced spikes, in particular the first spikes after the onset of a fixation, are locked to a specific epoch of the LFP modulation. We suggest that the modulation of neural excitability, which is reflected by the saccade-related LFP changes, serves as a corollary signal enabling precise timing of spikes in V1 and thereby providing a mechanism for spike synchronization. PMID:21459839

  4. Intrinsic excitability state of local neuronal population modulates signal propagation in feed-forward neural networks

    NASA Astrophysics Data System (ADS)

    Han, Ruixue; Wang, Jiang; Yu, Haitao; Deng, Bin; Wei, Xilei; Qin, Yingmei; Wang, Haixu

    2015-04-01

    Reliable signal propagation across distributed brain areas is an essential requirement for cognitive function, and it has been investigated extensively in computational studies where feed-forward network (FFN) is taken as a generic model. But it is still unclear how distinct local network states, which are intrinsically generated by synaptic interactions within each layer, would affect the ability of FFN to transmit information. Here we investigate the impact of such network states on propagating transient synchrony (synfire) and firing rate by a combination of numerical simulations and analytical approach. Specifically, local network dynamics is attributed to the competition between excitatory and inhibitory neurons within each layer. Our results show that concomitant with different local network states, the performance of signal propagation differs dramatically. For both synfire propagation and firing rate propagation, there exists an optimal local excitability state, respectively, that optimizes the performance of signal propagation. Furthermore, we find that long-range connections strongly change the dependence of spiking activity propagation on local network state and propose that these two factors work jointly to determine information transmission across distributed networks. Finally, a simple mean field approach that bridges response properties of long-range connectivity and local subnetworks is utilized to reveal the underlying mechanism.

  5. Dendritic and spinal alterations of neurons from Edinger-Westphal nucleus in Alzheimer's disease.

    PubMed

    Mavroudis, Ioannis Asterios; Manani, Marina George; Petrides, Foivos; Petsoglou, Constantina; Njau, Samuel N; Costa, Vasiliki G; Baloyannis, Stavros J

    2014-01-01

    Alzheimer's disease (AD) is a heterogeneous neurodegenerative disorder, causing a progressive decline of intellectual faculties, impairment of behavior and social performance, and impairment of speech eloquence, associated with various neurological manifestations based on a variable neuropathological background. Edinger-Westphal nucleus is a selective target of Alzheimer pathology early in the course of the disease. We attempted to determine the morphological alterations of the dendrites and the dendritic spines in Edinger-Westphal nucleus of 7 cases that fulfilled the diagnostic criteria for Alzheimer's disease. For the histological study, we applied (a) routine neuropathological techniques and (b) rapid Golgi method. We proceeded to 3D neuronal reconstruction for the estimation of dendritic and spinal changes in Alzheimer's disease. The morphological and morphometric analysis revealed a substantial neuronal loss and synaptic alterations in Edinger-Westphal nucleus in all the cases of Alzheimer's disease. Distal dendritic branches are prominently affected. The neuronal loss and alteration of the spines in Edinger-Westphal nucleus in Alzheimer's disease may be related to the exaggerated pupillary reaction to cholinergic antagonists. Furthermore, the vulnerability of distal branches to Alzheimer's disease might be related to neuroplasticity impairment.

  6. Nonmigraine-associated TRESK K+ channel variant C110R does not increase the excitability of trigeminal ganglion neurons

    PubMed Central

    Guo, Zhaohua; Liu, Ping; Ren, Fei

    2014-01-01

    Recent genetic studies suggest that dysfunction of ion channels and transporters may contribute to migraine pathophysiology. A migraine-associated frameshift mutation in the TWIK-related spinal cord K+ (TRESK) channel results in nonfunctional channels. Moreover, mutant TRESK subunits exert a dominant-negative effect on whole cell TRESK currents and result in hyperexcitability of small-diameter trigeminal ganglion (TG) neurons, suggesting that mutant TRESK may increase the gain of the neuronal circuit underlying migraine headache. However, the nonmigraine-associated TRESK C110R variant exhibits the same effect on TRESK currents as the mutant subunits in Xenopus oocytes, suggesting that dysfunction of TRESK is not sufficient to cause migraine. Here, we confirmed that the C110R variant formed nonfunctional channels and exerted a dominant-negative effect on TRESK currents in HEK293T cells, similar to the migraine-associated mutant TRESK. To compare the functional consequences of TRESK mutations/variants in a more physiological setting, we expressed the mutant TRESK and the C110R variant in cultured mouse TG neurons and investigated their effects on background K+ currents and neuronal excitability. Both mutant TRESK and the C110R variant reduced the endogenous TRESK currents in TG neurons, but the effect of the C110R variant was significantly smaller. Importantly, only TG neurons expressing mutant TRESK subunits, but not those expressing the C110R variant, exhibited a significant increase in excitability. Thus only the migraine-associated TRESK mutation, but not the C110R variant, reduces the endogenous TRESK currents to a degree that affects TG excitability. Our results support a potential causal relationship between the frameshift TRESK mutation and migraine susceptibility. PMID:24805079

  7. Novel modulatory effects of neurosteroids and benzodiazepines on excitatory and inhibitory neurons excitability: a multi-electrode array recording study

    PubMed Central

    Puia, Giulia; Gullo, Francesca; Dossi, Elena; Lecchi, Marzia; Wanke, Enzo

    2012-01-01

    The balance between glutamate- and GABA-mediated neurotransmission in the brain is fundamental in the nervous system, but it is regulated by the “tonic” release of a variety of endogenous factors. One such important group of molecules are the neurosteroids (NSs) which, similarly to benzodiazepines (BDZs), enhance GABAergic neurotransmission. The purpose of our work was to investigate, at in vivo physiologically relevant concentrations, the effects of NSs and BDZs as GABA modulators on dissociated neocortical neuron networks grown in long-term culture. We used a multi-electrode array (MEA) recording technique and a novel analysis that was able to both identify the action potentials of engaged excitatory and inhibitory neurons and to detect drug-induced network up-states (burst). We found that the NSs tetrahydrodeoxycorticosterone (THDOC) and allopregnanolone (ALLO) applied at low nanomolar concentrations, produced different modulatory effects on the two neuronal clusters. Conversely, at high concentrations (1 μM), both NSs, decreased excitatory and inhibitory neuron cluster excitability; however, even several hours after wash-out, the excitability of inhibitory neurons continued to be depressed, leading to a network long-term depression (LTD). The BDZs clonazepam (CLZ) and midazolam (MDZ) also decreased the network excitability, but only MDZ caused LTD of inhibitory neuron cluster. To investigate the origin of the LTD after MDZ application, we tested finasteride (FIN), an inhibitor of endogenous NSs synthesis. FIN did not prevent the LTD induced by MDZ, but surprisingly induced it after application of CLZ. The significance and possible mechanisms underlying these LTD effects of NSs and BDZs are discussed. Taken together, our results not only demonstrate that ex vivo networks show a sensitivity to NSs and BDZs comparable to that expressed in vivo, but also provide a new global in vitro description that can help in understanding their activity in more complex

  8. Removal of GABAA Receptor γ2 Subunits from Parvalbumin Neurons Causes Wide-Ranging Behavioral Alterations

    PubMed Central

    Leppä, Elli; Linden, Anni-Maija; Vekovischeva, Olga Y.; Swinny, Jerome D.; Rantanen, Ville; Toppila, Esko; Höger, Harald; Sieghart, Werner; Wulff, Peer; Wisden, William; Korpi, Esa R.

    2011-01-01

    We investigated the behavioral significance of fast synaptic inhibition by αβγ2-type GABAA receptors on parvalbumin (Pv) cells. The GABAA receptor γ2 subunit gene was selectively inactivated in Pv-positive neurons by Cre/loxP recombination. The resulting Pv-Δγ2 mice were relatively healthy in the first postnatal weeks; but then as Cre started to be expressed, the mice progressively developed wide-ranging phenotypic alterations including low body weight, motor deficits and tremor, decreased anxiety levels, decreased pain sensitivity and deficient prepulse inhibition of the acoustic startle reflex and impaired spatial learning. Nevertheless, the deletion was not lethal, and mice did not show increased mortality even after one year. Autoradiography with t-butylbicyclophosphoro[35S]thionate suggested an increased amount of GABAA receptors with only α and β subunits in central nervous system regions that contained high levels of parvalbumin neurons. Using BAC-transgenesis, we reduced some of the Pv-Δγ2 phenotype by selectively re-expressing the wild-type γ2 subunit back into some Pv cells (reticular thalamic neurons and cerebellar Pv-positive neurons). This produced less severe impairments of motor skills and spatial learning compared with Pv-Δγ2 mice, but all other deficits remained. Our results reveal the widespread significance of fast GABAergic inhibition onto Pv-positive neurons for diverse behavioral modalities, such as motor coordination, sensorimotor integration, emotional behavior and nociception. PMID:21912668

  9. HIV alters neuronal mitochondrial fission/fusion in the brain during HIV-associated neurocognitive disorders.

    PubMed

    Fields, Jerel Adam; Serger, Elisabeth; Campos, Sofia; Divakaruni, Ajit S; Kim, Changyoun; Smith, Kendall; Trejo, Margarita; Adame, Anthony; Spencer, Brian; Rockenstein, Edward; Murphy, Anne N; Ellis, Ronald J; Letendre, Scott; Grant, Igor; Masliah, Eliezer

    2016-02-01

    HIV-associated neurocognitive disorders (HAND) still occur in approximately 50% of HIV patients, and therapies to combat HAND progression are urgently needed. HIV proteins are released from infected cells and cause neuronal damage, possibly through mitochondrial abnormalities. Altered mitochondrial fission and fusion is implicated in several neurodegenerative disorders. Here, we hypothesized that mitochondrial fission/fusion may be dysregulated in neurons during HAND. We have identified decreased mitochondrial fission protein (dynamin 1-like; DNM1L) in frontal cortex tissues of HAND donors, along with enlarged and elongated mitochondria localized to the soma of damaged neurons. Similar pathology was observed in the brains of GFAP-gp120 tg mice. In vitro, recombinant gp120 decreased total and active DNM1L levels, reduced the level of Mitotracker staining, and increased extracellular acidification rate (ECAR) in primary neurons. DNM1L knockdown enhanced the effects of gp120 as measured by reduced Mitotracker signal in the treated cells. Interestingly, overexpression of DNM1L increased the level of Mitotracker staining in primary rat neurons and reduced neuroinflammation and neurodegeneration in the GFAP-gp120-tg mice. These data suggest that mitochondrial biogenesis dynamics are shifted towards mitochondrial fusion in brains of HAND patients and this may be due to gp120-induced reduction in DNM1L activity. Promoting mitochondrial fission during HIV infection of the CNS may restore mitochondrial biogenesis and prevent neurodegeneration.

  10. HIV alters neuronal mitochondrial fission/fusion in the brain during HIV-Associated Neurocognitive Disorders

    PubMed Central

    Fields, Jerel Adam; Serger, Elisabeth; Campos, Sofia; Divakaruni, Ajit S.; Kim, Changyoun; Smith, Kendall; Trejo, Margarita; Adame, Anthony; Spencer, Brian; Rockenstein, Edward; Murphy, Anne N.; Ellis, Ronald J.; Letendre, Scott; Grant, Igor; Masliah, Eliezer

    2015-01-01

    HIV-associated neurocognitive disorders (HAND) still occur in approximately 50% of HIV patients, and therapies to combat HAND progression are urgently needed. HIV proteins are released from infected cells and cause neuronal damage, possibly through mitochondrial abnormalities. Altered mitochondrial fission and fusion is implicated in several neurodegenerative disorders. Here, we hypothesized that mitochondrial fission/fusion may be dysregulated in neurons during HAND. We have identified decreased mitochondrial fission protein (dynamin 1-like; DNM1L) in frontal cortex tissues of HAND donors, along with enlarged and elongated mitochondria localized to the soma of damaged neurons. Similar pathology was observed in the brains of GFAP-gp120 tg mice. In vitro, recombinant gp120 decreased total and active DNM1L levels, reduced the level of Mitotracker staining, and increased extracellular acidification rate (ECAR) in primary neurons. DNM1L knockdown enhanced the effects of gp120 as measured by reduced Mitotracker signal in the treated cells. Interestingly, overexpression of DNM1L increased the level of Mitotracker staining in primary rat neurons and reduced neuroinflammation and neurodegeneration in the GFAP-gp120-tg mice. These data suggest that mitochondrial biogenesis dynamics are shifted towards mitochondrial fusion in brains of HAND patients and this may be due to gp120-induced reduction in DNM1L activity. Promoting mitochondrial fission during HIV infection of the CNS may restore mitochondrial biogenesis and prevent neurodegeneration. PMID:26611103

  11. Engrailed Alters the Specificity of Synaptic Connections of Drosophila Auditory Neurons with the Giant Fiber

    PubMed Central

    Pézier, Adeline; Jezzini, Sami H.; Marie, Bruno

    2014-01-01

    We show that a subset of sound-detecting Johnston's Organ neurons (JONs) in Drosophila melanogaster, which express the transcription factors Engrailed (En) and Invected (Inv), form mixed electrical and chemical synaptic inputs onto the giant fiber (GF) dendrite. These synaptic connections are detected by trans-synaptic Neurobiotin (NB) transfer and by colocalization of Bruchpilot-short puncta. We then show that misexpressing En postmitotically in a second subset of sound-responsive JONs causes them to form ectopic electrical and chemical synapses with the GF, in turn causing that postsynaptic neuron to redistribute its dendritic branches into the vicinity of these afferents. We also introduce a simple electrophysiological recording paradigm for quantifying the presynaptic and postsynaptic electrical activity at this synapse, by measuring the extracellular sound-evoked potentials (SEPs) from the antennal nerve while monitoring the likelihood of the GF firing an action potential in response to simultaneous subthreshold sound and voltage stimuli. Ectopic presynaptic expression of En strengthens the synaptic connection, consistent with there being more synaptic contacts formed. Finally, RNAi-mediated knockdown of En and Inv in postmitotic neurons reduces SEP amplitude but also reduces synaptic strength at the JON–GF synapse. Overall, these results suggest that En and Inv in JONs regulate both neuronal excitability and synaptic connectivity. PMID:25164665

  12. Functional alterations in immature cultured rat hippocampal neurons after sustained exposure to static magnetic fields.

    PubMed

    Hirai, Takao; Yoneda, Yukio

    2004-01-15

    In cultured rat hippocampal neurons, gradual increases were seen in the expression of microtubule-associated protein-2 (MAP-2), neuronal nuclei (NeuN) and growth-associated protein-43 (GAP-43), in proportion to increased duration, up to 9 days in vitro (DIV). Sustained exposure to static magnetic fields at 100 mT for up to 9 DIV significantly decreased expression of MAP-2 and NeuN in cultured rat hippocampal neurons without markedly affecting GAP-43 expression. Although a significant increase was seen in the expression of glial fibrillary acidic protein (GFAP) in hippocampal neuronal preparations cultured for 6-9 DIV under sustained magnetism, GFAP and proliferating cell nuclear antigen expression were not affected markedly in cultured astrocytes prepared from rat hippocampus and neocortex, irrespective of cellular maturity. No significant alteration was seen in cell survivability of hippocampal neurons or astrocytes cultured under sustained magnetism. In hippocampal neurons cultured for 3 DIV under sustained magnetism, marked mRNA expression was seen for N-methyl-D-aspartate (NMDA) receptor subunits, NR1, NR2A-2C, NR2D, and NR3A. In addition, significant potentiation of the ability of NMDA to increase intracellular free Ca(2+) ions was observed. Differential display analysis revealed a significant decrease in mRNA expression for the transcription factor ALF1 in response to sustained magnetism for 3 DIV. These results suggest that sustained exposure to static magnetic fields may affect cellular functionality and maturity in immature cultured rat hippocampal neurons through modulation of expression of particular NMDA receptor subunits.

  13. Altered excitatory and inhibitory inputs to striatal medium-sized spiny neurons and cortical pyramidal neurons in the Q175 mouse model of Huntington's disease.

    PubMed

    Indersmitten, Tim; Tran, Conny H; Cepeda, Carlos; Levine, Michael S

    2015-04-01

    The Q175 knockin mouse model of Huntington's disease (HD) carries a CAG trinucleotide expansion of the human mutant huntingtin allele in its native mouse genomic context and recapitulates the genotype more closely than transgenic models. In this study we examined the progression of changes in intrinsic membrane properties and excitatory and inhibitory synaptic transmission, using whole cell patch-clamp recordings of medium-sized spiny neurons (MSNs) in the dorsolateral striatum and cortical pyramidal neurons (CPNs) in layers 2/3 of the primary motor cortex in brain slices from heterozygous (Q175(+/-)) and homozygous (Q175(+/+)) mice. Input resistance in MSNs from Q175(+/+) and Q175(+/-) mice was significantly increased compared with wild-type (WT) littermates beginning at 2 mo. Furthermore, the frequency of spontaneous and miniature excitatory postsynaptic currents (EPSCs) was significantly reduced in MSNs from Q175(+/+) and Q175(+/-) mice compared with WTs beginning at 7 mo. In contrast, the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) and IPSC-to-EPSC ratios were increased in MSNs from Q175(+/+) mice beginning at 2 mo. Morphologically, significant decreases in spine density of MSNs from Q175(+/-) and Q175(+/+) mice occurred at 7 and 12 mo. In CPNs, sIPSC frequencies and IPSC-to-EPSC ratios were significantly increased in Q175(+/-) mice compared with WTs at 12 mo. There were no changes in intrinsic membrane properties or morphology. In summary, we show a number of alterations in electrophysiological and morphological properties of MSNs in Q175 mice that are similar to other HD mouse models. However, unlike other models, CPN inhibitory activity is increased in Q175(+/-) mice, indicating reduced cortical excitability.

  14. Alterations of cortical excitability and central motor conduction time in Wilson's disease.

    PubMed

    Jhunjhunwala, Ketan; Prashanth, D K; Netravathi, M; Nagaraju, B C; Pal, Pramod Kr

    2013-10-11

    Wilson's disease (WD) leads to widespread structural alterations of central nervous system and our objectives were to determine the cortical excitability changes in WD by using transcranial magnetic stimulation (TMS). Thirteen patients with WD, diagnosed by the presence of Kayser-Fleischer ring and biochemical tests, were studied. TMS was performed using a figure-of-eight coil attached to Magstim 200 stimulator. Motor evoked potentials (MEP) were recorded from right first dorsal interosseous at rest. Resting motor threshold (RMT) was determined using standard techniques and central motor conduction time (CMCT) by 'F' wave method. Comparison was made with control data of our laboratory. Dysarthria was the presenting symptom in 5 patients (38.5%) and chorea, tremors, dystonia and abnormal gait in 2 patients each (15.4%). RMT was recordable in 10 patients and not recordable in 3. Compared to controls, patients in whom RMT was recordable, had significantly higher mean RMT (80.9 ± 14.8 vs. 41.1 ± 7, p<0.0001) and CMCT (6.7 ± 0.5 ms vs. 4.8 ± 0.6 ms; p<0.0001). In 2 of the 3 patients with non-recordable RMT, MEP could be obtained with active contraction. CMCT in these 2 patients was also prolonged. Patients with WD have reduced cortical excitability and prolonged CMCT which may be due to the intracortical presynaptic motor dysfunction.

  15. Hypocretin/Orexin Peptides Excite Rat Neuroendocrine Dopamine Neurons through Orexin 2 Receptor-Mediated Activation of a Mixed Cation Current

    PubMed Central

    Lyons, David J.; Hellysaz, Arash; Ammari, Rachida; Broberger, Christian

    2017-01-01

    Hypocretin/Orexin (H/O) neurons of the lateral hypothalamus are compelling modulator candidates for the chronobiology of neuroendocrine output and, as a consequence, hormone release from the anterior pituitary. Here we investigate the effects of H/O peptides upon tuberoinfundibular dopamine (TIDA) neurons – cells which control, via inhibition, the pituitary secretion of prolactin. In whole cell recordings performed in male rat hypothalamic slices, application of H/O-A, as well as H/O-B, excited oscillating TIDA neurons, inducing a reversible depolarising switch from phasic to tonic discharge. The H/O-induced inward current underpinning this effect was post-synaptic (as it endured in the presence of tetrodotoxin), appeared to be carried by a Na+-dependent transient receptor potential-like channel (as it was blocked by 2-APB and was diminished by removal of extracellular Na+), and was a consequence of OX2R receptor activation (as it was blocked by the OX2R receptor antagonist TCS OX2 29, but not the OX1R receptor antagonist SB 334867). Application of the hormone, melatonin, failed to alter TIDA membrane potential or oscillatory activity. This first description of the electrophysiological effects of H/Os upon the TIDA network identifies cellular mechanisms that may contribute to the circadian rhythmicity of prolactin secretion. PMID:28145492

  16. Optical Communication among Oscillatory Reactions and Photo-Excitable Systems: UV and Visible Radiation Can Synchronize Artificial Neuron Models.

    PubMed

    Gentili, Pier Luigi; Giubila, Maria Sole; Germani, Raimondo; Romani, Aldo; Nicoziani, Andrea; Spalletti, Anna; Heron, B Mark

    2017-06-19

    Neuromorphic engineering promises to have a revolutionary impact in our societies. A strategy to develop artificial neurons (ANs) is to use oscillatory and excitable chemical systems. Herein, we use UV and visible radiation as both excitatory and inhibitory signals for the communication among oscillatory reactions, such as the Belousov-Zhabotinsky and the chemiluminescent Orban transformations, and photo-excitable photochromic and fluorescent species. We present the experimental results and the simulations regarding pairs of ANs communicating by either one or two optical signals, and triads of ANs arranged in both feed-forward and recurrent networks. We find that the ANs, powered chemically and/or by the energy of electromagnetic radiation, can give rise to the emergent properties of in-phase, out-of-phase, anti-phase synchronizations and phase-locking, dynamically mimicking the communication among real neurons. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  17. CK2 activity is required for the interaction of FGF14 with voltage-gated sodium channels and neuronal excitability

    PubMed Central

    Hsu, Wei-Chun J.; Scala, Federico; Nenov, Miroslav N.; Wildburger, Norelle C.; Elferink, Hannah; Singh, Aditya K.; Chesson, Charles B.; Buzhdygan, Tetyana; Sohail, Maveen; Shavkunov, Alexander S.; Panova, Neli I.; Nilsson, Carol L.; Rudra, Jai S.; Lichti, Cheryl F.; Laezza, Fernanda

    2016-01-01

    Recent data shows that fibroblast growth factor 14 (FGF14) binds to and controls the function of the voltage-gated sodium (Nav) channel with phenotypic outcomes on neuronal excitability. Mutations in the FGF14 gene in humans have been associated with brain disorders that are partially recapitulated in Fgf14−/− mice. Thus, signaling pathways that modulate the FGF14:Nav channel interaction may be important therapeutic targets. Bioluminescence-based screening of small molecule modulators of the FGF14:Nav1.6 complex identified 4,5,6,7-tetrabromobenzotriazole (TBB), a potent casein kinase 2 (CK2) inhibitor, as a strong suppressor of FGF14:Nav1.6 interaction. Inhibition of CK2 through TBB reduces the interaction of FGF14 with Nav1.6 and Nav1.2 channels. Mass spectrometry confirmed direct phosphorylation of FGF14 by CK2 at S228 and S230, and mutation to alanine at these sites modified FGF14 modulation of Nav1.6-mediated currents. In 1 d in vitro hippocampal neurons, TBB induced a reduction in FGF14 expression, a decrease in transient Na+ current amplitude, and a hyperpolarizing shift in the voltage dependence of Nav channel steady-state inactivation. In mature neurons, TBB reduces the axodendritic polarity of FGF14. In cornu ammonis area 1 hippocampal slices from wild-type mice, TBB impairs neuronal excitability by increasing action potential threshold and lowering firing frequency. Importantly, these changes in excitability are recapitulated in Fgf14−/− mice, and deletion of Fgf14 occludes TBB-dependent phenotypes observed in wild-type mice. These results suggest that a CK2-FGF14 axis may regulate Nav channels and neuronal excitability.—Hsu, W.-C. J., Scala, F., Nenov, M. N., Wildburger, N. C., Elferink, H., Singh, A. K., Chesson, C. B., Buzhdygan, T., Sohail, M., Shavkunov, A. S., Panova, N. I., Nilsson, C. L., Rudra, J. S., Lichti, C. F., Laezza, F. CK2 activity is required for the interaction of FGF14 with voltage-gated sodium channels and neuronal

  18. Voltage-dependent currents of vertebrate neurons and their role in membrane excitability.

    PubMed

    Adams, P R; Galvan, M

    1986-01-01

    This chapter reviews what is known of the voltage-dependent conductances of three classes of vertebrate nerve cell, as assessed by somatic voltage clamping. These classes are: (1) bullfrog paravertebral sympathetic ganglion cells; (2) rodent superior cervical sympathetic ganglion cells; and (3) rodent hippocampal pyramidal cells. Of these, bullfrog neurons are the most thoroughly characterized. They possess at least seven distinct voltage-activated conductances. Two of these, called GNa and GCa, carry inward, depolarizing current. They both activate rapidly, and can, under appropriate conditions, generate action potentials. The remaining five conductances are all potassium-mediated, and can thus in principle produce hyperpolarizations or repolarize the action potential. However, because each of these potassium conductances have different sizes, speeds, and voltage thresholds, they play a variety of hyperpolarizing, stabilizing, or braking roles. IC is large, fast, and voltage dependent. Action potentials trigger calcium influx, which rapidly turns on IC. This repolarizes the action potential and turns off IC. However another Ca-dependent current, IAHP, remains active even at negative potentials and leads to a prolonged hyperpolarization. If IC is blocked, spike repolarization slows somewhat, allowing the Hodgkin-Huxley delayed rectifier current IK to develop. This is also large enough to repolarize the spike rapidly, although it is normally preempted by IC. IA and IM are other small potassium currents that activate at more negative potentials than do IC, IK, and IAHP. IA is a transient outward current that mainly influences voltage trajectories following hyperpolarizing current pulses. IM activates progressively during prolonged depolarizing current pulses, and, together with IAHP, explains most of the adaptation seen in these cells. The harmonious counterpoint of this septet of currents explains most of the electrical excitability properties of these cells

  19. Effects of time delay and random rewiring on the stochastic resonance in excitable small-world neuronal networks

    NASA Astrophysics Data System (ADS)

    Yu, Haitao; Wang, Jiang; Du, Jiwei; Deng, Bin; Wei, Xile; Liu, Chen

    2013-05-01

    The effects of time delay and rewiring probability on stochastic resonance and spatiotemporal order in small-world neuronal networks are studied in this paper. Numerical results show that, irrespective of the pacemaker introduced to one single neuron or all neurons of the network, the phenomenon of stochastic resonance occurs. The time delay in the coupling process can either enhance or destroy stochastic resonance on small-world neuronal networks. In particular, appropriately tuned delays can induce multiple stochastic resonances, which appear intermittently at integer multiples of the oscillation period of the pacemaker. More importantly, it is found that the small-world topology can significantly affect the stochastic resonance on excitable neuronal networks. For small time delays, increasing the rewiring probability can largely enhance the efficiency of pacemaker-driven stochastic resonance. We argue that the time delay and the rewiring probability both play a key role in determining the ability of the small-world neuronal network to improve the noise-induced outreach of the localized subthreshold pacemaker.

  20. A co-operative regulation of neuronal excitability by UNC-7 innexin and NCA/NALCN leak channel.

    PubMed

    Bouhours, Magali; Po, Michelle D; Gao, Shangbang; Hung, Wesley; Li, Hang; Georgiou, John; Roder, John C; Zhen, Mei

    2011-04-13

    Gap junctions mediate the electrical coupling and intercellular communication between neighboring cells. Some gap junction proteins, namely connexins and pannexins in vertebrates, and innexins in invertebrates, may also function as hemichannels. A conserved NCA/Dmα1U/NALCN family cation leak channel regulates the excitability and activity of vertebrate and invertebrate neurons. In the present study, we describe a genetic and functional interaction between the innexin UNC-7 and the cation leak channel NCA in Caenorhabditis elegans neurons. While the loss of the neuronal NCA channel function leads to a reduced evoked postsynaptic current at neuromuscular junctions, a simultaneous loss of the UNC-7 function restores the evoked response. The expression of UNC-7 in neurons reverts the effect of the unc-7 mutation; moreover, the expression of UNC-7 mutant proteins that are predicted to be unable to form gap junctions also reverts this effect, suggesting that UNC-7 innexin regulates neuronal activity, in part, th