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ATP P2X receptors and sensory synaptic transmission between primary afferent fibers and spinal dorsal horn neurons in rats  

Microsoft Academic Search

of the lumbar spinal cord were examined by whole cell patch- clamp recording techniques. Experiments were designed to test postsynaptic P21 receptors in synaptic transmission between if ATP could serve as a transmitter at the lumbar spinal cord. primary afferent fibers and dorsal horn neurons is still unclear. Monosynaptic excitatory postsynaptic currents ( EPSCs ) were com- ATP may serve




Functional Roles of High-Affinity Glutamate Transporters in Cochlear Afferent Synaptic Transmission in the Mouse  

PubMed Central

In the cochlea, afferent transmission between inner hair cells and auditory neurons is mediated by glutamate receptors. Glutamate transporters located near the synapse and in spiral ganglion neurons are thought to maintain low synaptic levels of glutamate. We analyzed three glutamate transporter blockers for their ability to alter the effects of glutamate, exogenously applied to the synapse via perfusion of the scala tympani of the mouse, and compared that action to their ability to alter the effects of intense acoustic stimulation. Threo-beta-benzyloxyaspartate (TBOA) is a broad-spectrum glutamate transporter antagonist, affecting all three transporters [glutamate/aspartate transporter (GLAST), glutamate transporter-1 (GLT1), and excitatory amino acid carrier 1 (EAAC1)]. l-serine-O-sulfate (SOS) blocks both GLAST and EAAC1 without effect on GLT1. Dihydrokainate (DHK) is selective for GLT1. Infusion of glutamate (10 ?M for 220 min), TBOA (200 ?M for 220 min), or SOS (100 ?M for 180 min) alone did not alter auditory neural thresholds. When infused together with glutamate, TBOA and SOS produced significant neural threshold shifts, leaving otoacoustic emissions intact. In addition, both TBOA and SOS exacerbated noise-induced hearing loss by producing larger neural threshold shifts and delaying recovery. DHK did not alter glutamate- or noise-induced hearing loss. The evidence points to a major role for GLAST, both in protecting the synapse from exposure to excess extracellular glutamate and in attenuating hearing loss due to acoustic overstimulation.

Chen, Zhiqiang; Kujawa, Sharon G.



Synaptic processes in thoracic ?-motoneurons evoked by segmental afferent stimulation  

Microsoft Academic Search

Synaptic processes in various functional groups of thoracic motoneurons (Th9-Th11) evoked by stimulation of segmental nerves were investigated in anesthetized and decerebrate cats. No reciprocal relations were found between these groups of motoneurons. Only excitatory mono- and polysynaptic responses were recorded in the motoneurons of the principal intercostal nerve following stimulation of the homonymous nerve. Activation of the afferents of

N. N. Preobrazhenskii; A. P. Gokin; I. S. Bezhenary



Cholinergic transmission from mechanosensory afferents to an identified nonspiking interneuron in the crayfish Procambarus clarkii girard  

Microsoft Academic Search

Pharmacological properties of excitatory synaptic transmission from mechanosensory afferents to an identifiable nonspiking interneuron of crayfish were studied by drug perfusion experiments using acetylcholine (ACh) agonists and antagonists. Application of carbachol, a general agonist of ACh, caused sustained depolarization of the interneuron and a decrease in the peak amplitude of its excitatory synaptic response to sensory stimulation on the soma

A. Takashima; M. Niwa; H. Nakamura; M. Takahata



Neurotransmitters and Synaptic Transmission  

Microsoft Academic Search

\\u000a The hair cell transmits information about an acoustic signal by releasing a neurotransmitter to excite afferent nerve fibers.\\u000a This results in discharge of the auditory nerve. The release of neurotransmitter by the hair cell is triggered by the entry\\u000a of calcium into the hair cell through voltage-dependent calcium (Vca) channels. Even in the absence of acoustic stimulation, the small resting

William F. Sewell


Frequency-independent synaptic transmission supports a linear vestibular behavior  

PubMed Central

Summary The vestibular system is responsible for transforming head motion into precise eye, head, and body movements that rapidly stabilize gaze and posture. How do central excitatory synapses mediate behavioral outputs accurately matched to sensory inputs over a wide dynamic range? Here we demonstrate that vestibular afferent synapses in vitro express frequency-independent transmission that spans their in vivo dynamic range (5 – 150 spikes/s). As a result, the synaptic charge transfer per unit time is linearly related to vestibular afferent activity in both projection and intrinsic neurons of the vestibular nuclei. Neither postsynaptic glutamate receptor desensitization nor saturation affect the relative amplitude or frequency-independence of steady-state transmission. Finally, we show that vestibular nucleus neurons can transduce synaptic inputs into linear changes in firing rate output, without relying on one-to-one calyceal transmission. These data provide a physiological basis for the remarkable linearity of vestibular reflexes.

Bagnall, Martha W.; McElvain, Lauren E.; Faulstich, Michael; du Lac, Sascha



Synaptic Transmission Correlates of General Mental Ability  

ERIC Educational Resources Information Center

Nerve conduction velocity (NCV) and efficiency of synaptic transmission are two possible biological mechanisms that may underpin intelligence. Direct assessments of NCV, without synaptic transmission, show few substantial or reliable correlations with cognitive abilities ["Intelligence" 16 (1992) 273]. We therefore assessed the latencies of…

McRorie, Margaret; Cooper, Colin



Synaptic Transmission in Sympathetic Ganglia.  

National Technical Information Service (NTIS)

Properties of the atropine-sensitive slow synaptic responses in mammalian sympathetic ganglia were further analysed as to their 1) postsynaptic origin, 2) transmitter substances, and 3) durations of synaptic delays for each. Intracellular studies on singl...

B. Libet



Inhibition of afferent transmission in the feeding circuitry of aplysia: persistence can be as important as size.  


We are studying afferent transmission from a mechanoafferent, B21, to a follower, B8. During motor programs, afferent transmission is regulated so that it does not always occur. Afferent transmission is eliminated when spike propagation in B21 fails, i.e., when spike initiation is inhibited in one output region-B21's lateral process. Spike initiation in the lateral process is inhibited by the B52 and B4/5 cells. Individual B52 and B4/5-induced inhibitory postsynaptic potentials (IPSPs) in B21 differ. For example, the peak amplitude of a B4/5-induced IPSP is four times the amplitude of a B52 IPSP. Nevertheless, when interneurons fire in bursts at physiological (i.e., low) frequencies, afferent transmission is most effectively reduced by B52. Although individual B52-induced IPSPs are small, they have a long time constant and summate at low firing frequencies. Once IPSPs summate, they effectively block afferent transmission. In contrast, individual B4/5-induced IPSPs have a relatively short time constant and do not summate at low frequencies. B52 and B4/5 therefore differ in that once synaptic input from B52 becomes effective, afferent transmission is continuously inhibited. In contrast, periods of B4/5-induced inhibition are interspersed with relatively long intervals in which inhibition does not occur. Consequently, the probability that afferent transmission will be inhibited is low. In conclusion, it is widely recognized that afferent transmission can be regulated by synaptic input. Our experiments are, however, unusual in that they relate specific characteristics of postsynaptic potentials to functional inhibition. In particular we demonstrate the potential importance of the IPSP time constant. PMID:15625089

Evans, Colin G; Romero, Adarli; Cropper, Elizabeth C



Functional specializations of primary auditory afferents on the Mauthner cells: interactions between membrane and synaptic properties.  


Primary auditory afferents are usually perceived as passive, timing-preserving, lines of communication. Contrasting this view, a special class of auditory afferents to teleost Mauthner cells, a command neuron that organizes tail-flip escape responses, undergoes potentiation of their mixed (electrical and chemical) synapses in response to high frequency cellular activity. This property is likely to represent a mechanism of input sensitization as these neurons provide the Mauthner cell with essential information for the initiation of an escape response. We review here the anatomical and physiological specializations of these identifiable auditory afferents. In particular, we discuss how their membrane and synaptic properties act in concert to more efficaciously activate the Mauthner cells. The striking functional specializations of these neurons suggest that primary auditory afferents might be capable of more sophisticated contributions to auditory processing than has been generally recognized. PMID:19941953

Curti, Sebastian; Pereda, Alberto E



GPCR Mediated Regulation of Synaptic Transmission  

PubMed Central

Synaptic transmission is a finely regulated mechanism of neuronal communication. The release of neurotransmitter at the synapse is not only the reflection of membrane depolarization events, but rather, is the summation of interactions between ion channels, G protein coupled receptors, second messengers, and the exocytotic machinery itself which exposes the components within a synaptic vesicle to the synaptic cleft. The focus of this review is to explore the role of G protein signaling as it relates to neurotransmission, as well as to discuss the recently determined inhibitory mechanism of G?? dimers acting directly on the exocytotic machinery proteins to inhibit neurotransmitter release.

Betke, Katherine M.; Wells, Christopher A.; Hamm, Heidi E.



Hyperpolarization-activated and cyclic nucleotide-gated cation channel subunit 2 ion channels modulate synaptic transmission from nociceptive primary afferents containing substance P to secondary sensory neurons in laminae I-IIo of the rodent spinal dorsal horn  

Microsoft Academic Search

We have previously demonstrated that hyperpolarization-activated and cyclic nucleotide-gated cation channel subunit 2 (HCN2) is expressed by terminals of peptidergic nociceptive primary afferents in laminae I-IIo of the rat spinal dorsal horn. In this study, we investigated the possible neurotransmitters and postsynaptic targets of these HCN2-expressing primary afferent terminals in the superficial spinal dorsal horn by using immunocytochemical methods. We

Ildikó Papp; Krisztina Holló; Ferenc Erdélyi; Gábor Szabó; Miklós Antal



Segmental and supraspinal control of synaptic effectiveness of functionally identified muscle afferents in the cat.  


The present investigation documents the patterns of primary afferent depolarization (PAD) of single, functionally identified muscle afferents from the medial gastrocnemius nerve in the intact, anesthetized cat. Classification of the impaled muscle afferents as from muscle spindles or from tendon organs was made according to several criteria, which comprised measurement of conduction velocity and electrical threshold of the peripheral axons, and the maximal frequency followed by the afferent fibers during vibration, as well as the changes in discharge frequency during longitudinal stretch, the projection of the afferent fiber to the motor pool, and, in unparalyzed preparations, the changes in afferent activity during a muscle twitch. In confirmation of a previous study, we found that most muscle spindle afferents (46.1-66.6%, depending on the combination of criteria utilized for receptor classification) had a type A PAD pattern. That is, they were depolarized by stimulation of group I fibers of the posterior biceps and semitendinosus (PBSt) nerve, but not by stimulation of cutaneous nerves (sural and superficial peroneus) or the bulbar reticular formation (RF), which in many cases inhibited the PBSt-induced PAD. In addition, we found a significant fraction of muscle spindle primaries that were depolarized by stimulation of group I PBSt fibers and also by stimulation of the bulbar RF. Stimulation of cutaneous nerves produced PAD in 9.1-31.2% of these fibers (type B PAD pattern) and no PAD in 8.2-15.4% (type C PAD pattern). In contrast to muscle spindle afferents, only the 7.7-15.4% of fibers from tendon organs had a type A PAD pattern, 23-46.1% had a type B and 50-61.5% a type C PAD pattern. These observations suggest that the neuronal circuitry involved in the control of the synaptic effectiveness of muscle spindles and tendon organs is subjected to excitatory as well as to inhibitory influences from cutaneous and reticulospinal fibers. As shown in the accompanying paper, the balance between excitation and inhibition is not fixed, but can be changed by crushing the afferent axons in the peripheral nerve and allowing subsequent reconnection of these afferent fibers with muscle receptors. PMID:8821381

Enríquez, M; Jiménez, I; Rudomin, P



What is transmitted in "synaptic transmission"?  

NSDL National Science Digital Library

Even students that obtain a high grade in neurophysiology often carry away a serious misconception concerning the final result of the complex set of events that follows the arrival of an action potential at the presynaptic terminal. The misconception consists in considering that "at a synapse, information is passed on from one neuron to the next" is equivalent to (and often expressed explicitly as) "the action potential passes from one neuron to the next." More than half of four groups of students who were asked to comment on an excerpt from a recent physiology textbook that openly stated the misconception had no clear objection to the text presented. We propose that the first culprit in generating this misconception is the term "synaptic transmission," which promotes the notion of transferring something or passing something along (implicitly unchanged). To avoid establishing this misconception, the first simple suggestion is to use words like "synaptic integration" rather than "synaptic transmission" right from the start. More generally, it would be important to focus on the function of synaptic events rather than on rote listing of all the numerous steps that are known to occur, which are so complex as to saturate the mind of the student.

Erik Montagna (Institute of Chemistry); Adriana M. S. de Azevedo (Institute of Biomedical Sciences, University of SĂÂŁo Paulo); Camilla Romano (FacoltĂ  di Medicina e Chirurgia); Ronald Ranvaud (Institute of Biomedical Sciences, University of SĂÂŁo Paulo)



The Neurobiology of Slow Synaptic Transmission  

Microsoft Academic Search

Nerve cells communicate with each other through two mechanisms, referred to as fast and slow synaptic transmission. Fast-acting neurotransmitters, e.g., glutamate (excitatory) and gamma-aminobutyric acid (GABA) (inhibitory), achieve effects on their target cells within one millisecond by virtue of opening ligand-operated ion channels. In contrast, all of the effects of the biogenic amine and peptide neurotransmitters, as well as many

Paul Greengard



Distinct muscarinic receptors enhance spontaneous GABA release and inhibit electrically evoked GABAergic synaptic transmission in the chick lateral spiriform nucleus  

Microsoft Academic Search

The effects of muscarinic agonists on GABAergic synaptic transmission were examined using whole-cell patch-clamp recording in chick brain slices containing the lateral spiriform nucleus. Bath application of muscarine (10 ?M) both increased the frequency of spontaneous GABAergic postsynaptic currents and reduced the amplitude of evoked GABAergic polysynaptic postsynaptic currents elicited by focal afferent fiber electrical stimulation. Both of these muscarinic

J.-Z Guo; V. A Chiappinelli



post-synaptic excitation and inhibition from primary afferents in neurones of the spinocervical tract  

PubMed Central

1. Intra- and extracellular recordings were made from cells of the spinocervical tract in the lumbosacral spinal cord. A convergence of monosynaptic excitatory post-synaptic potentials (EPSPs) and disynaptic inhibitory post-synaptic potentials (IPSPs) was a general pattern of effects from the low threshold cutaneous fibres. Unitary IPSPs, probably mediated via the same disynaptic path, were evoked by light touch of hairs, which was also the adequate stimulus for exciting the cells. The receptive field for unitary IPSPs was closely related to the excitatory receptive field but was eccentric, not of a surround type. 2. EPSPs, IPSPs, or both, were evoked from the flexor reflex afferents in the great majority of neurones. Disynaptic IPSPs may be evoked from the interosseous nerve. No effects were produced by volleys in group I muscle afferents. 3. It is suggested, on the basis of the spatial organization of the excitatory and inhibitory receptive skin fields, that the spinocervical tract may give information regarding the direction of tactile stimuli.

Hongo, T.; Jankowska, Elzbieta; Lundberg, A.



Detection of weak synaptic interactions between single Ia afferent and motor-unit spike trains in the decerebrate cat.  

PubMed Central

1. Spike trains from identified single Ia afferents from soleus and lateral gastrocnemius muscles were recorded (while 'in continuity' with the spinal cord) simultaneously with single-motor-unit EMG spike trains from the same muscles in decerebrate cats. 2. A total of 143 Ia afferent-motor-unit pairs were examined for the presence of correlated activity between the Ia afferent and motor-unit and between the motor-unit and Ia afferent. Four types of correlation were identified on the basis of the cross-intensity function estimated for individual Ia afferent-motor-unit pairs. These correlations were attributed to the absence or presence of a central Ia afferent-motoneurone interaction or a peripheral motor-unit-muscle spindle interaction. 3. In addition to the cross-correlation-based second-order cross-intensity function, third-order cumulants were defined and used further to investigate Ia afferent-motor-unit interactions. A third-order cumulant density-based approach to signal processing offers improved signal-to-noise ratios, compared with the traditional product density approach, for parameters characterizing certain kinds of linear processes as well as a description of non-linear interactions. Two classes of third-order relations were described. One class was associated with a strong central connection and the other with a weak central connection. 4. Third-order cumulants estimated for Ia afferent-motor-unit pairs with significant second-order central correlations were able to detect a period of decreased motoneuronal excitability. In addition, temporal summation prior to spike initiation could be identified in cases where the afferent discharge was suitably high. 5. Third-order cumulants estimated for Ia afferent-motor-unit pairs in which no significant second-order central correlation existed identified the presence of weak synaptic interactions. It is argued that these interactions result from the summation from the recorded Ia afferent discharge and other spontaneous synaptic inputs to the motoneurone. 6. The results of the second-order cross-intensity analysis of Ia afferent-motor-unit interactions, combined with those from the third-order cumulant density analysis, showed that 77% of the recorded afferents had a detectable influence on motor-unit behaviour. 7. The results of this study suggest that the third-order cumulant, based on the analysis of spike trains, will provide a useful tool for detecting synaptic interactions not found by the use of the second-order cross-correlation histogram alone, and may also be used to estimate the time course of post-spike depression in motoneurones, as well as other non-linear regions of motoneurone membrane trajectory.

Conway, B A; Halliday, D M; Rosenberg, J R



Experience-Driven Axon Retraction in the Pharmacologically Inactivated Visual Cortex Does Not Require Synaptic Transmission  

PubMed Central

Background Experience during early postnatal development plays an important role in the refinement of specific neural connections in the brain. In the mammalian visual system, altered visual experiences induce plastic adaptation of visual cortical responses and guide rearrangements of afferent axons from the lateral geniculate nucleus. Previous studies using visual deprivation demonstrated that the afferents serving an open eye significantly retract when cortical neurons are pharmacologically inhibited by applying a ?-aminobutyric acid type A receptor agonist, muscimol, whereas those serving a deprived eye are rescued from retraction, suggesting that presynaptic activity can lead to the retraction of geniculocortical axons in the absence of postsynaptic activity. Because muscimol application suppresses the spike activity of cortical neurons leaving transmitter release intact at geniculocortical synapses, local synaptic interaction may underlie the retraction of active axons in the inhibited cortex. Method and Findings New studies reported here determined whether experience-driven axon retraction can occur in the visual cortex inactivated by blocking synaptic inputs. We inactivated the primary visual cortex of kittens by suppressing synaptic transmission with cortical injections of botulinum neurotoxin type E, which cleaves a synaptic protein, SNAP-25, and blocks transmitter release, and examined the geniculocortical axon morphology in the animals with normal vision and those deprived of vision binocularly. We found that afferent axons in the animals with normal vision showed a significant retraction in the inactivated cortex, as similarly observed in the muscimol-treated cortex, whereas the axons in the binocularly deprived animals were preserved. Conclusions Therefore, the experience-driven axon retraction in the inactivated cortex can proceed in the absence of synaptic transmission. These results suggest that presynaptic mechanisms play an important role in the experience-driven refinement of geniculocortical axons.

Watanabe, Kana; Morishima, Yu; Toigawa, Masahito; Hata, Yoshio



Potentiation of electrical and chemical synaptic transmission mediated by endocannabinoids.  


Endocannabinoids are well established as inhibitors of chemical synaptic transmission via presynaptic activation of the cannabinoid type 1 receptor (CB1R). Contrasting this notion, we show that dendritic release of endocannabinoids mediates potentiation of synaptic transmission at mixed (electrical and chemical) synaptic contacts on the goldfish Mauthner cell. Remarkably, the observed enhancement was not restricted to the glutamatergic component of the synaptic response but also included a parallel increase in electrical transmission. This effect involved the activation of CB1 receptors and was indirectly mediated via the release of dopamine from nearby varicosities, which in turn led to potentiation of the synaptic response via a cAMP-dependent protein kinase-mediated postsynaptic mechanism. Thus, endocannabinoid release can potentiate synaptic transmission, and its functional roles include the regulation of gap junction-mediated electrical synapses. Similar interactions between endocannabinoid and dopaminergic systems may be widespread and potentially relevant for the motor and rewarding effects of cannabis derivatives. PMID:18093525

Cachope, Roger; Mackie, Ken; Triller, Antoine; O'Brien, John; Pereda, Alberto E



Synaptic depression in the CA1 region of freely behaving mice is highly dependent on afferent stimulation parameters  

PubMed Central

Persistent synaptic plasticity has been subjected to intense study in the decades since it was first described. Occurring in the form of long-term potentiation (LTP) and long-term depression (LTD), it shares many cellular and molecular properties with hippocampus-dependent forms of persistent memory. Recent reports of both LTP and LTD occurring endogenously under specific learning conditions provide further support that these forms of synaptic plasticity may comprise the cellular correlates of memory. Most studies of synaptic plasticity are performed using in vitro or in vivo preparations where patterned electrical stimulation of afferent fibers is implemented to induce changes in synaptic strength. This strategy has proven very effective in inducing LTP, even under in vivo conditions. LTD in vivo has proven more elusive: although LTD occurs endogenously under specific learning conditions in both rats and mice, its induction has not been successfully demonstrated with afferent electrical stimulation alone. In this study we screened a large spectrum of protocols that are known to induce LTD either in hippocampal slices or in the intact rat hippocampus, to clarify if LTD can be induced by sole afferent stimulation in the mouse CA1 region in vivo. Low frequency stimulation at 1, 2, 3, 5, 7, or 10 Hz given in the range of 100 through 1800 pulses produced, at best, short-term depression (STD) that lasted for up to 60 min. Varying the administration pattern of the stimuli (e.g., 900 pulses given twice at 5 min intervals), or changing the stimulation intensity did not improve the persistency of synaptic depression. LTD that lasts for at least 24 h occurs under learning conditions in mice. We conclude that a coincidence of factors, such as afferent activity together with neuromodulatory inputs, play a decisive role in the enablement of LTD under more naturalistic (e.g., learning) conditions.

Goh, Jinzhong J.; Manahan-Vaughan, Denise



Glutamate transporters: confining runaway excitation by shaping synaptic transmission  

Microsoft Academic Search

Traditionally, glutamate transporters have been viewed as membrane proteins that harness the electrochemical gradient to slowly transport glutamate from the extracellular space into glial cells. However, recent studies have shown that glutamate transporters on glial and neuronal membranes also rapidly bind released glutamate to shape synaptic transmission. In this Review, we summarize the properties of glutamate transporters that influence synaptic

Anastassios V. Tzingounis; Jacques I. Wadiche



Multiple clusters of release sites formed by individual thalamic afferents onto cortical interneurons ensure reliable transmission  

PubMed Central

Summary Thalamic afferents supply the cortex with sensory information by contacting both excitatory neurons and inhibitory interneurons. Interestingly, thalamic contacts with interneurons constitute such a powerful synapse that even one afferent can fire interneurons, thereby driving feedforward inhibition. However, the spatial representation of this potent synapse on interneuron dendrites is poorly understood. Using Ca imaging and electron microscopy we show that an individual thalamic afferent forms multiple contacts with the interneuronal proximal dendritic arbor, preferentially near branch points. More contacts are correlated with larger amplitude synaptic responses. Each contact, consisting of a single bouton, can release up to 7 vesicles simultaneously, resulting in graded and reliable Ca transients. Computational modeling indicates that the release of multiple vesicles at each contact minimally reduces the efficiency of the thalamic afferent in exciting the interneuron. This strategy preserves the spatial representation of thalamocortical inputs across the dendritic arbor over a wide range of release conditions.

Bagnall, Martha W.; Hull, Court; Bushong, Eric A.; Ellisman, Mark H.; Scanziani, Massimo



Developmental Changes in Calcium Channel Types Mediating Central Synaptic Transmission  

Microsoft Academic Search

Multiple types of high-voltage-activated Ca 21 channels trigger neurotransmitter release at the mammalian central synapse. Among them, the v-conotoxin GVIA-sensitive N-type channels and the v-Aga-IVA-sensitive P\\/Q-type channels mediate fast synaptic transmission. However, at most central synapses, it is not known whether the contributions of different Ca 21 channel types to synaptic transmission remain stable throughout post- natal development. We have

Shinichi Iwasaki; Akiko Momiyama; Osvaldo D. Uchitel; Tomoyuki Takahashi



Segmental and supraspinal control of synaptic effectiveness of functionally identified muscle afferents in the cat  

Microsoft Academic Search

The present investigation documents the patterns of primary afferent depolarization (PAD) of single, functionally identified muscle afferents from the medial gastrocnemius nerve in the intact, anesthetized cat. Classification of the impaled muscle afferents as from muscle spindles or from tendon organs was made according to several criteria, which comprised measurement of conduction velocity and electrical threshold of the peripheral axons,

M. Enríquez; I. Jiménez; P. Rudomin



Laminar Selectivity of the Cholinergic Suppression of Synaptic Transmission in Rat Hippocampal Region CA 1: Computational Modeling and Brain Slice Physiology  

Microsoft Academic Search

ACh may set the dynamics of cortical function to those ap- propriate for learning new information. In models of the pu- tative associative memory function of piriform cortex, se- lective suppression of intrinsic but not afferent fiber synaptic transmission by ACh prevents recall of previous input from interfering with the learning of new input (Hasselmo, 1993). Selective cholinergic suppression may

Michael E. Hasselmo; Eric Schnell


Minireview: pH and synaptic transmission.  


As a general rule a rise in pH increases neuronal activity, whereas it is dampened by a fall of pH. Neuronal activity per se also challenges pH homeostasis by the increase of metabolic acid equivalents. Moreover, the negative membrane potential of neurons promotes the intracellular accumulation of protons. Synaptic key players such as glutamate receptors or voltage-gated calcium channels show strong pH dependence and effects of pH gradients on synaptic processes are well known. However, the processes and mechanisms that allow controlling the pH in synaptic structures and how these mechanisms contribute to normal synaptic function are only beginning to be resolved. PMID:23669358

Sinning, Anne; Hübner, Christian A



Synaptic transmission at retinal ribbon synapses  

PubMed Central

The molecular organization of ribbon synapses in photoreceptors and ON bipolar cells is reviewed in relation to the process of neurotransmitter release. The interactions between ribbon synapse-associated proteins, synaptic vesicle fusion machinery and the voltage-gated calcium channels that gate transmitter release at ribbon synapses are discussed in relation to the process of synaptic vesicle exocytosis. We describe structural and mechanistic specializations that permit the ON bipolar cell to release transmitter at a much higher rate than the photoreceptor does, under in vivo conditions. We also consider the modulation of exocytosis at photoreceptor synapses, with an emphasis on the regulation of calcium channels.

Heidelberger, Ruth; Thoreson, Wallace B.; Witkovsky, Paul



Drosophila Neuroligin 2 is Required Presynaptically and Postsynaptically for proper Synaptic Differentiation and Synaptic Transmission  

PubMed Central

Trans-synaptic adhesion between Neurexins and Neuroligins is thought to be required for proper synapse organization and modulation, and mutations in several human NEUROLIGINS have shown association with autism spectrum disorders (ASD). Here we report the generation and phenotypic characterization of Drosophila neuroligin 2 (dnlg2) mutants. Loss of dnlg2 results in reduced bouton numbers, aberrant pre- and post-synaptic development at neuromuscular junctions (NMJs), and impaired synaptic transmission. In dnlg2 mutants, the evoked responses are decreased in amplitude, whereas the total active zone numbers at the NMJ are comparable to wild type, suggesting a decrease in the release probability. Ultrastructurally, the presynaptic active zone number per bouton area and the postsynaptic density area are both increased in dnlg2 mutants, whereas the subsynaptic reticulum (SSR) is reduced in volume. We show that both pre- and post-synaptic expression of Dnlg2 is required to restore synaptic growth and function in dnlg2 mutants. Post-synaptic expression of Dnlg2 in dnlg2 mutants and wild type leads to reduced bouton growth whereas pre- and post-synaptic overexpression in wild type animals results in synaptic overgrowth. Since Neuroligins have been shown to bind to Neurexins, we created double mutants. These mutants are viable and display phenotypes that closely resemble those of dnlg2 and dnrx single mutants. Our results provide compelling evidence that Dnlg2 functions both pre- and post-synaptically together with Neurexin to determine the proper number of boutons as well as the number of active zones and size of synaptic densities during the development of NMJs.

Chen, Yu-Chi; Lin, Yong Qi; Banerjee, Swati; Venken, Koen; Li, Jingjun; Ismat, Afshan; Chen, Kuchuan; Duraine, Lita; Bellen, Hugo J.; Bhat, Manzoor A.



Calcium-sensing receptor activation depresses synaptic transmission.  


At excitatory synapses, decreases in cleft [Ca] arising from activity-dependent transmembrane Ca flux reduce the probability of subsequent transmitter release. Intense neural activity, induced by physiological and pathological stimuli, disturb the external microenvironment reducing extracellular [Ca] ([Ca](o)) and thus may impair neurotransmission. Increases in [Ca](o) activate the extracellular calcium sensing receptor (CaSR) which in turn inhibits nonselective cation channels at the majority of cortical nerve terminals. This pathway may modulate synaptic transmission by attenuating the impact of decreases in [Ca](o) on synaptic transmission. Using patch-clamp recording from isolated cortical terminals, cortical neuronal pairs and isolated neuronal soma we examined the modulation of synaptic transmission by CaSR. EPSCs were increased on average by 88% in reduced affinity CaSR-mutant (CaSR(-/-)) neurons compared with wild-type. Variance-mean analysis indicates that the enhanced synaptic transmission was due largely to an increase in average probability of release (0.27 vs 0.46 for wild-type vs CaSR(-/-) pairs) with little change in quantal size (23 +/- 4 pA vs 22 +/- 4 pA) or number of release sites (11 vs 13). In addition, the CaSR agonist spermidine reduced synaptic transmission and increased paired-pulse depression at physiological [Ca](o). Spermidine did not affect quantal size, consistent with a presynaptic mechanism of action, nor did it affect voltage-activated Ca channel currents. In summary, reduced CaSR function enhanced synaptic transmission and CaSR stimulation had the opposite effect. Thus CaSR provides a mechanism that may compensate for the fall in release probability that accompanies decreases in [Ca](o). PMID:19005071

Phillips, Cecilia G; Harnett, Mark T; Chen, Wenyan; Smith, Stephen M



Low-frequency stimulation of trigeminal afferents induces long-term depression of human sensory processing  

Microsoft Academic Search

Electric low-frequency stimulation (LFS) of afferent nerve fibers reliably induces long-term depression (LTD) of synaptic transmission in vitro. LTD is suggested to be one important mechanism of synaptic plasticity in the mammalian brain. The study demonstrated an LTD of evoked cortical potentials (?30%) and perception ratings (?25%) by noxious electric LFS of trigeminal afferents in man, indicating that LTD may

Jens Ellrich; Anila Schorr



John Eccles' pioneering role in understanding central synaptic transmission.  


This chapter deals with the central role that Sir John Eccles played in the elucidation of the mechanisms of synaptic transmission within the central nervous system during the three decades between the late 1930s and 1966. His seminal discoveries involved studies of synaptic input to spinal motoneurons using intracellular recording via glass micropipettes after their introduction in the late 1940s. After defending the hypothesis that electrical currents alone explained central synaptic events, his observations of reversal potentials and sensitivity to ion injections instantly converted Eccles to the idea that central synapses generate postsynaptic potentials, designated IPSPs and EPSPs, by liberating chemical transmitters. He and his collaborators used pharmacological manipulations of recurrent inhibition to support the idea that a given neuron liberates the same chemical transmitter substance at all of its synapses, which he called "Dale's Principle". His team worked out the mechanisms and spinal circuits underlying disynaptic and recurrent inhibition, as well as those of presynaptic inhibition. Not content with the view that central synapses were static entities, Eccles also made seminal observations on synaptic plasticity induced by alterations in use and disuse. Although his firmly held belief that the extensive dendritic trees of motoneurons were essentially irrelevant to synaptic events at the soma was later refuted by others in the mid-1960s, Eccles stands as a towering figure in the history of neuroscience. His prodigious energy and commanding intellect gave the field of central synaptic transmission the conceptual bases that have guided it for over 40 years. PMID:16647800

Burke, Robert E



Measuring action potential-evoked transmission at individual synaptic contacts  

NASA Astrophysics Data System (ADS)

In the neuronal culture experimental system, the total synaptic connection between two neurons can consist of large numbers of synaptic sites, each behaving probabilistically. Studies of synaptic function with paired recordings typically consider the summed response across all of these sites and from this infer the average response. Understanding of synaptic transmission and plasticity could be improved by examination of activity at as few synaptic sites as possible. To this end, we develop a system for recording responses from individual contacts. It relies on a precisely regulated pneumatic/hydrostatic pressure system to create a microenvironment within which individual synapses are active, and an acoustic signature method to monitor the stability of this microenvironment noninvasively. With this method we are able to record action potential-evoked postsynaptic currents consistent with individual quanta. The approach does not distort synaptic current waveforms and permits stable recording for several hours. The method is applied to address mechanisms of short-term plasticity, the variability of latency at individual synaptic sites and, in a preliminary experiment, the independence of nearby synapses on the same axon.

Nauen, David W.; Bi, Guo-Qiang



Estrogen Facilitates Spinal Cord Synaptic Transmission via Membrane-bound Estrogen Receptors  

PubMed Central

Recent evidence suggests that estrogen is synthesized in the spinal dorsal horn and plays a role in nociceptive processes. However, the cellular and molecular mechanisms underlying these effects remain unclear. Using electrophysiological, biochemical, and morphological techniques, we here demonstrate that 17?-estradiol (E2), a major form of estrogen, can directly modulate spinal cord synaptic transmission by 1) enhancing NMDA receptor-mediated synaptic transmission in dorsal horn neurons, 2) increasing glutamate release from primary afferent terminals, 3) increasing dendritic spine density in cultured spinal cord dorsal horn neurons, and 4) potentiating spinal cord long term potentiation (LTP) evoked by high frequency stimulation (HFS) of Lissauer's tract. Notably, E2-BSA, a ligand that acts only on membrane estrogen receptors, can mimic E2-induced facilitation of HFS-LTP, suggesting a nongenomic action of this neurosteroid. Consistently, cell surface biotinylation demonstrated that three types of ERs (ER?, ER?, and GPER1) are localized on the plasma membrane of dorsal horn neurons. Furthermore, the ER? and ER? antagonist ICI 182,780 completely abrogates the E2-induced facilitation of LTP. ER? (but not ER?) activation can recapitulate E2-induced persistent increases in synaptic transmission (NMDA-dependent) and dendritic spine density, indicating a critical role of ER? in spinal synaptic plasticity. E2 also increases the phosphorylation of ERK, PKA, and NR2B, and spinal HFS-LTP is prevented by blockade of PKA, ERK, or NR2B activation. Finally, HFS increases E2 release in spinal cord slices, which can be prevented by aromatase inhibitor androstatrienedione, suggesting activity-dependent local synthesis and release of endogenous E2.

Zhang, Yan; Xiao, Xiao; Zhang, Xiao-Meng; Zhao, Zhi-Qi; Zhang, Yu-Qiu



Scaffold remodeling in space and time controls synaptic transmission  

PubMed Central

Scaffolding proteins that are associated with glutamate receptors in dendritic spines govern the location and function of receptors to control synaptic transmission. Unraveling the spatio-temporal dynamics of protein-protein interactions within components of the scaffolding complex will bring to light the function of these interactions. Combining bioluminescence resonance energy transfer (BRET) imaging to electrophysiological recordings, we have recently shown that GKAP, a core protein of the scaffolding complex, interacts with DLC2, a protein associated with molecular motors. Synaptic activity-induced GKAP-DLC2 interaction in spines stabilizes the scaffolding complex and enhances the NMDA currents. Interestingly, this work placed emphasis on the bioarchitectural dependence of protein-protein interaction dynamics. Depending on physiological conditions, the modulation in space and time of protein-protein interaction is acutely regulated, engendering a subtle control of synaptic transmission in the state of the individual synapse.

Perroy, Julie; Moutin, Enora



Defective Glycinergic Synaptic Transmission in Zebrafish Motility Mutants  

PubMed Central

Glycine is a major inhibitory neurotransmitter in the spinal cord and brainstem. Recently, in vivo analysis of glycinergic synaptic transmission has been pursued in zebrafish using molecular genetics. An ENU mutagenesis screen identified two behavioral mutants that are defective in glycinergic synaptic transmission. Zebrafish bandoneon (beo) mutants have a defect in glrbb, one of the duplicated glycine receptor (GlyR) ? subunit genes. These mutants exhibit a loss of glycinergic synaptic transmission due to a lack of synaptic aggregation of GlyRs. Due to the consequent loss of reciprocal inhibition of motor circuits between the two sides of the spinal cord, motor neurons activate simultaneously on both sides resulting in bilateral contraction of axial muscles of beo mutants, eliciting the so-called ‘accordion’ phenotype. Similar defects in GlyR subunit genes have been observed in several mammals and are the basis for human hyperekplexia/startle disease. By contrast, zebrafish shocked (sho) mutants have a defect in slc6a9, encoding GlyT1, a glycine transporter that is expressed by astroglial cells surrounding the glycinergic synapse in the hindbrain and spinal cord. GlyT1 mediates rapid uptake of glycine from the synaptic cleft, terminating synaptic transmission. In zebrafish sho mutants, there appears to be elevated extracellular glycine resulting in persistent inhibition of postsynaptic neurons and subsequent reduced motility, causing the ‘twitch-once’ phenotype. We review current knowledge regarding zebrafish ‘accordion’ and ‘twitch-once’ mutants, including beo and sho, and report the identification of a new ?2 subunit that revises the phylogeny of zebrafish GlyRs.

Hirata, Hiromi; Carta, Eloisa; Yamanaka, Iori; Harvey, Robert J.; Kuwada, John Y.



A neural synaptic compression codec for efficient image transmission  

Microsoft Academic Search

For efficient cellular communication channel usage, we propose a neural computation model for image coding. In a constant-time unsupervised learning, our neural model approximates optimal pattern clustering from training example images through a memory adaptation process, and builds a compression codebook in its synaptic weight matrix. This neural codebook can be distributed to both ends of a transmission channel for

Willie Chang; Hamdy S. Soliman



Progesterone Regulation of Synaptic Transmission and Plasticity in Rodent Hippocampus  

ERIC Educational Resources Information Center

|Ovarian hormones influence memory formation by eliciting changes in neural activity. The effects of various concentrations of progesterone (P4) on synaptic transmission and plasticity associated with long-term potentiation (LTP) and long-term depression (LTD) were studied using in vitro hippocampal slices. Extracellular studies show that the…

Foy, Michael R.; Akopian, Garnik; Thompson, Richard F.



Progesterone Regulation of Synaptic Transmission and Plasticity in Rodent Hippocampus  

ERIC Educational Resources Information Center

Ovarian hormones influence memory formation by eliciting changes in neural activity. The effects of various concentrations of progesterone (P4) on synaptic transmission and plasticity associated with long-term potentiation (LTP) and long-term depression (LTD) were studied using in vitro hippocampal slices. Extracellular studies show that the…

Foy, Michael R.; Akopian, Garnik; Thompson, Richard F.



An evaluation of causes for unreliability of synaptic transmission.  

PubMed Central

Transmission at individual synaptic contacts on CA1 hippocampal pyramidal neurons has been found to be very unreliable, with greater than half of the arriving presynaptic nerve impulses failing to evoke a postsynaptic response. This conclusion has been reached using the method of minimal stimulation of Schaffer collaterals and whole cell recording in hippocampal slices; with minimal stimulation only one or a few synapses are activated on the target neuron and the behavior of individual synapses can be examined. Four sources for the unreliability of synaptic transmission have been investigated: (i) the fluctuation of axon thresholds at the site of stimulation causing the failure to generate a nerve impulse in the appropriate Schaffer collaterals, (ii) the failure of nerve impulses generated at the site of stimulation to arrive at the synapse because of conduction failures at axon branch points, (iii) an artifactual synaptic unreliability due to performing experiments in vitro at temperatures well below the normal mammalian body temperature, and (iv) transmission failures due to probabilistic release mechanisms at synapses with a very low capacity to release transmitter. We eliminate the first three causes as significant contributions and conclude that probabilistic release mechanisms at low capacity synapses are the main cause of unreliability of synaptic transmission. Images

Allen, C; Stevens, C F



Depression of transmission from group II muscle afferents by electrical stimulation of the cuneiform nucleus in the cat  

Microsoft Academic Search

The effects of short trains of electrical stimuli applied within the cuneiform nucleus and the subcuneiform region were examined on transmission from group I and group II muscle afferents to first-order spinal neurons. Variations in the effectiveness of transmission from these afferents were assessed from changes in the sizes of the monosynaptic component of extracellular field potentials evoked following stimulation

B. R. Noga; E. Jankowska; B. Skoog



Odor-Specific Habituation Arises from Interaction of Afferent Synaptic Adaptation and Intrinsic Synaptic Potentiation in Olfactory Cortex  

ERIC Educational Resources Information Center

|Segmentation of target odorants from background odorants is a fundamental computational requirement for the olfactory system and is thought to be behaviorally mediated by olfactory habituation memory. Data from our laboratory have shown that odor-specific adaptation in piriform neurons, mediated at least partially by synaptic adaptation between…

Linster, Christiane; Menon, Alka V.; Singh, Christopher Y.; Wilson, Donald A.



Central Cholinesterase Inhibition Enhances Glutamatergic Synaptic Transmission  

PubMed Central

Central cholinergic overstimulation results in prolonged seizures of status epilepticus in humans and experimental animals. Cellular mechanisms of underlying seizures caused by cholinergic stimulation remain uncertain, but enhanced glutamatergic transmission is a potential mechanism. Paraoxon, an organophosphate cholinesterase inhibitor, enhanced glutamatergic transmission on hippocampal granule cells synapses by increasing the frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) in a concentration-dependent fashion. The amplitude of mEPSCs was not increased, which suggested the possibility of enhanced action potential-dependent release. Analysis of EPSCs evoked by minimal stimulation revealed reduced failures and increased amplitude of evoked responses. The ratio of amplitudes of EPSCs evoked by paired stimuli was also altered. The effect of paraoxon on glutamatergic transmission was blocked by the muscarinic antagonist atropine and partially mimicked by carbachol. The nicotinic receptor antagonist ? -bungarotoxin did not block the effects of paraoxon; however, nicotine enhanced glutamatergic transmission. These studies suggested that cholinergic overstimulation enhances glutamatergic transmission by enhancing neurotransmitter release from presynaptic terminals.

Kozhemyakin, Maxim; Rajasekaran, Karthik



Synaptic Physiology of Horizontal Afferents to Layer I in Slices of Rat SI Neocortex  

Microsoft Academic Search

Layer I is a dense synaptic zone ubiquitous in cerebral cor- tex. Here we describe a novel in vitro preparation of rat somatosensory (9) neocortical slices that isolates the fibers that extend horizontally through layer I, and allows intracel- lular and extracellular analysis of synaptic input to dendrites in layer I. Current source-density analysis of this isolated horizontal layer I

Lawrence J. Cauller; Barry W. Connors



Effect of barbiturates on `quantal' synaptic transmission in spinal motoneurones  

PubMed Central

1. Monosynaptic excitatory post-synaptic potentials (EPSPs) produced in triceps surae motoneurones of the cat by stimulation of single afferent fibres in the muscle nerve were recorded with intracellular electrodes before and after the administration of thiopentone or pentobarbitone. 2. The average amplitude of the `unit' EPSP was 0·11-0·21 mV and remained unchanged after the administration of the barbiturates (10 mg/kg, I.V.). 3. Mean quantum content (m) ranged from 1·9 to more than 5 before drug administration. The m was reduced by thiopentone (10 mg/kg, I.V.) and pentobarbitone (10 mg/kg, I.V.) by 23·1 and 24·7% respectively. 4. The barbiturates, in the doses employed, produced no alterations in the input resistance of the motoneurone membrane or in the strength—duration relation obtained by passing depolarizing current pulses through the micro-electrode. 5. It is concluded that the action of thiopentone and pentobarbitone, in the doses used, is confined to the presynaptic nerve terminals and results in a reduction in the amount of transmitter released by afferent impulses.

Weakly, J. N.



The action of carbon dioxide on afferent transmission in the dorsal column--lemniscal system  

PubMed Central

1. Transmission in the lemniscal afferent pathway was studied in thirteen decerebrate, unanaesthetized cats while changing the concentration of inspired PCO2. 2. 2-20% CO2, when inhaled for ? 10 min, raised the mean tissue PCO2, recorded from the surface of the medulla or cerebellum, from 22 torr to between 26 and 93 torr. 3. Medial lemniscal potentials were evoked by stimulation of a forelimb nerve and recorded from the transected surface of the contralateral mid-brain. The transmission of supramaximal responses was progressively and reversibly depressed as tissue levels of PCO2 were raised and lowered. The time course of the changes in transmission corresponded closely to changes in the tissue PCO2. 4. The amplitude of the main early lemniscal peak was decreased to 80% by the inhalation of 20% CO2. A late component of the lemniscal response, presumably due to repetitive firing and conduction in smaller fibres and polysynaptic pathways, was more affected than the early main response. 5. The failure of transmission was unrelated to threshold changes in the peripheral nerve, since potentials recorded close to the site of stimulation showed no changes. 6. Increases in the transmission time of the main lemniscal potentials were uniform and < 10% during the administration of CO2 and did not appear to contribute to amplitude changes. 7. The inhibition of afferent transmission from one nerve by a preceding conditioning volley in a second nerve was not altered by hypercarbia. 8. It is concluded that CO2 has a blocking action on afferent transmission in the pre-thalamic lemniscal system. The site of this block may be at the synapses and/or other regions of low safety factor in the afferent fibres.

Morris, Mary E.



MPTP-meditated hippocampal dopamine deprivation modulates synaptic transmission and activity-dependent synaptic plasticity  

SciTech Connect

Parkinson's disease (PD)-like symptoms including learning deficits are inducible by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Therefore, it is possible that MPTP may disturb hippocampal memory processing by modulation of dopamine (DA)- and activity-dependent synaptic plasticity. We demonstrate here that intraperitoneal (i.p.) MPTP injection reduces the number of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra (SN) within 7 days. Subsequently, the TH expression level in SN and hippocampus and the amount of DA and its metabolite DOPAC in striatum and hippocampus decrease. DA depletion does not alter basal synaptic transmission and changes pair-pulse facilitation (PPF) of field excitatory postsynaptic potentials (fEPSPs) only at the 30 ms inter-pulse interval. In addition, the induction of long-term potentiation (LTP) is impaired whereas the duration of long-term depression (LTD) becomes prolonged. Since both LTP and LTD depend critically on activation of NMDA and DA receptors, we also tested the effect of DA depletion on NMDA receptor-mediated synaptic transmission. Seven days after MPTP injection, the NMDA receptor-mediated fEPSPs are decreased by about 23%. Blocking the NMDA receptor-mediated fEPSP does not mimic the MPTP-LTP. Only co-application of D1/D5 and NMDA receptor antagonists during tetanization resembled the time course of fEPSP potentiation as observed 7 days after i.p. MPTP injection. Together, our data demonstrate that MPTP-induced degeneration of DA neurons and the subsequent hippocampal DA depletion alter NMDA receptor-mediated synaptic transmission and activity-dependent synaptic plasticity. - Highlights: > I.p. MPTP-injection mediates death of dopaminergic neurons. > I.p. MPTP-injection depletes DA and DOPAC in striatum and hippocampus. > I.p. MPTP-injection does not alter basal synaptic transmission. > Reduction of LTP and enhancement of LTD after i.p. MPTP-injection. > Attenuation of NMDA-receptors mediated fEPSPs after i.p. MPTP-injection.

Zhu Guoqi; Chen Ying; Huang Yuying [Institutes of Brain Science, Fudan University, 138 Yi Xue Yuan Road, Shanghai 200032 (China); State Key Laboratory of Medical Neurobiology, Fudan University, 138 Yi Xue Yuan Road, Shanghai 200032 (China); Li Qinglin [Key laboratory of XinAn Medicine, Anhui University of Traditional Chinese Medicine, Hefei 230038 (China); Behnisch, Thomas, E-mail: [Institutes of Brain Science, Fudan University, 138 Yi Xue Yuan Road, Shanghai 200032 (China); State Key Laboratory of Medical Neurobiology, Fudan University, 138 Yi Xue Yuan Road, Shanghai 200032 (China)



Calcium-dependent synaptic vesicle trafficking underlies indefatigable release at the hair cell afferent fiber synapse  

PubMed Central

Sensory hair cell ribbon synapses respond to graded stimulation in a linear, indefatigable manner, requiring that vesicle trafficking to synapses is rapid and non rate limiting. Real time monitoring of vesicle fusion identified two release components. The first was saturable with both release rate and magnitude varying linearly with Ca2+, however the magnitude was too small to account for sustained afferent firing rates. A second superlinear release component required recruitment, in a Ca2+-dependent manner, of vesicles not in the immediate vicinity of the synapse. The superlinear component had a constant rate with its onset varying with Ca2+ load. High-speed Ca2+ imaging revealed a nonlinear increase in internal Ca2+ correlating with the superlinear capacitance change, implicating release of stored Ca2+ in driving vesicle recruitment. These data, supported by a mass action model, suggest sustained release at hair cell afferent fiber synapse is dictated by Ca2+-dependent vesicle recruitment from a reserve pool.

Schnee, M.E.; Santos-Sacchi, J.; Castellano-Munoz, M.; Kong, J-H.; Ricci, A.J.



Synaptic connections from large afferents of wrist flexor and extensor muscles to synergistic motoneurones in man  

Microsoft Academic Search

Short-latency excitatory Ia reflex connections were determined between pairs of human wrist flexor and extensor muscles.\\u000a Spindle Ia afferents were stimulated by either tendon tap or electrical stimulation. The activity of voluntarily activated\\u000a single motor units was recorded intramuscularly from pairs of wrist flexor or extensor muscles. Cross-correlation between\\u000a stimuli and the discharge of the motor units provided a measure

G. R. Chalmers; P. Bawa



How do astrocytes shape synaptic transmission? Insights from electrophysiology  

PubMed Central

A major breakthrough in neuroscience has been the realization in the last decades that the dogmatic view of astroglial cells as being merely fostering and buffering elements of the nervous system is simplistic. A wealth of investigations now shows that astrocytes actually participate in the control of synaptic transmission in an active manner. This was first hinted by the intimate contacts glial processes make with neurons, particularly at the synaptic level, and evidenced using electrophysiological and calcium imaging techniques. Calcium imaging has provided critical evidence demonstrating that astrocytic regulation of synaptic efficacy is not a passive phenomenon. However, given that cellular activation is not only represented by calcium signaling, it is also crucial to assess concomitant mechanisms. We and others have used electrophysiological techniques to simultaneously record neuronal and astrocytic activity, thus enabling the study of multiple ionic currents and in depth investigation of neuro-glial dialogues. In the current review, we focus on the input such approach has provided in the understanding of astrocyte-neuron interactions underlying control of synaptic efficacy.

Dallerac, Glenn; Chever, Oana; Rouach, Nathalie



Regulation of synaptic transmission by mitochondrial ion channels.  


Mitochondria are abundant within neuronal presynaptic terminals, where they provide energy for sustained neurotransmitter secretion. Injection of Bcl-xL protein into squid giant presynaptic terminal potentiates neurotransmitter release, while a naturally occurring, proteolytic fragment of BCL-xL causes rundown of synaptic function. The cleaved form of BCL-xL generates large, multiconductance ion channel activity in synaptic mitochondrial outer membranes. A rapid onset of synaptic rundown can also be produced by depriving the synapse of oxygen, and hypoxia also induces large channel activity in mitochondrial outer membranes. Channel activity induced by cleaved BCL-xL or by hypoxia is attenuated by NADH, an inhibitor of the voltage-dependent anion channel (VDAC) of mitochondrial outer membranes. Finally, the large conductances elicited by hypoxia are prevented by the addition of a protease inhibitor that prevents cleavage of BCL-xL. The opposing activities of BCL-xL and its proteolytic fragment may regulate the release of ATP from mitochondria during synaptic transmission. PMID:15377872

Jonas, Elizabeth



Alcohol effects on synaptic transmission in periaqueductal gray dopamine neurons.  


The role of dopamine (DA) signaling in regulating the rewarding properties of drugs, including alcohol, has been widely studied. The majority of these studies, however, have focused on the DA neurons located in the ventral tegmental area (VTA), and their projections to the nucleus accumbens. DA neurons within the ventral periaqueductal gray (vPAG) have been shown to regulate reward but little is known about the functional properties of these neurons, or how they are modified by drugs of abuse. This lack of knowledge is likely due to the highly heterogeneous cell composition of the vPAG, with both ?-aminobutyric acid (GABA) and glutamate neurons present in addition to DA neurons. In this study, we performed whole-cell recordings in a TH-eGFP transgenic mouse line to evaluate the properties of vPAG-DA neurons. Following this initial characterization, we examined how both acute and chronic alcohol exposure modify synaptic transmission onto vPAG-DA neurons. We found minimal effects of acute alcohol exposure on GABA transmission, but a robust enhancement of glutamatergic synaptic transmission in vPAG-DA. Consistent with this effect on excitatory transmission, we also found that alcohol caused an increase in firing rate. These data were in contrast to the effects of chronic intermittent alcohol exposure, which had no significant impact on either inhibitory or excitatory synaptic transmission on the vPAG-DA neurons. These data add to a growing body of literature that points to alcohol having both region-dependent and cell-type dependent effects on function. PMID:23597415

Li, Chia; McCall, Nora M; Lopez, Alberto J; Kash, Thomas L



Drosophila neuroligin 2 is required presynaptically and postsynaptically for proper synaptic differentiation and synaptic transmission.  


Trans-synaptic adhesion between Neurexins (Nrxs) and Neuroligins (Nlgs) is thought to be required for proper synapse organization and modulation, and mutations in several human Nlgs have shown association with autism spectrum disorders. Here we report the generation and phenotypic characterization of Drosophila neuroligin 2 (dnlg2) mutants. Loss of dnlg2 results in reduced bouton numbers, aberrant presynaptic and postsynaptic development at neuromuscular junctions (NMJs), and impaired synaptic transmission. In dnlg2 mutants, the evoked responses are decreased in amplitude, whereas the total active zone (AZ) numbers at the NMJ are comparable to wild type, suggesting a decrease in the release probability. Ultrastructurally, the presynaptic AZ number per bouton area and the postsynaptic density area are both increased in dnlg2 mutants, whereas the subsynaptic reticulum is reduced in volume. We show that both presynaptic and postsynaptic expression of Dnlg2 is required to restore synaptic growth and function in dnlg2 mutants. Postsynaptic expression of Dnlg2 in dnlg2 mutants and wild type leads to reduced bouton growth whereas presynaptic and postsynaptic overexpression in wild-type animals results in synaptic overgrowth. Since Nlgs have been shown to bind to Nrxs, we created double mutants. These mutants are viable and display phenotypes that closely resemble those of dnlg2 and dnrx single mutants. Our results provide compelling evidence that Dnlg2 functions both presynaptically and postsynaptically together with Neurexin to determine the proper number of boutons as well as the number of AZs and size of synaptic densities during the development of NMJs. PMID:23136438

Chen, Yu-Chi; Lin, Yong Qi; Banerjee, Swati; Venken, Koen; Li, Jingjun; Ismat, Afshan; Chen, Kuchuan; Duraine, Lita; Bellen, Hugo J; Bhat, Manzoor A



Graded synaptic transmission at the Caenorhabditis elegans neuromuscular junction  

PubMed Central

Most neurotransmission is mediated by action potentials, whereas sensory neurons propagate electrical signals passively and release neurotransmitter in a graded manner. Here, we demonstrate that Caenorhabditis elegans neuromuscular junctions release neurotransmitter in a graded fashion. When motor neurons were depolarized by light-activation of channelrhodopsin-2, the evoked postsynaptic current scaled with the strength of the stimulation. When motor neurons were hyperpolarized by light-activation of halorhodopsin, tonic release of synaptic vesicles was decreased. These data suggest that both evoked and tonic neurotransmitter release is graded in response to membrane potential. Acetylcholine synapses are depressed by high-frequency stimulation, in part due to desensitization of the nicotine-sensitve ACR-16 receptor. By contrast, GABA synapses facilitate before becoming depressed. Graded transmission and plasticity confer a broad dynamic range to these synapses. Graded release precisely transmits stimulation intensity, even hyperpolarizing inputs. Synaptic plasticity alters the balance of excitatory and inhibitory inputs into the muscle in a use-dependent manner.

Liu, Qiang; Hollopeter, Gunther; Jorgensen, Erik M.



Short-term plasticity optimizes synaptic information transmission.  


Short-term synaptic plasticity (STP) is widely thought to play an important role in information processing. This major function of STP has recently been challenged, however, by several computational studies indicating that transmission of information by dynamic synapses is broadband, i.e., frequency independent. Here we developed an analytical approach to quantify time- and rate-dependent synaptic information transfer during arbitrary spike trains using a realistic model of synaptic dynamics in excitatory hippocampal synapses. We found that STP indeed increases information transfer in a wide range of input rates, which corresponds well to the naturally occurring spike frequencies at these synapses. This increased information transfer is observed both during Poisson-distributed spike trains with a constant rate and during naturalistic spike trains recorded in hippocampal place cells in exploring rodents. Interestingly, we found that the presence of STP in low release probability excitatory synapses leads to optimization of information transfer specifically for short high-frequency bursts, which are indeed commonly observed in many excitatory hippocampal neurons. In contrast, more reliable high release probability synapses that express dominant short-term depression are predicted to have optimal information transmission for single spikes rather than bursts. This prediction is verified in analyses of experimental recordings from high release probability inhibitory synapses in mouse hippocampal slices and fits well with the observation that inhibitory hippocampal interneurons do not commonly fire spike bursts. We conclude that STP indeed contributes significantly to synaptic information transfer and may serve to maximize information transfer for specific firing patterns of the corresponding neurons. PMID:21994397

Rotman, Ziv; Deng, Pan-Yue; Klyachko, Vitaly A



Influence of afferent synaptic innervation on the discharge variability of cat abducens motoneurones  

PubMed Central

The discharge variability of abducens motoneurones was studied after blocking inhibitory synaptic inputs or both excitatory and inhibitory inputs by means of an intramuscular (lateral rectus) injection of either a low (0.5 ng kg?1) or a high dose (5 ng kg?1) of tetanus neurotoxin (TeNT), respectively. Motoneuronal firing increased after low-dose TeNT. High-dose treatment, however, produced a firing depression, and in some cells, a total lack of modulation in relation to eye movements. Firing became increasingly more regular with larger TeNT doses as shown by significant reductions in the coefficient of variation after low- and high-dose treatments. Similarly, autocorrelation histograms of interspike intervals increased the number of resolvable peaks twofold in low-dose-treated motoneurones and sevenfold in high-dose-treated motoneurones. The plots of standard deviation versus the mean instantaneous firing frequency showed an upward deflexion with low firing frequencies. The upward deflexion occurred in controls at 39.9 ± 4.9 ms, an interval similar to the mean afterhyperpolarisation (AHP) duration (48.4 ± 8.8 ms). Low-dose TeNT treatment shifted the deflexion point to 20.9 ± 3.9 ms, whereas the high dose increased it to 60.7 ± 6.1 ms, in spite of the fact that no differences in AHP parameters between groups were found. The density of synaptophysin-immunoreactive boutons decreased by 14 % after the low-dose treatment and 40.5 % after the high-dose treatment, indicating that protracted synaptic blockade produces elimination of synaptic boutons. It is concluded that abducens motoneurone spike variability during spontaneous ocular fixations depends largely on the balance between inhibitory and excitatory synaptic innervation.

Gonzalez-Forero, David; Alvarez, Francisco J; de la Cruz, Rosa R; Delgado-Garcia, Jose Maria; Pastor, Angel M



From Synaptic Transmission to Cognition: An Intermediary Role for Dendritic Spines  

ERIC Educational Resources Information Center

Dendritic spines are cytoplasmic protrusions that develop directly or indirectly from the filopodia of neurons. Dendritic spines mediate excitatory neurotransmission and they can isolate the electrical activity generated by synaptic impulses, enabling them to translate excitatory afferent information via several types of plastic changes, including…

Gonzalez-Burgos, Ignacio



From Synaptic Transmission to Cognition: An Intermediary Role for Dendritic Spines  

ERIC Educational Resources Information Center

|Dendritic spines are cytoplasmic protrusions that develop directly or indirectly from the filopodia of neurons. Dendritic spines mediate excitatory neurotransmission and they can isolate the electrical activity generated by synaptic impulses, enabling them to translate excitatory afferent information via several types of plastic changes,…

Gonzalez-Burgos, Ignacio



MPTP modulates hippocampal synaptic transmission and activity-dependent synaptic plasticity via dopamine receptors.  


Parkinson's disease (PD)-like symptoms and cognitive deficits are inducible by 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP). Since cognitive abilities, including memory formations rely also on hippocampus, we set out to clarify the effects of MPTP on hippocampal physiology. We show that bath-application of MPTP (25??M) to acute hippocampal slices enhanced AMPA receptor-mediated field excitatory postsynaptic potentials (AMPAr-fEPSPs) transiently, whereas N-methyl-D-aspartate (NMDA) receptor-mediated fEPSPs (NMDAr-fEPSPs) were facilitated persistently. The MPTP-mediated transient AMPAr-fEPSP facilitation was antagonized by the dopamine D2-like receptor antagonists, eticlopride (1??M) and sulpiride (1 and 40??M). In contrast, the persistent enhancement of NMDAr-fEPSPs was prevented by the dopamine D1-like receptor antagonist SCH23390 (10??M). In addition, we show that MPTP decreased paired-pulse facilitation of fEPSPs and mEPSCs frequency. Regarding activity-dependent synaptic plasticity, 25??M MPTP transformed short-term potentiation (STP) into a long-term potentiation (LTP) and caused a slow onset potentiation of a non-tetanized synaptic input after induction of LTP in a second synaptic input. This heterosynaptic slow onset potentiation required activation of dopamine D1-like and NMDA-receptors. We conclude that acute MPTP application affects basal synaptic transmission by modulation of presynaptic vesicle release and facilitates NMDAr-fEPSPs as well as activity-dependent homo- and heterosynaptic plasticity under participation of dopamine receptors. PMID:22651101

Zhu, Guoqi; Huang, Yuying; Chen, Ying; Zhuang, Yinghan; Behnisch, Thomas



A genetic selection for Caenorhabditis elegans synaptic transmission mutants.  

PubMed Central

We have isolated 165 Caenorhabditis elegans mutants, representing 21 genes, that are resistant to inhibitors of cholinesterase (Ric mutants). Since mutations in 20 of the genes appear not to affect acetylcholine reception, we suggest that reduced acetylcholine release contributes to the Ric phenotype of most Ric mutants. Mutations in 15 of the genes lead to defects in a gamma-aminobutyric acid-dependent behavior; these genes are likely to encode proteins with general, rather than cholinergic-specific, roles in synaptic transmission. Ten of the genes have been cloned. Seven encode homologs of proteins that function in the synaptic vesicle cycle: two encode cholinergic-specific proteins, while five encode general presynaptic proteins. Two other Ric genes encode homologs of G-protein signaling molecules. Our assessment of synaptic function in Ric mutants, combined with the homologies of some Ric mutants to presynaptic proteins, suggests that the analysis of Ric genes will continue to yield insights into the regulation and functioning of synapses.

Miller, K G; Alfonso, A; Nguyen, M; Crowell, J A; Johnson, C D; Rand, J B



Quercetin Targets Cysteine String Protein (CSP?) and Impairs Synaptic Transmission  

PubMed Central

Background Cysteine string protein (CSP?) is a synaptic vesicle protein that displays unique anti-neurodegenerative properties. CSP? is a member of the conserved J protein family, also called the Hsp40 (heat shock protein of 40 kDa) protein family, whose importance in protein folding has been recognized for many years. Deletion of the CSP? in mice results in knockout mice that are normal for the first 2–3 weeks of life followed by an unexplained presynaptic neurodegeneration and premature death. How CSP? prevents neurodegeneration is currently not known. As a neuroprotective synaptic vesicle protein, CSP? represents a promising therapeutic target for the prevention of neurodegenerative disorders. Methodology/Principal Findings Here, we demonstrate that the flavonoid quercetin promotes formation of stable CSP?-CSP? dimers and that quercetin-induced dimerization is dependent on the unique cysteine string region. Furthermore, in primary cultures of Lymnaea neurons, quercetin induction of CSP? dimers correlates with an inhibition of synapse formation and synaptic transmission suggesting that quercetin interfers with CSP? function. Quercetin's action on CSP? is concentration dependent and does not promote dimerization of other synaptic proteins or other J protein family members and reduces the assembly of CSP?:Hsc70 units (70kDa heat shock cognate protein). Conclusions/Significance Quercetin is a plant derived flavonoid and popular nutritional supplement proposed to prevent memory loss and altitude sickness among other ailments, although its precise mechanism(s) of action has been unclear. In view of the therapeutic promise of upregulation of CSP? and the undesired consequences of CSP? dysfunction, our data establish an essential proof of principle that pharmaceutical agents can selectively target the neuroprotective J protein CSP?.

Xu, Fenglian; Proft, Juliane; Gibbs, Sarah; Winkfein, Bob; Johnson, Jadah N.; Syed, Naweed; Braun, Janice E. A.



Correlated calcium uptake and release by mitochondria and endoplasmic reticulum of CA3 hippocampal dendrites after afferent synaptic stimulation.  


Mitochondria and endoplasmic reticulum (ER) are important modulators of intracellular calcium signaling pathways, but the role of these organelles in shaping synaptic calcium transients in dendrites of pyramidal neurons remains speculative. We have measured directly the concentrations of total Ca (bound plus free) within intracellular compartments of proximal dendrites of CA3 hippocampal neurons at times after synaptic stimulation corresponding to the peak of the cytoplasmic free Ca2+ transient (1 sec), to just after its decay (30 sec), and to well after its return to prestimulus levels (180 sec). Electron probe microanalysis of cryosections from rapidly frozen slice cultures has revealed that afferent mossy fiber stimulation evokes large, rapid elevations in the concentration of total mitochondrial Ca ([Ca](mito)) in depolarized dendrites. A single tetanus (50 Hz/1 sec) elevated [Ca](mito) more than fivefold above characteristically low basal levels within 1 sec of stimulation and >10-fold by 30 sec after stimulation. This strong Ca accumulation was reversible, because [Ca](mito) had recovered by 180 sec after the tetanus. Ca sequestered within mitochondria was localized to small inclusions that were distributed heterogeneously within, and probably among, individual mitochondria. By 30 sec after stimulation an active subpopulation of ER cisterns had accumulated more Ca than had mitochondria despite a approximately 1 sec delay before the onset of accumulation. Active ER cisterns retained their Ca load much longer (>3 min) than mitochondria. The complementary time courses of mitochondrial versus ER Ca2+ uptake and release suggest that these organelles participate in a choreographed interplay, each shaping dendritic Ca2+ signals within characteristic regimes of cytosolic Ca2+ concentration and time. PMID:12486158

Pivovarova, Natalia B; Pozzo-Miller, Lucas D; Hongpaisan, Jarin; Andrews, S Brian



Side effects of phosphorylated acetylcholinesterase reactivators on neuronal membrane and synaptic transmission  

Microsoft Academic Search

The side effects of four phosphorylated cholinesterase reactivators (oximes): contrathion, TMB4, toxogonine and 1574 SEBC on membrane properties and synaptic transmission of Aplysia central neurons were investigated.

P. Fossier; L. Tauc; G. Baux



SNAP-29-mediated modulation of synaptic transmission in cultured hippocampal neurons.  


Identifying the molecules that regulate both the recycling of synaptic vesicles and the SNARE components required for fusion is critical for elucidating the molecular mechanisms underlying synaptic plasticity. SNAP-29 was initially isolated as a syntaxin-binding and ubiquitously expressed protein. Previous studies have suggested that SNAP-29 inhibits SNARE complex disassembly, thereby reducing synaptic transmission in cultured superior cervical ganglion neurons in an activity-dependent manner. However, the role of SNAP-29 in regulating synaptic vesicle recycling and short-term plasticity in the central nervous system remains unclear. In the present study, we examined the effect of SNAP-29 on synaptic transmission in cultured hippocampal neurons by dual patch clamp whole-cell recording, FM dye imaging, and immunocytochemistry. Our results demonstrated that exogenous expression of SNAP-29 in presynaptic neurons significantly decreased the efficiency of synaptic transmission after repetitive firing within a few minutes under low and moderate frequency stimulations (0.1 and 1 Hz). In contrast, SNAP-29 did not affect the density of synapses and basal synaptic transmission. Whereas neurotransmitter release was unaffected during intensive stimulation, recovery after synaptic depression was impaired by SNAP-29. Furthermore, knockdown of SNAP-29 expression in neurons by small interfering RNA increased the efficiency of synaptic transmission during repetitive firing. These findings suggest that SNAP-29 acts as a negative modulator for neurotransmitter release, probably by slowing recycling of the SNARE-based fusion machinery and synaptic vesicle turnover. PMID:15890653

Pan, Ping-Yue; Cai, Qian; Lin, Lin; Lu, Pei-Hua; Duan, Shumin; Sheng, Zu-Hang



Huperzia saururus, activity on synaptic transmission in the hippocampus.  


Huperzia saururus (Lam.) Trevis. (Lycopodiaceae) known as cola de quirquincho is used in folk medicine to improve memory. The cholinergic neurons of the basal forebrain, including those in the medial septum, and in the vertical limbs of the diagonal band of Broca and the nucleus basalis of Meynert, provide a major source of cholinergic enervation of the cortex and hippocampus. These neurons have also been shown to play an important role in learning and memory processes. Thus, the effects of this traditional Argentinean species were studied in relation to its activity on synaptic transmission in the hippocampus. The alkaloid extract obtained first by decoction of the aerial parts and by subsequent alkaline extraction, was purified by using a Sephadex LH 20 packed column. Electrophysiological experiments were developed with the purified extract (E(2)) on rat hippocampus slices, thus eliciting long-term potentiation (LTP). Results show a marked increase in the hippocampal synaptic plasticity. The threshold value for generation of LTP was 22 +/- 1.01 Hz on average for E(2), while for controls it was 86 +/- 0.92 Hz. All of these factors could explain the use of Huperzia saururus as a memory improver as is reported in the ethnomedicine. PMID:16325360

Ortega, M G; Vallejo, M G; Cabrera, J L; Pérez, M F; Almirón, R S; Ramírez, O A; Agnese, A M



Homeostatic control of synaptic transmission by distinct glutamate receptors.  


Glutamate is the most abundant excitatory neurotransmitter in the brain, and distinct classes of glutamate receptors coordinate synaptic transmission and spike generation upon various levels of neuronal activity. However, the mechanisms remain unclear. Here, we found that loss of synaptic AMPA receptors increased kainate receptor activity in cerebellar granule cells without changing NMDA receptors. The augmentation of kainate receptor-mediated currents in the absence of AMPA receptor activity is required for spike generation and is mediated by the increased expression of the GluK5 high-affinity kainate receptor subunit. Increase in GluK5 expression is sufficient to enhance kainate receptor activity by modulating receptor channel properties, but not localization. Furthermore, we demonstrate that the combined loss of the AMPA receptor auxiliary TARP?-2 subunit and the GluK5 subunit leads to early mouse lethality. Our findings reveal mechanisms mediated by distinct classes of postsynaptic glutamate receptors for the homeostatic maintenance of the neuronal activity. PMID:23719165

Yan, Dan; Yamasaki, Miwako; Straub, Christoph; Watanabe, Masahiko; Tomita, Susumu



Adenosine-mediated inhibition of striatal GABAergic synaptic transmission during in vitro ischaemia  

Microsoft Academic Search

Summary Several reports have shown that energy deprivation, as a result of hypoxia, hypoglycaemia or ischaemia, depresses excitatory synaptic transmission in virtually all brain areas. How this pathological condition affects inhibitory synaptic transmission is still unclear. In the present in vitro study, we coupled whole-cell patch clamp recordings from striatal neurones with focal stimulation of GABAergic nerve terminals in order

Diego Centonze; Emilia Saulle; Antonio Pisani; Giorgio Bernardi; Paolo Calabresi



The effect of knee joint afferent discharge on transmission in flexion reflex pathways in decerebrate cats.  

PubMed Central

1. Changes in excitability of reflex arcs mediating flexion withdrawal ad crossed extensor reflexes have been examined in decerebrate cats. 2. The excitability of flexion withdrawal and crossed extensor reflexes was shown to be modulated by knee joint position. Flexion withdrawal reflexes were most easily elicited when the knee was extended and crossed extensor reflexes were most easily elicited when the knee was flexed. 3. The modulation of transmission was not confined to reflex pathways to muscles acting at the knee but also included pathways to muscles acting at the hip and ankle, as well as pathways to muscles in the contralateral limb. 4. The changing excitability of reflex pathways caused by movement of the knee joint was unrelated to the stretch applied to muscles acting at the knee and to cutaneous afferent discharge. Modulation of reflex excitability by joint movement was totally abolished by local anaesthesia of the knee joint in an otherwise intact limb. 5. The results of the present experiments indicate that transmission in flexion reflex pathways can be inhibited by knee joint afferent discharge.

Baxendale, R H; Ferrell, W R



Paradigms for Pharmacological Characterization of C. elegans Synaptic Transmission Mutants  

PubMed Central

The nematode, Caenorhabditis elegans, has become an expedient model for studying neurotransmission. C. elegans is unique among animal models, as the anatomy and connectivity of its nervous system has been determined from electron micrographs and refined by pharmacological assays. In this video, we describe how two complementary neural stimulants, an acetylcholinesterase inhibitor, called aldicarb, and a gamma-aminobutyric acid (GABA) receptor antagonist, called pentylenetetrazole (PTZ), may be employed to specifically characterize signaling at C. elegans neuromuscular junctions (NMJs) and facilitate our understanding of antagonistic neural circuits. Of 302 C. elegans neurons, nineteen GABAergic D-type motor neurons innervate body wall muscles (BWMs), while four GABAergic neurons, called RMEs, innervate head muscles. Conversely, thirty-nine motor neurons express the excitatory neurotransmitter, acetylcholine (ACh), and antagonize GABA transmission at BWMs to coordinate locomotion. The antagonistic nature of GABAergic and cholinergic motor neurons at body wall NMJs was initially determined by laser ablation and later buttressed by aldicarb exposure. Acute aldicarb exposure results in a time-course or dose-responsive paralysis in wild-type worms. Yet, loss of excitatory ACh transmission confers resistance to aldicarb, as less ACh accumulates at worm NMJs, leading to less stimulation of BWMs. Resistance to aldicarb may be observed with ACh-specific or general synaptic function mutants. Consistent with antagonistic GABA and ACh transmission, loss of GABA transmission, or a failure to negatively regulate ACh release, confers hypersensitivity to aldicarb. Although aldicarb exposure has led to the isolation of numerous worm homologs of neurotransmission genes, aldicarb exposure alone cannot efficiently determine prevailing roles for genes and pathways in specific C. elegans motor neurons. For this purpose, we have introduced a complementary experimental approach, which uses PTZ. Neurotransmission mutants display clear phenotypes, distinct from aldicarb-induced paralysis, in response to PTZ. Wild-type worms, as well as mutants with specific inabilities to release or receive ACh, do not show apparent sensitivity to PTZ. However, GABA mutants, as well as general synaptic function mutants, display anterior convulsions in a time-course or dose-responsive manner. Mutants that cannot negatively regulate general neurotransmitter release and, thus, secrete excessive amounts of ACh onto BWMs, become paralyzed on PTZ. The PTZ-induced phenotypes of discrete mutant classes indicate that a complementary approach with aldicarb and PTZ exposure paradigms in C. elegans may accelerate our understanding of neurotransmission. Moreover, videos demonstrating how we perform pharmacological assays should establish consistent methods for C. elegans research.

Locke, Cody; Berry, Kalen; Kautu, Bwarenaba; Lee, Kyle; Caldwell, Kim; Caldwell, Guy



Crucial role of Drosophila neurexin in proper active zone apposition to postsynaptic densities, synaptic growth, and synaptic transmission.  


Neurexins have been proposed to function as major mediators of the coordinated pre- and postsynaptic apposition. However, key evidence for this role in vivo has been lacking, particularly due to gene redundancy. Here, we have obtained null mutations in the single Drosophila neurexin gene (dnrx). dnrx loss of function prevents the normal proliferation of synaptic boutons at glutamatergic neuromuscular junctions, while dnrx gain of function in neurons has the opposite effect. DNRX mostly localizes to the active zone of presynaptic terminals. Conspicuously, dnrx null mutants display striking defects in synaptic ultrastructure, with the presence of detachments between pre- and postsynaptic membranes, abnormally long active zones, and increased number of T bars. These abnormalities result in corresponding alterations in synaptic transmission with reduced quantal content. Together, our results provide compelling evidence for an in vivo role of neurexins in the modulation of synaptic architecture and adhesive interactions between pre- and postsynaptic compartments. PMID:17785181

Li, Jingjun; Ashley, James; Budnik, Vivian; Bhat, Manzoor A



Modulation of electrical synaptic transmission in zebrafish retinal horizontal cells.  


Electrical synaptic transmission is widespread in the vertebrate CNS and its modulation plays a critical role in altering the properties of coupled neural networks. In order to define further the mechanisms of electrical synaptic plasticity in the vertebrate retina, the electrophysiological characteristics of solitary horizontal cells and horizontal cell pairs from the zebrafish (Brachydanio rerio) were examined by whole-cell patch-clamp recordings from cells in primary cell culture. In solitary cells, the current-voltage relation exhibited inward current at potentials negative to -60 mV, a linear region of high resistance from -50 mV to 0 mV, and outward current positive to +20 mV. The inward current at negative potentials was blocked by substituting Cs+ for K+ in the extracellular medium, while the outward current at positive potentials was blocked by substitution of Cs+ for K+ in the pipette solution. Measurements of gap junctional conductance from electrically coupled cell pairs revealed that zebrafish horizontal cells expressed a mean junctional conductance of considerably smaller magnitude than other teleost retinal horizontal cells. Junctional conductance was found to be voltage dependent, exhibiting time-dependent closure with increasing transjunctional voltage. Voltage sensitivity was symmetrical about 0 mV junctional potential. At +/- 90 mV the ratio of steady state to peak current was approximately 0.5 and the time constant for inactivation of the junctional current was approximately 120 msec. Junctional conductance was also modulated by dopamine and cAMP. Pairs of horizontal cells responded to puff application of dopamine with a two- to threefold reduction in junctional conductance, but there was no discernible effect on extrajunctional conductances. The action of dopamine on coupling was mimicked by application of the dopamine agonist (+/-)-6,7-dihydroxy-2-amino-tetralin (ADTN) and the membrane permeable cAMP analog 8-bromo-cAMP. The selective D1 dopamine receptor antagonist SCH23390 blocked uncoupling by dopamine. These data provide a primary description of the electrophysiological characteristics of solitary horizontal cells and the electrical coupling between pairs of horizontal cells dissociated from the zebrafish retina. They indicate that zebrafish horizontal cells are distinct from the horizontal cells of other teleosts in their coupling characteristics. The results suggest that zebrafish horizontal cells exhibit differences in the regulation of synaptic assembly and maintenance that have important implications for the function of the zebrafish horizontal cell network in vivo. PMID:8126566

McMahon, D G



Glutamate-receptor-induced modulation of GABAergic synaptic transmission in the hippocampus  

Microsoft Academic Search

There is a large body of evidence about the short- and long-term changes in GABAergic transmission in the hippocampus produced by the action of different endogenous neuromodulators and in particular neurotransmitters. Both intrinsic hippocampal cells and afferent fibres coming into the hippocampus from various parts of the CNS release substances that are capable of changing inhibitory transmission. This review surveys

P. V. Belan; P. G. Kostyuk



Transmission from group II muscle afferents is depressed by stimulation of locus coeruleus\\/subcoeruleus, Kölliker-Fuse and raphe nuclei in the cat  

Microsoft Academic Search

The effects of brief trains of electrical stimuli applied within the locus coeruleus and subcoeruleus, the Kölliker-Fuse nucleus and the raphe magnus, obscurus and pallidus nuclei were tested on transmission from group I and group II muscle afferent fibres in mid-lumbar spinal segments of chloralose anaesthetized cats. Changes in the effectiveness of transmission from these afferents were assessed from changes

B. R. Noga; H. Bras; E. Jankowska



Locust primary neuronal culture for the study of synaptic transmission.  


We have designed a cell culture system for thoracic neurons of adult Locusta migratoria that enables the establishment of functional synapses in vitro. Patch-clamp recordings revealed three different neuron classes. About half of the neurons (47%) had unexcitable somata with outward and no inward conductance. The other half generated either single (37%) or multiple action potentials (18%) and differed mainly in lower outward conductance. Selectively stained motor neurons were analyzed to demonstrate varied physiological properties due to culture conditions. Using paired patch clamp recordings we demonstrate directly synaptic transmission in morphologically connected neurons in vitro. Presynaptic stimulation resulted in postsynaptic potentials in 42 pairs of neurons tested, independent of the type of neuron. According to pharmacological experiments most of these synapses were either glutamatergic or GABAergic. In addition to these chemical synapses, electrical synapses were found. With the demonstration of synapse formation in cell culture of adult locust neurons, this study provides the basis for the future analysis of more defined insect neuronal circuits in culture. PMID:22403023

Weigel, Stefan; Schulte, Petra; Meffert, Simone; Bräunig, Peter; Offenhäusser, Andreas



Caffeine-Sensitive Calcium Stores Regulate Synaptic Transmission from Retinal Rod Photoreceptors  

Microsoft Academic Search

We investigated the role of caffeine-sensitive intracellular stores in regulating intracellular calcium ((Ca 21)i) and glutamatergic synaptic transmission from rod photoreceptors. Caffeine tran- siently elevated and then markedly depressed (Ca 21)i to below prestimulus levels in rod inner segments and synaptic termi- nals. Concomitant with the depression was a reduction of glutamate release and a hyperpolarization of horizontal cells, neurons

David Krizaj; Jian-Xin Bao; Yvonne Schmitz; Paul Witkovsky



Myosin VI contributes to synaptic transmission and development at the Drosophila neuromuscular junction  

PubMed Central

Background Myosin VI, encoded by jaguar (jar) in Drosophila melanogaster, is a unique member of the myosin superfamily of actin-based motor proteins. Myosin VI is the only myosin known to move towards the minus or pointed ends of actin filaments. Although Myosin VI has been implicated in numerous cellular processes as both an anchor and a transporter, little is known about the role of Myosin VI in the nervous system. We previously recovered jar in a screen for genes that modify neuromuscular junction (NMJ) development and here we report on the genetic analysis of Myosin VI in synaptic development and function using loss of function jar alleles. Results Our experiments on Drosophila third instar larvae revealed decreased locomotor activity, a decrease in NMJ length, a reduction in synaptic bouton number, and altered synaptic vesicle localization in jar mutants. Furthermore, our studies of synaptic transmission revealed alterations in both basal synaptic transmission and short-term plasticity at the jar mutant neuromuscular synapse. Conclusions Altogether these findings indicate that Myosin VI is important for proper synaptic function and morphology. Myosin VI may be functioning as an anchor to tether vesicles to the bouton periphery and, thereby, participating in the regulation of synaptic vesicle mobilization during synaptic transmission.



Activation of Synaptic NMDA Receptors by Action Potential Dependent Release of Transmitter during Hypoxia Impairs Recovery of Synaptic Transmission on Reoxygenation  

Microsoft Academic Search

Increased levels of glutamate and the subsequent activation of NMDA receptors are responsible for neuronal damage that occurs after an ischemic or hypoxic episode. In the present work, we investigated the relative contribution of presynaptic and postsynaptic blockade of synaptic transmission, as well as of blockade of NMDA receptors, for the facilitation of recovery of synaptic transmission in the CA1

Ana M. Sebastiao; Alexandre de Mendonca; Tiago Moreira; J. Alexandre Ribeiro



ATP mediates fast synaptic transmission in mammalian neurons  

Microsoft Academic Search

IN addition to its diverse functions inside cells, ATP can act at several types of cell-surface receptor1-3. One of these (P2x-purinoceptor) is believed to be a ligand-gated cation channel1-6. The presence of P2x receptors on autonomic, sensory and central neurons suggests that ATP might be released to act as a fast excitatory synaptic transmitter. Here we record excitatory synaptic potentials

Richard J. Evans; Victor Derkach; Annmarie Surprenant



Synaptic transmission and the susceptibility of HIV infection to anti-viral drugs  

NASA Astrophysics Data System (ADS)

Cell-to-cell viral transmission via virological synapses has been argued to reduce susceptibility of the virus population to anti-viral drugs through multiple infection of cells, contributing to low-level viral persistence during therapy. Using a mathematical framework, we examine the role of synaptic transmission in treatment susceptibility. A key factor is the relative probability of individual virions to infect a cell during free-virus and synaptic transmission, a currently unknown quantity. If this infection probability is higher for free-virus transmission, then treatment susceptibility is lowest if one virus is transferred per synapse, and multiple infection of cells increases susceptibility. In the opposite case, treatment susceptibility is minimized for an intermediate number of virions transferred per synapse. Hence, multiple infection via synapses does not simply lower treatment susceptibility. Without further experimental investigations, one cannot conclude that synaptic transmission provides an additional mechanism for the virus to persist at low levels during anti-viral therapy.

Komarova, Natalia L.; Levy, David N.; Wodarz, Dominik



Synaptic Mitochondria in Synaptic Transmission and Organization of Vesicle Pools in Health and Disease  

PubMed Central

Cell types rich in mitochondria, including neurons, display a high energy demand and a need for calcium buffering. The importance of mitochondria for proper neuronal function is stressed by the occurrence of neurological defects in patients suffering from a great variety of diseases caused by mutations in mitochondrial genes. Genetic and pharmacological evidence also reveal a role of these organelles in various aspects of neuronal physiology and in the pathogenesis of neurodegenerative disorders. Yet the mechanisms by which mitochondria can affect neurotransmission largely remain to be elucidated. In this review we focus on experimental data that suggest a critical function of synaptic mitochondria in the function and organization of synaptic vesicle pools, and in neurotransmitter release during intense neuronal activity. We discuss how calcium handling, ATP production and other mitochondrial mechanisms may influence synaptic vesicle pool organization and synaptic function. Given the link between synaptic mitochondrial function and neuronal communication, efforts toward better understanding mitochondrial biology may lead to novel therapeutic approaches of neurological disorders including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and psychiatric disorders that are at least in part caused by mitochondrial deficits.

Vos, Melissa; Lauwers, Elsa; Verstreken, Patrik



Potentiation of glutamatergic synaptic transmission by protein kinase C-mediated sensitization of TRPV1 at the first sensory synapse  

PubMed Central

Sensory input from the periphery to the CNS is critically dependent on the strength of synaptic transmission at the first sensory synapse formed between primary afferent dorsal root ganglion (DRG) and superficial dorsal horn (DH) neurons of the spinal cord. Transient receptor potential vanilloid 1 (TRPV1) expressed on a subset of sensory neurons plays an important role in chronic inflammatory thermal nociception. Activation of protein kinase C (PKC) sensitizes TRPV1, which may contribute to the pathophysiology of chronic pain conditions. In this study, we have examined the modulation of TRPV1-mediated enhancement of excitatory synaptic transmission in response to PKC activation. Miniature excitatory postsynaptic currents (mEPSCs) from embryonic rat DRG–DH neuronal cocultures were recorded by patch clamping DH neurons. Capsaicin potently increased the frequency but not the amplitude of mEPSCs in a calcium-dependent manner, suggesting TRPV1-mediated glutamate release from presynaptic terminals of sensory neurons. Continued or repeated applications of capsaicin reduced the frequency of mEPSCs over time. The PKC activator phorbol 12,13-dibutyrate (PDBu) alone increased mEPSC events to a certain extent in a reversible manner but capsaicin further synergistically enhanced the frequency of mEPSCs. The PKC inhibitor bisindolylmaleimide (BIM) abolished PDBu-mediated potentiation of TRPV1-dependent increases in mEPSC frequency, suggesting modulation of TRPV1 by PKC-induced phosphorylation. In addition, at normal body temperatures (?37°C) PKC-mediated enhancement of mEPSC frequency is significantly decreased by a specific TRPV1 antagonist, suggesting a physiological role of TRPV1 at the central terminals. Furthermore, bradykinin (BK) significantly potentiated TRPV1-modulated synaptic responses by activating the PLC-PKC pathway. Our results indicate that TRPV1 activation can modulate excitatory synaptic transmission at the first sensory synapse and its effects can further be augmented by activation of PKC. Increased gain of sensory input by TRPV1-induced enhancement of glutamate release and its potentiation by various inflammatory mediators may contribute to persistent pain conditions. Selective targeting of TRPV1 expressed on the central terminals of sensory neurons may serve as a strategy to alleviate chronic intractable pain conditions.

Sikand, Parul; Premkumar, Louis S



Synaptic Transmission Mediated by Single Club Endings on the Goldfish Mauthner Cell. I. Characteristics of Electrotonic and Chemical Postsynaptic Potentials  

Microsoft Academic Search

Simultaneous pre- and postsynaptic intracellular recordings, combined with HRP injections, were used to study the prop- erties of junctional transmission between club endings of saccular nerve afferents and the Mauthner (M-) cell in gold- fish. All endings were electrotonically coupled to the M-cell, but impulses in less than 20% of the afferents produced chemically mediated excitatory postsynaptic potentials as well.

Jen-Wei Lit-P; Donald S. Faber



Cannabidiol inhibits synaptic transmission in rat hippocampal cultures and slices via multiple receptor pathways  

PubMed Central

BACKGROUND AND PURPOSE Cannabidiol (CBD) has emerged as an interesting compound with therapeutic potential in several CNS disorders. However, whether it can modulate synaptic activity in the CNS remains unclear. Here, we have investigated whether CBD modulates synaptic transmission in rat hippocampal cultures and acute slices. EXPERIMENTAL APPROACH The effect of CBD on synaptic transmission was examined in rat hippocampal cultures and acute slices using whole cell patch clamp and standard extracellular recordings respectively. KEY RESULTS Cannabidiol decreased synaptic activity in hippocampal cultures in a concentration-dependent and Pertussis toxin-sensitive manner. The effects of CBD in culture were significantly reduced in the presence of the cannabinoid receptor (CB1) inverse agonist, LY320135 but were unaffected by the 5-HT1A receptor antagonist, WAY100135. In hippocampal slices, CBD inhibited basal synaptic transmission, an effect that was abolished by the proposed CB1 receptor antagonist, AM251, in addition to LY320135 and WAY100135. CONCLUSIONS AND IMPLICATIONS Cannabidiol reduces synaptic transmission in hippocampal in vitro preparations and we propose a role for both 5-HT1A and CB1 receptors in these CBD-mediated effects. These data offer some mechanistic insights into the effects of CBD and emphasize that further investigations into the actions of CBD in the CNS are required in order to elucidate the full therapeutic potential of CBD.

Ledgerwood, CJ; Greenwood, SM; Brett, RR; Pratt, JA; Bushell, TJ



A two-stage cascade nonlinear dynamical model of single neurons for the separation and quantification of pre- and post-synaptic mechanisms of synaptic transmission.  


Neurons receive pre-synaptic spike trains and transform them into post-synaptic spike trains. This spike train to spike train temporal transformation underlies all cognitive functions performed by neurons, e.g., learning and memory. The transformation is a highly nonlinear dynamical process that involves both pre- and post-synaptic mechanisms. The ability to separate and quantify the nonlinear dynamics of pre- and post-synaptic mechanism is needed to gain insights into this transformation. In this study, we developed a Volterra kernel based two-stage cascade model of synaptic transmission using synaptically-driven intracellular activities, to which broadband stimulation conditions were imposed. The first stage of the model represents the pre-synaptic mechanisms and describes the nonlinear dynamical transformation from pre-synaptic spike trains to transmitter vesicle release strengths. The vesicle release strengths were obtained from the intracellularly recorded excitatory post-synaptic currents (EPSCs). The second stage of the model represents the post-synaptic mechanisms and describes the nonlinear dynamical transformation from release strengths to excitatory post-synaptic potentials (EPSPs). One application of this cascade model is to analyze the pre- and post-synaptic mechanism change induced by long-term potentiation (LTP). This future application is expected to shed new light on the expression locus of LTP. PMID:22254586

Lu, Ude; Roach, Shane M; Song, Dong; Berger, Theodore W



Effects of sciatic nerve axotomy on excitatory synaptic transmission in rat substantia gelatinosa.  


Injury or section of a peripheral nerve can promote chronic neuropathic pain. This is initiated by the appearance and persistence of ectopic spontaneous activity in primary afferent neurons that promotes a secondary, enduring increase in excitability of sensory circuits in the spinal dorsal horn ("central sensitization"). We have previously shown that 10-20 days of chronic constriction injury (CCI) of rat sciatic nerve produce a characteristic "electrophysiological signature" or pattern of changes in synaptic excitation of five different electrophysiologically defined neuronal phenotypes in the substantia gelatinosa of the dorsal horn. Although axotomy and CCI send different signals to the dorsal horn, we now find, using whole cell recording, that the "electrophysiological signature" produced 12-22 days after sciatic axotomy is quite similar to that seen with CCI. Axotomy thus has little effect on resting membrane potential, rheobase, current-voltage characteristics, or excitability of most neuron types; however, it does decrease excitatory synaptic drive to tonic firing neurons, while increasing that to delay firing neurons. Since many tonic neurons are GABAergic, whereas delay neurons do not contain gamma-aminobutyric acid, axotomy may reduce synaptic excitation of inhibitory neurons while increasing that of excitatory neurons. Further analysis of spontaneous and miniature (tetrodotoxin-resistant) excitatory postsynaptic currents is consistent with the possibility that decreased excitation of tonic neurons reflects loss of presynaptic contacts. By contrast, increased excitation of "delay" neurons may reflect increased frequency of discharge of presynaptic action potentials. This would explain how synaptic excitation of tonic cells decreases despite the fact that axotomy increases spontaneous activity in primary afferent neurons. PMID:19793881

Chen, Yishen; Balasubramanyan, Sridhar; Lai, Aaron Y; Todd, Kathryn G; Smith, Peter A



Calcium and endocannabinoids in the modulation of inhibitory synaptic transmission  

Microsoft Academic Search

Synapses in the central nervous system can be highly plastic devices, being able to modify their efficacy in relaying information in response to several factors. Calcium ions are often fundamental in triggering synaptic plasticity. Here, we will shortly review the effects induced by postsynaptic increases of calcium concentration at GABAergic and glycinergic synapses. Both postsynaptic and presynaptic mechanisms mediating changes

Marco A. Diana; Piotr Bregestovski



Seipin regulates excitatory synaptic transmission in cortical neurons.  


Heterozygosity for missense mutations in Seipin, namely N88S and S90L, leads to a broad spectrum of motor neuropathy, while a number of loss-of-function mutations in Seipin are associated with the Berardinelli-Seip congenital generalized lipodystrophy type 2 (CGL2, BSCL2), a condition that is characterized by severe lipoatrophy, insulin resistance, and intellectual impairment. The mechanisms by which Seipin mutations lead to motor neuropathy, lipodystrophy, and insulin resistance, and the role Seipin plays in central nervous system (CNS) remain unknown. The goal of this study is to understand the functions of Seipin in the CNS using a loss-of-function approach, i.e. by knockdown (KD) of Seipin gene expression. Excitatory post-synaptic currents (EPSCs) were impaired in Seipin-KD neurons, while the inhibitory post-synaptic currents (IPSCs) remained unaffected. Expression of a shRNA-resistant human Seipin rescued the impairment of EPSC produced by Seipin KD. Furthermore, ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-induced whole-cell currents were significantly reduced in Seipin KD neurons, which could be rescued by expression of a shRNA-resistant human Seipin. Fluorescent imaging and biochemical studies revealed reduced level of surface AMPA receptors, while no obvious ultrastructural changes in the pre-synapse were found. These data suggest that Seipin regulates excitatory synaptic function through a post-synaptic mechanism. PMID:23173741

Wei, Shunhui; Soh, Stephanie Li-Ying; Qiu, Wenjie; Yang, Wulin; Seah, Cheyenne Jia-Yan; Guo, Jing; Ong, Wei-Yi; Pang, Zhiping P; Han, Weiping



Exposure to cocaine regulates inhibitory synaptic transmission from the ventral tegmental area to the nucleus accumbens.  


Abstract? Synaptic projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) make up the backbone of the brain reward pathway, a neural circuit that mediates behavioural responses elicited by natural rewards as well as by cocaine and other drugs of abuse. In addition to the well-known modulatory dopaminergic projection, the VTA also provides fast excitatory and inhibitory synaptic input to the NAc, directly regulating NAc medium spiny neurons (MSNs). However, the cellular nature of VTA-to-NAc fast synaptic transmission and its roles in drug-induced adaptations are not well understood. Using viral-mediated in vivo expression of channelrhodopsin 2, the present study dissected fast excitatory and inhibitory synaptic transmission from the VTA to NAc MSNs in rats. Our results suggest that, following repeated exposure to cocaine (15 mg kg(-1) day(-1) × 5 days, i.p., 1 or 21 day withdrawal), a presynaptic enhancement of excitatory transmission and suppression of inhibitory transmission occurred at different withdrawal time points at VTA-to-NAc core synapses. In contrast, no postsynaptic alterations were detected at either type of synapse. These results suggest that changes in VTA-to-NAc fast excitatory and inhibitory synaptic transmissions may contribute to cocaine-induced alteration of the brain reward circuitry. PMID:23918773

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



Differential regulation of synaptic transmission by pre- and postsynaptic SK channels in the spinal locomotor network.  


The generation of activity in the central nervous system requires precise tuning of cellular properties and synaptic transmission. Neural networks in the spinal cord produce coordinated locomotor movements. Synapses in these networks need to be equipped with multiple mechanisms that regulate their operation over varying regimes to produce locomotor activity at different frequencies. Using the in vitro lamprey spinal cord, we explored whether Ca(2+) influx via different routes in postsynaptic soma and dendrites and in presynaptic terminals can activate apamin-sensitive Ca(2+)-activated K(+) (SK) channels and thereby shape synaptic transmission. We show that postsynaptic SK channels are tightly coupled to Ca(2+) influx via NMDA receptors. Activation of these channels by synaptically induced NMDA-dependent Ca(2+) transients restrains the time course of the synaptic current and the amplitude of the synaptic potential. In addition, presynaptic SK channels are activated by Ca(2+) influx via voltage-gated channels and control the waveform of the action potential and the resulting Ca(2+) dynamics in the axon terminals. The coupling of SK channels to different Ca(2+) sources, pre- and postsynaptically, acts as a negative feedback mechanism to shape synaptic transmission. Thus SK channels can play a pivotal role in setting the dynamic range of synapses and enabling short-term plasticity in the spinal locomotor network. PMID:23554432

Nanou, Evanthia; Alpert, Michael H; Alford, Simon; El Manira, Abdeljabbar



Intrinsic and synaptic long-term depression of NTS relay of nociceptin- and capsaicin-sensitive cardiopulmonary afferents hyperactivity  

Microsoft Academic Search

The nucleus tractus solitarius (NTS) in the caudal medulla is a gateway for a variety of cardiopulmonary afferents important\\u000a for homeostatic regulation and defense against airway and cardiovascular insults and is a key central target potentially mediating\\u000a the response habituation to these inputs. Here, whole-cell and field population action potential recordings and infrared imaging\\u000a in rat brainstem slices in vitro

Armenak Bantikyan; Gang Song; Paula Feinberg-Zadek; Chi-Sang Poon



The effect of nitric oxide on the efficacy of synaptic transmission through the chick ciliary ganglion.  

PubMed Central

1. The effect of nitric oxide on the efficacy of synaptic transmission in the chick ciliary ganglion of post-hatched birds has been determined by use of the size of the postganglionic compound action potential resulting from chemical transmission through the ganglion as a measure of synaptic efficacy. 2. Sodium nitroprusside (100 microM) increased the synaptic efficacy by an average 26%. This is likely to be due to its ability to release nitric oxide, as potassium ferricyanide (100 microM) did not cause a potentiation. Sodium azide (100 microM), shown in sympathetic ganglia to stimulate production of cyclic GMP, did not modulate synaptic efficacy significantly. 3. 8-Br-cyclic-GMP (100 microM) increased synaptic efficacy by an average 61%. The addition of 8-Br-cyclic-AMP (100 microM) had less effect, increasing transmission by on average 46%. 4. The nitric oxide synthase blocker, NG-nitro-L-arginine methyl ester (L-NAME, 100 microM) was added prior to the tetanic stimulation of the preganglionic nerves at 30 Hz for 20 s, a procedure known to produce both post-tetanic potentiation and long-term potentiation of synaptic transmission through the ganglion. L-NAME reduced the long-term potentiation by an average of 47% but did not significantly change the post-tetanic potentiation. 5. Following the brief application of 8-Br-cyclic AMP, 8-Br-cyclic GMP and sodium nitroprusside there was an enhancement of the efficacy of synaptic transmission that persisted after the withdrawal of the drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

Scott, T. R.; Bennett, M. R.



Bi-directional modulation of fast inhibitory synaptic transmission by leptin  

PubMed Central

The hormone leptin has widespread actions in the CNS. Indeed, leptin markedly influences hippocampal excitatory synaptic transmission and synaptic plasticity. However, the effects of leptin on fast inhibitory synaptic transmission in the hippocampus have not been evaluated. Here we show that leptin modulates GABAA receptor-mediated synaptic transmission onto hippocampal CA1 pyramidal cells. Leptin promotes a rapid and reversible increase in the amplitude of evoked GABAA receptor-mediated IPSCs; an effect that was paralleled by increases in the frequency and amplitude of miniature IPSCs, but with no change in paired pulse ratio or CV, suggesting a postsynaptic expression mechanism. Following washout of leptin, a persistent depression (I-LTD) of evoked IPSCs was observed. Whole cell dialysis or bath application of inhibitors of PI 3-kinase or Akt prevented leptin-induced enhancement of IPSCs indicating involvement of a postsynaptic PI 3-kinase/Akt-dependent pathway. In contrast, blockade of PI 3-kinase or Akt activity failed to alter the ability of leptin to induce I-LTD, suggesting that this process is independent of PI 3-kinase/Akt. In conclusion these data indicate that the hormone leptin bi-directionally modulates GABAA receptor-mediated synaptic transmission in the hippocampus. These findings have important implications for the role of this hormone in regulating hippocampal pyramidal neuron excitability.

Solovyova, N.; Moult, P.R.; Milojkovic, B.; Lambert, J.J.; Harvey, J.



Dopamine Inhibits N-Type Channels in Visceral Afferents to Reduce Synaptic Transmitter Release Under Normoxic and Chronic Intermittent Hypoxic Conditions  

PubMed Central

Glutamatergic synaptic currents elicited in second-order neurons in the nucleus of the solitary tract (nTS) by activation of chemosensory and other visceral afferent fibers are severely reduced following 10 days of chronic intermittent hypoxia (CIH). The mechanism by which this occurs is unknown. A strong candidate for producing the inhibition is dopamine, which is also released from the presynaptic terminals and which we have shown exerts a tonic presynaptic inhibition on glutamate release. We postulated that tonic activation of the D2 receptors inhibits presynaptic calcium currents to reduce transmitter release and that in CIH this occurs in conjunction with an increase in the dopamine inhibitory response due to the increase in presynaptic D2 receptors or an increase in dopamine release further suppressing the evoked excitatory postsynaptic current (eEPSC). Thus we predicted that blockade of the D2 receptors would return the EPSC to values of animals maintained under normoxic conditions. We found that dopamine and quinpirole, the selective D2-like agonist, inhibit calcium currents via the D2 receptors by acting on the N-type calcium channel in presynaptic neurons and their nTS central terminals. However, in brain slice studies from CIH animals, although the D2 antagonist sulpiride increased the CIH-reduced amplitude of synaptic currents, EPSCs were not restored to normal levels. This indicates that while the dopamine inhibitory effect remains intact in CIH, most of the reduction in the eEPSC amplitude occurs via alternative mechanisms.

Kline, David D.; Hendricks, Gabriel; Hermann, Gerlinda; Rogers, Richard C.; Kunze, Diana L.



Static and dynamic properties of synaptic transmission at the cyto- neural junction of frog labyrinth posterior canal  

PubMed Central

The properties of synaptic transmission have been studied at the cyto- neural junction of the frog labyrinth posterior canal by examining excitatory postsynaptic potential (EPSP) activity recorded intraaxonally from the afferent nerve after abolishing spike firing by tetrodotoxin. The waveform, amplitude, and rate of occurrence of the EPSPs have been evaluated by means of a procedure of fluctuation analysis devised to continuously monitor these parameters, at rest as well as during stimulation of the semicircular canal by sinusoidal rotation at 0.1 Hz, with peak accelerations ranging from 8 to 87 deg.s- 2. Responses to excitatory and inhibitory accelerations were quantified in terms of maximum and minimum EPSP rates, respectively, as well as total numbers of EPSPs occurring during the excitatory and inhibitory half cycles. Excitatory responses were systematically larger than inhibitory ones (asymmetry). Excitatory responses were linearly related either to peak acceleration or to its logarithm, and the same occurred for inhibitory responses. In all units examined, the asymmetry of the response yielded nonlinear two-sided input-output intensity functions. Silencing of EPSPs during inhibition (rectification) was never observed. Comparison of activity during the first cycle of rotation with the average response over several cycles indicated that variable degrees of adaptation (up to 48%) characterize the excitatory response, whereas no consistent adaptation was observed in the inhibitory response. All fibers appeared to give responses nearly in phase with angular velocity, at 0.1 Hz, although the peak rates generally anticipated by a few degrees the peak angular velocity. From the data presented it appears that asymmetry, adaptation, and at least part of the phase lead in afferent nerve response are of presynaptic origin, whereas rectification and possible further phase lead arise at the encoder. To confirm these conclusions a simultaneous though limited study of spike firing and EPSP activity has been attempted in a few fibers.



Impairment of cortical GABAergic synaptic transmission in an environmental rat model of autism.  


The biological mechanisms of autism spectrum disorders (ASDs) are largely unknown in spite of extensive research. ASD is characterized by altered function of multiple brain areas including the temporal cortex and by an increased synaptic excitation:inhibition ratio. While numerous studies searched for evidence of increased excitation in ASD, fewer have investigated the possibility of reduced inhibition. We characterized the cortical ?-amino butyric acid (GABA)ergic system in the rat temporal cortex of an ASD model [offspring of mothers prenatally injected with valproic acid (VPA)], by monitoring inhibitory post-synaptic currents (IPSCs) with patch-clamp. We found that numerous features of inhibition were severely altered in VPA animals compared to controls. Among them were the frequency of miniature IPSCs, the rise time and decay time of electrically-evoked IPSCs, the slope and saturation of their input/output curves, as well as their modulation by adrenergic and muscarinic agonists and by the synaptic GABAA receptor allosteric modulator zolpidem (but not by the extra-synaptic modulator gaboxadol). Our data suggest that both pre- and post-synaptic, but not extra-synaptic, inhibitory transmission is impaired in the offspring of VPA-injected mothers. We speculate that impairment in the GABAergic system critically contributes to an increase in the ratio between synaptic excitation and inhibition, which in genetically predisposed individuals may alter cortical circuits responsible for emotional, communication and social impairments at the core of ASD. PMID:23228615

Banerjee, Anwesha; García-Oscos, Francisco; Roychowdhury, Swagata; Galindo, Luis C; Hall, Shawn; Kilgard, Michael P; Atzori, Marco



Neurochemistry of the afferents to the rat cochlear root nucleus: Possible synaptic modulation of the acoustic startle  

PubMed Central

Afferents to the primary startle circuit are essential for the elicitation and modulation of the acoustic startle reflex (ASR). In the rat, cochlear root neurons (CRNs) comprise the first component of the acoustic startle circuit and play a crucial role in mediating the ASR. Nevertheless, the neurochemical pattern of their afferents remains unclear. To determine the distribution of excitatory and inhibitory inputs, we used confocal microscopy to analyze the immunostaining for vesicular glutamate and GABA transporter proteins (VGLUT1 and VGAT) on retrogradely labeled CRNs. We also used reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry to detect and localize specific neurotransmitter receptor subunits in the cochlear root. Our results show differential distributions of VGLUT1- and VGAT-immunoreactive endings around cell bodies and dendrites. The RT-PCR data showed a positive band for several ionotropic glutamate receptor subunits, M1- M5 muscarinic receptor subtypes, the glycine receptor ?1 subunit (GlyR?1), GABAA, GABAB, and subunits of ?2 and ?-noradrenergic receptors. By immunohistochemistry, we confirmed that CRN cell bodies exhibit positive immunoreaction for the GluR3 and NR1 glutamate receptor subunits. Cell bodies and dendrites were also positive for M2 and M4, and GlyR?1. Other subunits, such as GluR1 and GluR4 of the AMPA glutamate receptors, were observed in glial cells neighboring unlabeled CRN cell bodies. We further confirmed the existence of noradrenergic afferents onto CRNs from the locus coeruleus by combining tyrosine hydroxylase immunohistochemistry and tract-tracing experiments. Our results provide valuable information toward understanding how CRNs might integrate excitatory and inhibitory inputs, and hence how they could elicit and modulate the acoustic startle reflex.

Gomez-Nieto, R; Horta-Junior, JAC; Castellano, O; Herrero-Turrion, MJ; Rubio, ME; Lopez, DE



Ovarian Hormone Loss Impairs Excitatory Synaptic Transmission at Hippocampal CA3-CA1 Synapses.  


Premature and long-term ovarian hormone loss following ovariectomy (OVX) is associated with cognitive impairment. This condition is prevented by estradiol (E2) therapy when initiated shortly following OVX but not after substantial delay. To determine whether these clinical findings are correlated with changes in synaptic functions, we used adult OVX rats to evaluate the consequences of short-term (7-10 d, OVXControl) and long-term (?5 months, OVXLT) ovarian hormone loss, as well as subsequent in vivo E2 treatment, on excitatory synaptic transmission at the hippocampal CA3-CA1 synapses important for learning and memory. The results show that ovarian hormone loss was associated with a marked decrease in synaptic strength. E2 treatment increased synaptic strength in OVXControl but not OVXLT rats, demonstrating a change in the efficacy for E2 5 months following OVX. E2 also had a more rapid effect: within minutes of bath application, E2 acutely increased synaptic strength in all groups except OVXLT rats that did not receive in vivo E2 treatment. E2's acute effect was mediated postsynaptically, and required Ca(2+) influx through the voltage-gated Ca(2+) channels. Despite E2's acute effect, synaptic strength of OVXLT rats remained significantly lower than that of OVXControl rats. Thus, changes in CA3-CA1 synaptic transmission associated with ovarian hormone loss cannot be fully reversed with delayed E2 treatment. Given that synaptic strength at CA3-CA1 synapses is related to the ability to learn hippocampus-dependent tasks, these findings provide additional insights for understanding cognitive impairment-associated long-term ovarian hormone loss and ineffectiveness for delayed E2 treatment to maintain cognitive functions. PMID:24107948

Wu, Wendy W; Bryant, Damani N; Dorsa, Daniel M; Adelman, John P; Maylie, James



Local dendrodendritic inhibition regulates fast synaptic transmission in visual thalamus  

PubMed Central

Inhibition from thalamic interneurons plays a critical role in modulating information transfer between thalamus and neocortex. Interestingly, these neurons yield inhibition via two distinct outputs: presynaptic dendrites that innervate thalamocortical relay neurons and axonal outputs. Since the dendrites of thalamic interneurons are the primary targets of incoming synaptic information, it has been hypothesized that local synaptic input could produce highly focused dendritic output. To gain additional insight to the computational power of these presynaptic dendrites, we have combined two-photon laser scanning microscopy, glutamate uncaging, and whole-cell electrophysiological recordings in order to locally activate dendritic terminals and study their inhibitory contribution onto rat thalamocortical relay neurons. Our findings demonstrate that local dendritic release from thalamic interneurons is controlled locally by AMPA/NMDA receptor-mediated recruitment of L-type calcium channels. Moreover, by mapping these connections with single-dendrite resolution we not only found that presynaptic dendrites preferentially target proximal regions, but such actions differ significantly across branches. Furthermore, local stimulation of interneuron dendrites did not result in global excitation, supporting the notion that these interneurons can operate as multiplexors, containing numerous independently operating input-output devices.

Crandall, Shane R.; Cox, Charles L.



Multiple roles for mammalian target of rapamycin signaling in both glutamatergic and GABAergic synaptic transmission.  


The mammalian target of rapamycin (mTOR) signaling pathway in neurons integrates a variety of extracellular signals to produce appropriate translational responses. mTOR signaling is hyperactive in neurological syndromes in both humans and mouse models that are characterized by epilepsy, autism, and cognitive disturbances. In addition, rapamycin, a clinically important immunosuppressant, is a specific and potent inhibitor of mTOR signaling. While mTOR is known to regulate growth and synaptic plasticity of glutamatergic neurons, its effects on basic parameters of synaptic transmission are less well studied, and its role in regulating GABAergic transmission is unexplored. We therefore performed an electrophysiological and morphological comparison of glutamatergic and GABAergic neurons in which mTOR signaling was either increased by loss of the repressor Pten or decreased by treatment with rapamycin. We found that hyperactive mTOR signaling increased evoked synaptic responses in both glutamatergic and GABAergic neurons by ?50%, due to an increase in the number of synaptic vesicles available for release, the number of synapses formed, and the miniature event size. Prolonged (72 h) rapamycin treatment prevented these abnormalities and also decreased synaptic transmission in wild-type glutamatergic, but not GABAergic, neurons. Further analyses suggested that hyperactivation of the mTOR pathway also impairs presynaptic function, possibly by interfering with vesicle fusion. Despite this presynaptic impairment, the net effect of Pten loss is enhanced synaptic transmission in both GABAergic and glutamatergic neurons, which has numerous implications, depending on where in the brain mutations of an mTOR suppressor gene occur. PMID:22895726

Weston, Matthew C; Chen, Hongmei; Swann, John W



Pathway-specific use-dependent dynamics of excitatory synaptic transmission in rat intracortical circuits  

PubMed Central

Information processing in neuronal networks is determined by the use-dependent dynamics of synaptic transmission. Here we characterize the dynamic properties of excitatory synaptic transmission in two major intracortical pathways that target the output neurons of the neocortex, by recording unitary EPSPs from layer 5 pyramidal neurons evoked in response to action potential trains of increasing complexity in presynaptic layer 2/3 or layer 5 pyramidal neurons. We find that layer 2/3 to layer 5 synaptic transmission is dominated by frequency-dependent depression when generated at fixed frequencies of > 10 Hz. Synaptic depression evolved on a spike-by-spike basis in response to action potential trains that possessed a broad range of interspike intervals, but a low mean frequency (10 Hz). Layer 2/3 to layer 2/3 and layer 2/3 to layer 5 synapses were incapable of sustained release during prolonged, complex trains of presynaptic action potential firing (mean frequency, 48 Hz). By contrast, layer 5 to layer 5 synapses operated effectively across a wide range of frequencies, exhibiting increased efficacy at frequencies > 10 Hz. Furthermore, layer 5 to layer 5 synapses sustained release throughout the duration of prolonged, complex spike trains. The use-dependent properties of synaptic transmission could be modulated by pharmacologically changing the probability of release and by induction of long-term depression. The dynamic properties of intracortical excitatory synapses are therefore pathway-specific. We suggest that the synaptic output of layer 5 pyramidal neurons is ideally suited to control the neocortical network across a wide range of frequencies and for sustained periods of time, a behaviour that helps to explain the pivotal role played by layer 5 neurons in the genesis of periods of network ‘up’ states and epileptiform activity in the neocortex.

Williams, Stephen R; Atkinson, Susan E



Estimation of single channel conductance underlying synaptic transmission between pyramidal cells in the visual cortex  

Microsoft Academic Search

Axon collaterals originating from pyramidal cells are one of the most abundant presynaptic elements in the neocortical circuits.[3, 5, 15]To understand a quantitative aspect of synaptic transmission between pyramidal cells, we attempted to estimate single channel conductance by applying non-stationary noise analysis to unitary excitatory postsynaptic currents. Simultaneous recordings were carried out in two pyramidal cells of superficial layers in

Y Yoshimura; F Kimura; T Tsumoto



Analysis of synaptic transmission in Caenorhabditis elegans using an aldicarb-sensitivity assay  

Microsoft Academic Search

Caenorhabditis elegans has emerged as a powerful model system for studying the biology of the synapse. Here we describe a widely used assay for synaptic transmission at the C. elegans neuromuscular junction. This protocol monitors the sensitivity of C. elegans to the paralyzing affects of an acetylcholinesterase inhibitor, aldicarb. Briefly, adult worms are incubated in the presence of aldicarb and

Timothy R Mahoney; Shuo Luo; Michael L Nonet



Cocaine and Amphetamine Depress Striatal GABAergic Synaptic Transmission through D2 Dopamine Receptors  

Microsoft Academic Search

The striatum is a brain area implicated in the pharmacological action of drugs of abuse. To test the possible involvement of both cocaine and amphetamine in the modulation of synaptic transmission in this nucleus, we coupled whole-cell patch clamp recordings from striatal spiny neurons to the focal stimulation of glutamatergic or GABAergic nerve terminals. We found that neither cocaine (1–600

Diego Centonze; Barbara Picconi; Christelle Baunez; Emiliana Borrelli; Antonio Pisani; Giorgio Bernardi; Paolo Calabresi



Saffron extract and trans-crocetin inhibit glutamatergic synaptic transmission in rat cortical brain slices  

Microsoft Academic Search

Saffron, the dried stigmata of Crocus sativus L., is used in traditional medicine for a wide range of indications including cramps, asthma, and depression. To investigate the influence of hydro-ethanolic saffron extract (CSE) and trans-crocetin on synaptic transmission, postsynaptic potentials (PSPs) were elicited by focal electrical stimulation and recorded using intracellular placed microelectrodes in pyramidal cells from rat cingulate cortex.

F. Berger; A. Hensel; K. Nieber



High-throughput study of synaptic transmission at the neuromuscular junction enabled by optogenetics and microfluidics  

Microsoft Academic Search

Over the past several years, optogenetic techniques have become widely used to help elucidate a variety of neuroscience problems. The unique optical control of neurons within a variety of organisms provided by optogenetics allows researchers to probe neural circuits and investigate neuronal function in a highly specific and controllable fashion. Recently, optogenetic techniques have been introduced to investigate synaptic transmission

Jeffrey N. Stirman; Martin Brauner; Alexander Gottschalk; Hang Lu



Therapeutic testosterone administration preserves excitatory synaptic transmission in the hippocampus during autoimmune demyelinating disease  

PubMed Central

Over 50% of multiple sclerosis (MS) patients experience cognitive deficits, and hippocampal-dependent memory impairment has been reported in over 30% of these patients. While post-mortem pathology studies and in vivo magnetic resonance imaging (MRI) demonstrate that the hippocampus is targeted in MS, the neuropathology underlying hippocampal dysfunction remains unknown. Furthermore, there are no treatments available to date to effectively prevent neurodegeneration and associated cognitive dysfunction in MS. We have recently demonstrated that the hippocampus is also targeted in experimental autoimmune encephalomyelitis (EAE), the most widely used animal model of MS. The objective of this study was to assess whether a candidate treatment (testosterone) could prevent hippocampal synaptic dysfunction and underlying pathology when administered in either a preventative or a therapeutic (post-disease induction) manner. Electrophysiological studies revealed impairments in basal excitatory synaptic transmission that involved both AMPA receptor-mediated changes in synaptic currents, and faster decay rates of NMDA receptor-mediated currents in mice with EAE. Neuropathology revealed atrophy of the pyramidal and dendritic layers of hippocampal cornu ammonis 1 (CA1), decreased pre (Synapsin-1) and post (postsynaptic density 95; PSD-95) synaptic staining, diffuse demyelination, and microglial activation. Testosterone treatment administered either before or after disease induction restores excitatory synaptic transmission as well as pre- and postsynaptic protein levels within the hippocampus. Furthermore, cross-modality correlations demonstrate that fluctuations in excitatory postsynaptic potentials are significantly correlated to changes in postsynaptic protein levels and suggest that PSD-95 is a neuropathological substrate to impaired synaptic transmission in the hippocampus during EAE. This is the first report demonstrating that testosterone is a viable therapeutic treatment option that can restore both hippocampal function and disease-associated pathology that occur during autoimmune disease.

Ziehn, Marina O.; Avedisian, Andrea A.; Dervin, Shannon M.; Umeda, Elizabeth A.; O'Dell, Thomas J.; Voskuhl, Rhonda R.



Genetic deletion of TNF receptor suppresses excitatory synaptic transmission via reducing AMPA receptor synaptic localization in cortical neurons  

PubMed Central

The distribution of postsynaptic glutamate receptors has been shown to be regulated by proimmunocytokine tumor necrosis factor ? (TNF-?) signaling. The role of TNF-? receptor subtypes in mediating glutamate receptor expression, trafficking, and function still remains unclear. Here, we report that TNF receptor subtypes (TNFR1 and TNFR2) differentially modulate ?-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) clustering and function in cultured cortical neurons. We find that genetic deletion of TNFR1 decreases surface expression and synaptic localization of the AMPAR GluA1 subunit, reduces the frequency of miniature excitatory postsynaptic current (mEPSC), and reduces AMPA-induced maximal whole-cell current. In addition, these results are not observed in TNFR2-deleted neurons. The decreased AMPAR expression and function in TNFR1-deleted cells are not significantly restored by short (2 h) or long (24 h) term exposure to TNF-?. In TNFR2-deleted cells, TNF-? promotes AMPAR trafficking to the synapse and increases mEPSC frequency. In the present study, we find no significant change in the GluN1 subunit of NMDAR clusters, location, and mEPSC. This includes applying or withholding the TNF-? treatment in both TNFR1- and TNFR2-deleted neurons. Our results indicate that TNF receptor subtype 1 but not 2 plays a critical role in modulating AMPAR clustering, suggesting that targeting TNFR1 gene might be a novel approach to preventing neuronal AMPAR-mediated excitotoxicity.—He, P., Liu, Q., Wu, J., Shen, Y. Genetic deletion of TNF receptor suppresses excitatory synaptic transmission via reducing AMPA receptor synaptic localization in cortical neurons.

He, Ping; Liu, Qiang; Wu, Jie; Shen, Yong



Dopaminergic modulation of synaptic transmission and neuronal activity patterns in the zebrafish homolog of olfactory cortex  

PubMed Central

Dopamine (DA) is an important modulator of synaptic transmission and plasticity that is causally involved in fundamental brain functions and dysfunctions. We examined the dopaminergic modulation of synaptic transmission and sensory responses in telencephalic area Dp of zebrafish, the homolog of olfactory cortex. By combining anatomical tracing and immunohistochemistry, we detected no DA neurons in Dp itself but long-range dopaminergic input from multiple other brain areas. Whole-cell recordings revealed no obvious effects of DA on membrane potential or input resistance in the majority of Dp neurons. Electrical stimulation of the olfactory tracts produced a complex sequence of synaptic currents in Dp neurons. DA selectively decreased inhibitory currents with little or no effect on excitatory components. Multiphoton calcium imaging showed that population responses of Dp neurons to olfactory tract stimulation or odor application were enhanced by DA, consistent with its effect on inhibitory synaptic transmission. These effects of DA were blocked by an antagonist of D2-like receptors. DA therefore disinhibits and reorganizes sensory responses in Dp. This modulation may affect sensory perception and could be involved in the experience-dependent modification of odor representations.

Scharer, Yan-Ping Zhang; Shum, Jennifer; Moressis, Anastasios; Friedrich, Rainer W.



Compound vesicle fusion increases quantal size and potentiates synaptic transmission.  


Exocytosis at synapses involves fusion between vesicles and the plasma membrane. Although compound fusion between vesicles was proposed to occur at ribbon-type synapses, whether it exists, how it is mediated, and what role it plays at conventional synapses remain unclear. Here we report the existence of compound fusion, its underlying mechanism, and its role at a nerve terminal containing conventional active zones in rats and mice. We found that high potassium application and high frequency firing induced giant capacitance up-steps, reflecting exocytosis of vesicles larger than regular ones, followed by giant down-steps, reflecting bulk endocytosis. These intense stimuli also induced giant vesicle-like structures, as observed with electron microscopy, and giant miniature excitatory postsynaptic currents (mEPSCs), reflecting more transmitter release. Calcium and its sensor for vesicle fusion, synaptotagmin, were required for these giant events. After high frequency firing, calcium/synaptotagmin-dependent mEPSC size increase was paralleled by calcium/synaptotagmin-dependent post-tetanic potentiation. These results suggest a new route of exocytosis and endocytosis composed of three steps. First, calcium/synaptotagmin mediates compound fusion between vesicles. Second, exocytosis of compound vesicles increases quantal size, which increases synaptic strength and contributes to the generation of post-tetanic potentiation. Third, exocytosed compound vesicles are retrieved via bulk endocytosis. We suggest that this vesicle cycling route be included in models of synapses in which only vesicle fusion with the plasma membrane is considered. PMID:19279571

He, Liming; Xue, Lei; Xu, Jianhua; McNeil, Benjamin D; Bai, Li; Melicoff, Ernestina; Adachi, Roberto; Wu, Ling-Gang



Growth hormone modulates hippocampal excitatory synaptic transmission and plasticity in old rats.  


Alterations in the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor (AMPA-R) and N-methyl-D-aspartate receptor (NMDA-R) have been documented in aged animals and may contribute to changes in hippocampal-dependent memory. Growth hormone (GH) regulates AMPA-R and NMDA-R-dependent excitatory transmission and decreases with age. Chronic GH treatment mitigates age-related cognitive decline. An in vitro CA1 hippocampal slice preparation was used to compare hippocampal excitatory transmission and plasticity in old animals treated for 6-8 months with either saline or GH. Our findings indicate that GH treatment restores NMDA-R-dependent basal synaptic transmission in old rats to young adult levels and enhances both AMPA-R-dependent basal synaptic transmission and long-term potentiation. These alterations in synaptic function occurred in the absence of changes in presynaptic function, as measured by paired-pulse ratios, the total protein levels of AMPA-R and NMDA-R subunits or in plasma or hippocampal levels of insulin-like growth factor-I. These data suggest a direct role for GH in altering age-related changes in excitatory transmission and provide a possible cellular mechanism through which GH changes the course of cognitive decline. PMID:22015312

Molina, Doris P; Ariwodola, Olusegun J; Linville, Constance; Sonntag, William E; Weiner, Jeff L; Brunso-Bechtold, Judy K; Adams, Michelle M



Growth hormone modulates hippocampal excitatory synaptic transmission and plasticity in old rats  

PubMed Central

Alterations in the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA-R) receptor and N-methyl-D-aspartate receptor (NMDA-R) have been documented in aged animals and may contribute to changes in hippocampal-dependent memory. Growth Hormone (GH) regulates AMPA-R and NMDA-R-dependent excitatory transmission and decreases with age. Chronic GH treatment mitigates age-related cognitive decline. An in vitro CA1 hippocampal slice preparation was used to compare hippocampal excitatory transmission and plasticity in old animals treated for 6–8 months with either saline or GH. Our findings indicate that GH treatment restores NMDA-R dependent basal synaptic transmission in old rats to young adult levels and enhances both AMPA-R-dependent basal synaptic transmission and long-term potentiation. These alterations in synaptic function occurred in the absence of changes in presynaptic function, as measured by paired-pulse ratios, the total protein levels of AMPA-R and NMDA-R subunits or in plasma or hippocampal levels of insulin-like growth factor-I. These data suggest a direct role for GH in altering age-related changes in excitatory transmission and provide a possible cellular mechanism through which GH changes the course of cognitive decline.

Molina, Doris P.; Ariwodola, Olusegun J.; Linville, Constance; Sonntag, William E.; Weiner, Jeff L.; Brunso-Bechtold, Judy K.; Adams, Michelle M.



Group III mGluR regulation of synaptic transmission at the SCCA1 synapse is developmentally regulated  

Microsoft Academic Search

Group III metabotropic glutamate receptors (mGluRs) reduce synaptic transmission at the Schaffer collateral-CA1 (SC-CA1) synapse in rats by a presynaptic mechanism. Previous studies show that low concentrations of the group III-selective agonist, L-AP4, reduce synaptic transmission in slices from neonatal but not adult rats, whereas high micromolar concentrations reduce transmission in both age groups. L-AP4 activates mGluRs 4 and 8

Jennifer E. Ayala; Colleen M. Niswender; Qingwei Luo; Jessica L. Banko; P. Jeffrey Conn



[Neuromuscular synaptic transmission at different stages of postnatal development in rats].  


On the nerve-muscle preparation of rats diaphragm muscle on different stages of postnatal development, the comparison of morphological features and functions of synaptic apparatus, including induced secretion time parameters was carried out. It was found that, along with the reduced, compared to the adult animals, area of nerve endings in the newborn the speed of the motor nerve excitation was slower, intensity of spontaneous and induced secretion of quantum fluctuations was reduced and real synaptic delays in the end plate were intense. Severe degree of acetylcholine quanta asynchronous secretion with longer open state of the ion channel in newborns synapses can compensate reduction in reliability of synaptic transmission due to a decrease of the quantal content of the postsynaptic response. PMID:23461198

Khuzakhmetova, B F; Samigullin, D V; Nurullin, L F; Nikol'ski?, E E; Bukhareva, É A



Role of Rab27 in synaptic transmission at the squid giant synapse  

PubMed Central

Small GTPase Rab is a member of a large family of Ras-related proteins, highly conserved in eukaryotic cells, and thought to regulate specific type(s) and/or specific step(s) in intracellular membrane trafficking. Given our interest in synaptic transmission, we addressed the possibility that Rab27 (a close isoform of Rab3) could be involved in cytosolic synaptic vesicle mobilization. Indeed, preterminal injection of a specific antibody against squid Rab27 (anti-sqRab27 antibody) combined with confocal microscopy demonstrated that Rab27 is present on squid synaptic vesicles. Electrophysiological study of injected synapses showed that the anti-sqRab27 antibody inhibited synaptic release in a stimulation-dependent manner without affecting presynaptic action potentials or inward Ca2+ current. This result was confirmed in in vitro synaptosomes by using total internal reflection fluorescence microscopy. Thus, synaptosomal Ca2+-stimulated release of FM1-43 dye was greatly impaired by intraterminal anti-sqRab27 antibody. Ultrastructural analysis of the injected giant preterminal further showed a reduced number of docked synaptic vesicles and an increase in nondocked vesicular profiles distant from the active zone. These results, taken together, indicate that Rab27 is primarily involved in the maturation of recycled vesicles and/or their transport to the presynaptic active zone in the squid giant synapse.

Yu, Eunah; Kanno, Eiko; Choi, Soonwook; Sugimori, Mutsuyuki; Moreira, Jorge E.; Llinas, Rodolfo R.; Fukuda, Mitsunori



Enhancement of inhibitory synaptic transmission in large aspiny neurons after transient cerebral ischemia  

PubMed Central

Large aspiny neurons and most of the GABAergic interneurons survive transient cerebral ischemia while medium spiny neurons degenerate in 24 h. Expression of a long-term enhancement of excitatory transmission in medium spiny neurons but not in large aspiny neurons has been indicated to contribute to this selective vulnerability. Because neuronal excitability is determined by the counterbalance of excitation and inhibition, the present study examined inhibitory synaptic transmission in large aspiny neurons after ischemia in rats. Transient cerebral ischemia was induced for 22 minutes using the four-vessel occlusion method and whole-cell voltage-clamp recording was performed on striatal slices. The amplitudes of evoked inhibitory postsynaptic currents in large aspiny neurons were significantly increased at 3 h and 24 h after ischemia, which was mediated by the increase of presynaptic release. Postsynaptic responses were depressed at 24 h after ischemia. Inhibitory postsynaptic currents could be evoked in large aspiny neurons at 24 h after ischemia, suggesting that they receive GABAergic inputs from the survived GABAergic interneurons. Muscimol, a GABAA receptor agonist, presynaptically facilitated inhibitory synaptic transmission at 24 h after ischemia. Such facilitation was dependent on the extracellular calcium and voltage-gated sodium channels. The present study demonstrates an enhancement of inhibitory synaptic transmission in large aspiny neurons after ischemia, which might reduce excitotoxicity and contribute, at least in part, to the survival of large aspiny neurons. Our data also suggests that large aspiny neurons might receive inhibitory inputs from GABAergic interneurons.

Li, Yan; Lei, Zhigang; Xu, Zao C.



Glycolysis prevents anoxia-induced synaptic transmission damage in rat hippocampal slices.  


Prolonged anoxia can cause permanent damage to synaptic transmission in the mammalian CNS. We tested the hypothesis that lack of glucose is the major cause of irreversible anoxic transmission damage, and that anoxic synaptic transmission damage could be prevented by glycolysis in rat hippocampal slices. The evoked population spike (PS) was extracellularly recorded in the CA1 pyramidal cell layer after stimulation of the Schaffer collaterals. When the slice was superfused with artificial cerebrospinal fluid (ACSF) containing 4 mM glucose, following 10 min anoxia, the evoked PS did not recover at all after 60 min reoxygenation. When superfusion ACSF contained 10 mM glucose with or without 0.5 mM alpha-cyano-4-hydroxycinnate (4-CIN), after 60 min reoxygenation the evoked PS completely recovered following 10 min anoxia. When superfusion ACSF contained 20 mM glucose with or without 1 mM sodium cyanide (NaCN), after 60 min reoxygenation the evoked PS completely recovered even following 120 min anoxia. In contrast, when superfusion ACSF contained 4 mM glucose, following 10 min 1 mM NaCN chemical anoxia alone, without anoxic anoxia, the evoked PS displayed no recovery after 60 min reoxygenation. Moreover, when 16 mM mannitol and 16 sodium L-lactate were added into 4 mM glucose ACSF, following 10 min anoxia the evoked PS failed to recover at all after 60 min reoxygenation. The results indicate that elevated glucose concentration powerfully protected the synaptic transmission against anoxic damage, and the powerful protection is due to anaerobic metabolism of glucose and not a result of the higher osmolality in higher glucose ACSF. We conclude that lack of glucose is the major cause of anoxia-induced synaptic transmission damage, and that if sufficient glucose is supplied, glycolysis could prevent this damage in vitro. PMID:10758095

Tian, G F; Baker, A J



Controlling the first-spike latency response of a single neuron via unreliable synaptic transmission  

NASA Astrophysics Data System (ADS)

Previous experimental and theoretical studies suggest that first-spike latency is an efficient information carrier and may contain more amounts of neural information than those of other spikes. Therefore, the biophysical mechanisms underlying the first-spike response latency are of considerable interest. Here we present a systematical investigation on the response latency dynamics of a single Hodgkin-Huxley neuron subject to both a suprathreshold periodic forcing and background activity. In contrast to most earlier works, we consider a biophysically realistic noise model which allows us to relate the synaptic background activity to unreliable synapses and latency. Our results show that first-spike latency of a neuron can be regulated via unreliable synapses. An intermediate level of successful synaptic transmission probability significantly increases both the latency and its jitter, indicating that the unreliable synaptic transmission constrains the signal detection ability of neurons. Furthermore, we demonstrate that the destructive influence of synaptic unreliability can be controlled by the input regime and by the excitatory coupling strength. Better tuning of these two factors could help the H-H neuron encode information more accurately in terms of the first-spike latency.

Uzuntarla, M.; Ozer, M.; Guo, D. Q.



ATP hydrolysis is required for the rapid regulation of AMPA receptors during basal synaptic transmission and long-term synaptic plasticity.  


ATP hydrolysis is critical for many cellular processes; however, the acute requirement for ATP hydrolysis in synaptic transmission and plasticity in neurons is unknown. Here we studied the effects of postsynaptically applying the non-hydrolyzable ATP analogue adenosine 5'-[beta,gamma-methylene]triphosphate (AMP-PCP) into hippocampal CA1 pyramidal cells in hippocampal slices. The effects of this manipulation were investigated on basal transmission and on two forms of long-term synaptic plasticity, long-term potentiation (LTP) and long-term depression (LTD). AMP-PCP caused an increase in basal AMPA receptor (AMPAR)-mediated transmission, which occurred rapidly within minutes of infusing the drug. This effect was selective for AMPARs, since pharmacologically isolated NMDAR-mediated synaptic currents did not exhibit this run up. In two-pathway experiments infusion of AMP-PCP blocked the induction of both LTD and LTP. These findings show an acute and selective role for ATP hydrolysis in regulating AMPAR function both during basal transmission and long-term synaptic plasticity. Recent evidence indicates that AMPARs are selectively and acutely regulated by the ATPase N-ethylmaleimide-sensitive factor (NSF), which forms part of a multi-protein complex with AMPARs. Our data are consistent with the idea that such a mechanism that can acutely bi-directionally regulate AMPAR function at synapses and requires ATP hydrolysis is necessary for rapid activity-dependent changes in synaptic strength. PMID:15857621

Lim, Wonil; Isaac, John T R



Genetic analysis in Drosophila reveals a role for the mitochondrial protein p32 in synaptic transmission.  


Mitochondria located within neuronal presynaptic terminals have been shown to play important roles in the release of chemical neurotransmitters. In the present study, a genetic screen for synaptic transmission mutants of Drosophila has identified the first mutation in a Drosophila homolog of the mitochondrial protein P32. Although P32 is highly conserved and has been studied extensively, its physiological role in mitochondria remains unknown and it has not previously been implicated in neural function. The Drosophila P32 mutant, referred to as dp32(EC1), exhibited a temperature-sensitive (TS) paralytic behavioral phenotype. Moreover, electrophysiological analysis at adult neuromuscular synapses revealed a TS reduction in the amplitude of excitatory postsynaptic currents (EPSC) and indicated that dP32 functions in neurotransmitter release. These studies are the first to address P32 function in Drosophila and expand our knowledge of mitochondrial proteins contributing to synaptic transmission. PMID:22384382

Lutas, Andrew; Wahlmark, Christopher J; Acharjee, Shaona; Kawasaki, Fumiko



Efficiency of neural transmission as a function of synaptic noise, threshold, and source characteristics.  


There has been a growing interest in the estimation of information carried by a single neuron and multiple single units or population of neurons to specific stimuli. In this paper we analyze, inspired by article of Levy and Baxter (2002), the efficiency of a neuronal communication by considering dendrosomatic summation as a Shannon-type channel (1948) and by considering such uncertain synaptic transmission as part of the dendrosomatic computation. Specifically, we study Mutual Information between input and output signals for different types of neuronal network architectures by applying efficient entropy estimators. We analyze the influence of the following quantities affecting transmission abilities of neurons: synaptic failure, activation threshold, firing rate and type of the input source. We observed a number of surprising non-intuitive effects. It turns out that, especially for lower activation thresholds, significant synaptic noise can lead even to twofold increase of the transmission efficiency. Moreover, the efficiency turns out to be a non-monotonic function of the activation threshold. We find a universal value of threshold for which a local maximum of Mutual Information is achieved for most of the neuronal architectures, regardless of the type of the source (correlated and non-correlated). Additionally, to reach the global maximum the optimal firing rates must increase with the threshold. This effect is particularly visible for lower firing rates. For higher firing rates the influence of synaptic noise on the transmission efficiency is more advantageous. Noise is an inherent component of communication in biological systems, hence, based on our analysis, we conjecture that the neuronal architecture was adjusted to make more effective use of this attribute. PMID:21439348

Paprocki, Bartosz; Szczepanski, Janusz



Presynaptic large-conductance calcium-activated potassium channels control synaptic transmission in the superficial dorsal horn of the mouse  

Microsoft Academic Search

Large-conductance calcium-activated potassium channels (BK channels) have been suggested to play a substantial role in synaptic transmission in the spinal cord dorsal horn. In the present experiments, we attempted to clarify the physiological significance of BK channels in the modulation of synaptic transmission in the superficial dorsal horn where nociceptive information is processed. Spontaneously occurring excitatory postsynaptic currents (sEPSCs) were

Naoki Furukawa; Toshifumi Takasusuki; Teruyuki Fukushima; Yuuichi Hori



Effects of hemoglobin and its breakdown products on synaptic transmission in rat hippocampal CA1 neurons.  


During head injuries and hemorrhagic stroke, blood is released into the extravascular space. The pooled erythrocytes get lysed and hemoglobin is released into the intracranial cavities. Therefore, neurons may be exposed to hemoglobin and/or its breakdown products, hemin and iron, for long periods of time. In this study, the electrophysiological actions of these agents on synaptic transmission in rat hippocampal CA1 pyramidal neurons were studied using extracellular field- and whole cell patch-recordings. Previously our laboratory reported that commercially available hemoglobin produced a dose dependent suppression of synaptic transmission in hippocampal CA1 neurons. In the present study, however, we found that this depression was caused by impurities present in the hemoglobin samples. Commercially available hemoglobin and methemoglobin did not have a significant effect on synaptic transmission. Although, reduced-hemoglobin prepared using a method described by Martin et al. [J. Pharm. Exp. Ther. 232 (1985) 708], produced a significant depression of synaptic transients, these effects were due to contamination with bisulfite that was present due to the reducing procedure. Therefore, the technique of Martin et al. was inadequate in removing the reducing agents or their breakdown products. A number of studies in literature used commercial samples of hemoglobin or reduced hemoglobin prepared using the method of Martin et al. Our observations indicate that it would be important to determine if contaminants, rather than hemoglobin, are responsible for the observed effects in these studies. Unlike hemoglobin, its breakdown products, ferrous chloride and hemin, produced an irreversible and significant depression of field excitatory postsynaptic potentials. The relevance of these effects in neurological complications that follow head injuries and hemorrhagic stroke awaits further investigation. PMID:10793181

Yip, S; Sastry, B R



Modulation of synaptic transmission by the BCL-2 family protein BCL-xL.  


BCL-2 family proteins are known to regulate cell death during development by influencing the permeability of mitochondrial membranes. The anti-apoptotic BCL-2 family protein BCL-xL is highly expressed in the adult brain and localizes to mitochondria in the presynaptic terminal of the adult squid stellate ganglion. Application of recombinant BCL-xL through a patch pipette to mitochondria inside the giant presynaptic terminal triggered multiconductance channel activity in mitochondrial membranes. Furthermore, injection of full-length BCL-xL protein into the presynaptic terminal enhanced postsynaptic responses and enhanced the rate of recovery from synaptic depression, whereas a recombinant pro-apoptotic cleavage product of BCL-xL attenuated postsynaptic responses. The effect of BCL-xL on synaptic responses persisted in the presence of a blocker of mitochondrial calcium uptake and was mimicked by injection of ATP into the terminal. These studies indicate that the permeability of outer mitochondrial membranes influences synaptic transmission, and they raise the possibility that modulation of mitochondrial conductance by BCL-2 family proteins affects synaptic stability. PMID:12968005

Jonas, Elizabeth A; Hoit, Daniel; Hickman, John A; Brandt, Teresa A; Polster, Brian M; Fannjiang, Yihru; McCarthy, Erin; Montanez, Marlena K; Hardwick, J Marie; Kaczmarek, Leonard K



Possible mechanisms for long-lasting potentiation of synaptic transmission in hippocampal slices from guinea-pigs.  

PubMed Central

1. Long-lasting potentiation of synaptic transmission was studied in the CA1 region of guinea-pig hippocampal slices maintained in vitro. 2. Stimulating pulses were delivered alternately to two independent afferent pathways, stratum radiatum and stratum oriens. The presynaptic volleys and field e.p.s.p.s. were recorded from the same two layers, while an electrode in the pyramidal cell body layer recorded the population spike or in other experiments the extra- or intracellular potentials from a single pyramidal cell. 3. A short tetanus to either of the two input pathways produced a long-lasting enhancement of the field e.p.s.p. as well as an increased size and a reduced latency of the population spike. This long-lasting potentiation was observed for up to 110 min after tetanization. Extracellular unit recordings showed that this potentiation is accompanied by an increased probability of firing and a reduced firing latency. Intracellular recordings showed an increased e.p.s.p., through the increase was smaller and less regular than for the extracellular field e.p.s.p. 4. No corresponding changes were seen in the field potential responses to stimulation of the untetanized input path, or in the intracellularly measured soma membrane potential, resistance, or excitability. The latter two properties were measured by intracellular injection of current pulses. It is concluded that long-lasting potentiation is specific to the pathway which has received the tetanization. 5. Following tetanization there was also a short-lasting (usually 2-4 min) depression, most often seen for the control pathway but sometimes visible on the tetanized side as well, superimposed on the potentiation. It is concluded that the short-lasting depression is not confined to any particular pathway but is a generalized (unspecific) phenomenon.

Andersen, P; Sundberg, S H; Sveen, O; Swann, J W; Wigstrom, H



Anandamide potentiation of miniature spontaneous excitatory synaptic transmission is mediated via an IP3 pathway  

PubMed Central

Although arachidonoyl ethanolamide (AEA or anandamide) is the first identified endocannabinoid, its roles in synaptic signaling and neuronal survival are still controversial. Here we report that AEA induced a dose-dependent elevation of the frequency of miniature excitatory postsynaptic currents (mEPSCs) in mouse hippocampal neurons in culture. This potentiation was not blocked by SR141716 or AM251, selective cannabinoid receptor antagonists), indicating that the AEA elevation of mEPSCs is not mediated via the CB1 receptor. Similarly, capsazepine and iodoresiniferatoxin, selective vanilloid receptor antagonists, and ryanodine also failed to inhibit the effect of AEA on mEPSCs. However, 2-APB and Xestospongin C, IP3 inhibitors, significantly attenuated AEA-induced increase in hippocampal excitatory synaptic transmission. Application of 3-deoxy-3-fluoro-D-myo-inositol 1,4,5-trisphosphate enhanced the frequency of mEPSCs and occluded the effect of AEA on mEPSCs. Our results suggest that AEA-produced stimulatory effect on excitatory glutamatergic synaptic transmission is likely mediated via an IP3 pathway.

Sang, Nan; Zhang, Jian; Chen, Chu



Synaptic transmission in low extracellular calcium is preserved by 3,4-diaminopyridine.  


Synaptic transmission in the isolated bullfrog sympathetic ganglion was studied during graded reductions in extracellular Ca++, from the normal of 1.8 mM, in the absence and in the presence of different concentrations of 3,4-diaminopyridine (3,4-DAP). In drug-free Ringer's synaptic transmission, measured as the amplitude of the postganglionic compound action potential, failed progressively as Ca++ was reduced from 1.8 to 0.47 mM. This Ca++-dependence curve of synaptic transmission was shifted to the left (lower Ca++) by 3,4-DAP in dose-related fashion with threshold at 0.1 microM and maximum shift at 10 microM 3,4-DAP. At maximum shift (4- to 5-fold) in the Ca++-dependence curve, compound action potential amplitude was normal at 0.33 mM Ca++ then failed progressively as Ca++ was reduced to 0.12 mM. Also 3,4-DAP causes stimulus-bound repetitive postganglionic responses (SBR) to single preganglionic stimuli (Apatoff and Riker, 1982). SBR were selectively abolished as Ca++ was reduced form 1.8 to 0.47 mM. The data reveal that 3,4-DAP facilitates presynaptic influx or binding of Ca++. Furthermore, the high Ca++ requirement for 3,4-DAP-induced SBR, as well as the difference between threshold drug concentrations for preserving transmission (0.1 microM) and for generating SBR (2-5 microM), lead to the speculation that there may be two presynaptic receptors for 3,4-DAP. PMID:6312015

Matsumoto, M; Riker, W K



Fast synaptic transmission mediated by P2X receptors in CA3 pyramidal cells of rat hippocampal slice cultures  

PubMed Central

A fast ATP-mediated synaptic current was identified in CA3 pyramidal cells in organotypic hippocampal slice cultures. In the presence of inhibitors for ionotropic glutamate and GABA receptors, extracellular stimulation in the pyramidal cell layer evoked fast synaptic currents that reversed near 0 mV, reflecting an increase in a non-selective cationic conductance. This response was mimicked by focal application of ATP. Antagonists of ionotropic P2X receptors reduced both synaptic and ATP-induced currents. Using a pharmacological approach, the source of synaptically released ATP was determined. Synaptic ATP responses were insensitive to presynaptic blockade of GABAergic transmission between interneurons and CA3 pyramidal cells with the ?-opioid receptor agonist D-Ala2,MePhe4,Met(O)5-ol-enkephalin (FK33-824), but were blocked by adenosine, which inhibits glutamate release from synaptic terminals in the hippocampus. However, selective inhibition of mossy fibre glutamatergic transmission with the metabotropic glutamate receptor group II agonist (2S,2?R,3?R)-2-(2?,3?-dicarboxycyclopropyl)glycine (DCG IV) did not affect the response. This result points to the associational fibres as the source of the ATP-mediated synaptic response. These results suggest that ATP, coreleased with glutamate, induces a synaptic response in CA3 pyramidal cells that is observed mainly under conditions of synchronous discharge from multiple presynaptic inputs.

Mori, Masahiro; Heuss, Christian; Gahwiler, Beat H; Gerber, Urs



Transient Enhancement of Inhibitory Synaptic Transmission in Hippocampal CA1 Pyramidal Neurons after Cerebral Ischemia  

PubMed Central

Pyramidal neurons in hippocampal CA1 regions are highly sensitive to cerebral ischemia. Alterations of excitatory and inhibitory synaptic transmission may contribute to the ischemia-induced neuronal degeneration. However, little is known about the changes of GABAergic synaptic transmission in the hippocampus following reperfusion. We examined the GABAA receptor-mediated inhibitory postsynaptic currents (IPSCs) in CA1 pyramidal neurons 12 hours and 24 hours after transient forebrain ischemia. The amplitudes of evoked IPSCs (eIPSCs) were increased significantly 12 hours after ischemia and returned to control levels 24 hours following reperfusion. The potentiation of eIPSCs was accompanied by an increase of miniature IPSCs (mIPSCs) amplitude, and an enhanced response to exogenous application of GABA, indicating the involvement of postsynaptic mechanisms. Furthermore, there was no obvious change of the paired-pulse ratio (PPR) of eIPSCs and the frequency of mIPSCs, suggesting that the potentiation of eIPSCs might not be due to the increased presynaptic release. Blockade of adenosine A1 receptors led to a decrease of eIPSCs amplitude in post-ischemic neurons but not in control neurons, without affecting the frequency of mIPSCs and the PPR of eIPSCs. Thus, tonic activation of adenosine A1 receptors might, at least in part, contribute to the enhancement of inhibitory synaptic transmission in CA1 neurons after forebrain ischemia. The transient enhancement of inhibitory neurotransmission might temporarily protect CA1 pyramidal neurons, and delay the process of neuronal death after cerebral ischemia.

Liang, Rui; Pang, Zhi-Ping; Deng, Ping; Xu, Zao C.



Group II metabotropic glutamate receptors depress synaptic transmission onto subicular burst firing neurons.  


The subiculum (SUB) is a pivotal structure positioned between the hippocampus proper and various cortical and subcortical areas. Despite the growing body of anatomical and intrinsic electrophysiological data of subicular neurons, modulation of synaptic transmission in the SUB is not well understood. In the present study we investigated the role of group II metabotropic glutamate receptors (mGluRs), which have been shown to be involved in the regulation of synaptic transmission by suppressing presynaptic cAMP activity. Using field potential and patch-clamp whole cell recordings we demonstrate that glutamatergic transmission at CA1-SUB synapses is depressed by group II mGluRs in a cell-type specific manner. Application of the group II mGluR agonist (2S,1'R,2'R,3'R)-2-(2, 3-dicarboxycyclopropyl)glycine (DCG-IV) led to a significantly higher reduction of excitatory postsynaptic currents in subicular bursting cells than in regular firing cells. We further used low-frequency stimulation protocols and brief high-frequency bursts to test whether synaptically released glutamate is capable of activating presynaptic mGluRs. However, neither frequency facilitation is enhanced in the presence of the group II mGluR antagonist LY341495, nor is a test stimulus given after a high-frequency burst. In summary, we present pharmacological evidence for presynaptic group II mGluRs targeting subicular bursting cells, but both low- and high-frequency stimulation protocols failed to activate presynaptically located mGluRs. PMID:22984605

Kintscher, Michael; Breustedt, Jörg; Miceli, Stéphanie; Schmitz, Dietmar; Wozny, Christian



Group II Metabotropic Glutamate Receptors Depress Synaptic Transmission onto Subicular Burst Firing Neurons  

PubMed Central

The subiculum (SUB) is a pivotal structure positioned between the hippocampus proper and various cortical and subcortical areas. Despite the growing body of anatomical and intrinsic electrophysiological data of subicular neurons, modulation of synaptic transmission in the SUB is not well understood. In the present study we investigated the role of group II metabotropic glutamate receptors (mGluRs), which have been shown to be involved in the regulation of synaptic transmission by suppressing presynaptic cAMP activity. Using field potential and patch-clamp whole cell recordings we demonstrate that glutamatergic transmission at CA1-SUB synapses is depressed by group II mGluRs in a cell-type specific manner. Application of the group II mGluR agonist (2S,1?R,2?R,3?R)-2-(2, 3-dicarboxycyclopropyl)glycine (DCG-IV) led to a significantly higher reduction of excitatory postsynaptic currents in subicular bursting cells than in regular firing cells. We further used low-frequency stimulation protocols and brief high-frequency bursts to test whether synaptically released glutamate is capable of activating presynaptic mGluRs. However, neither frequency facilitation is enhanced in the presence of the group II mGluR antagonist LY341495, nor is a test stimulus given after a high-frequency burst. In summary, we present pharmacological evidence for presynaptic group II mGluRs targeting subicular bursting cells, but both low- and high-frequency stimulation protocols failed to activate presynaptically located mGluRs.

Kintscher, Michael; Breustedt, Jorg; Miceli, Stephanie; Schmitz, Dietmar; Wozny, Christian



N-arachidonyl-glycine modulates synaptic transmission in superficial dorsal horn  

PubMed Central

BACKGROUND AND PURPOSE The arachidonyl-amino acid N-arachidonyl-glycine (NAGly) is an endogenous lipid, generated within the spinal cord and producing spinally mediated analgesia via non-cannabinoid mechanisms. In this study we examined the actions of NAGly on neurons within the superficial dorsal horn, a key site for the actions of many analgesic agents. EXPERIMENTAL APPROACH Whole cell patch clamp recordings were made from lamina II neurons in rat spinal cord slices to examine the effect of NAGly on glycinergic and NMDA-mediated synaptic transmission. KEY RESULTS N-arachidonyl-glycine prolonged the decay of glycine, but not ?-alanine induced inward currents and decreased the amplitude of currents induced by both glycine and ?-alanine. NAGly and ALX-1393 (inhibitor of the glycine transporter, GLYT2), but not the GLYT1 inhibitor, ALX-5407, produced a strychnine-sensitive inward current. ALX-5407 and ALX-1393, but not NAGly prolonged the decay phase of glycine receptor-mediated miniature inhibitory postsynaptic currents (IPSCs). NAGly prolonged the decay phase of evoked IPSCs, although to a lesser extent than ALX-5407 and ALX-1393. In the presence of ALX-1393, NAGly shortened the decay phase of evoked IPSCs. ALX-5407 increased and NAGly decreased the amplitude of evoked NMDA-mediated excitatory postsynaptic currents. CONCLUSIONS AND IMPLICATIONS Our results suggest that NAGly enhanced inhibitory glycinergic synaptic transmission within the superficial dorsal horn by blocking glycine uptake via GLYT2. In addition, NAGly decreased excitatory NMDA-mediated synaptic transmission. Together, these findings provide a cellular explanation for the spinal analgesic actions of NAGly.

Jeong, Hyo-Jin; Vandenberg, Robert J; Vaughan, Christopher W



Stochastic resonance in Hodgkin-Huxley neuron induced by unreliable synaptic transmission.  


We systematically investigate the stochastic dynamics of a single Hodgkin-Huxley neuron driven by stochastic excitatory and inhibitory input spikes via unreliable synapses in this paper. Based on the mean-filed theory, a novel intrinsic neuronal noise regulation mechanism stemming from unreliable synapses is presented. Our simulation results show that, under certain conditions, the stochastic resonance phenomenon is able to be induced by the unreliable synaptic transmission, which can be well explained by the theoretical prediction. To a certain degree, the results presented here provide insights into the functional roles of unreliable synapses in neural information processing. PMID:22687443

Guo, Daqing; Li, Chunguang



Tuning synaptic transmission in the hippocampus by stress: the CRH system  

PubMed Central

To enhance survival, an organism needs to remember—and learn from—threatening or stressful events. This fact necessitates the presence of mechanisms by which stress can influence synaptic transmission in brain regions, such as hippocampus, that subserve learning and memory. A major focus of this series of monographs is on the role and actions of adrenal-derived hormones, corticosteroids, and of brain-derived neurotransmitters, on synaptic function in the stressed hippocampus. Here we focus on the contribution of hippocampus-intrinsic, stress-activated CRH-CRH receptor signaling to the function and structure of hippocampal synapses. Corticotropin-releasing hormone (CRH) is expressed in interneurons of adult hippocampus, and is released from axon terminals during stress. The peptide exerts time- and dose-dependent effects on learning and memory via modulation of synaptic function and plasticity. Whereas physiological levels of CRH, acting over seconds to minutes, augment memory processes, exposure to presumed severe-stress levels of the peptide results in spine retraction and loss of synapses over more protracted time-frames. Loss of dendritic spines (and hence of synapses) takes place through actin cytoskeleton collapse downstream of CRHR1 receptors that reside within excitatory synapses on spine heads. Chronic exposure to stress levels of CRH may promote dying-back (atrophy) of spine-carrying dendrites. Thus, the acute effects of CRH may contribute to stress-induced adaptive mechanisms, whereas chronic or excessive exposure to the peptide may promote learning problems and premature cognitive decline.

Chen, Yuncai; Andres, Adrienne L.; Frotscher, Michael; Baram, Tallie Z.



Tuning synaptic transmission in the hippocampus by stress: the CRH system.  


To enhance survival, an organism needs to remember-and learn from-threatening or stressful events. This fact necessitates the presence of mechanisms by which stress can influence synaptic transmission in brain regions, such as hippocampus, that subserve learning and memory. A major focus of this series of monographs is on the role and actions of adrenal-derived hormones, corticosteroids, and of brain-derived neurotransmitters, on synaptic function in the stressed hippocampus. Here we focus on the contribution of hippocampus-intrinsic, stress-activated CRH-CRH receptor signaling to the function and structure of hippocampal synapses. Corticotropin-releasing hormone (CRH) is expressed in interneurons of adult hippocampus, and is released from axon terminals during stress. The peptide exerts time- and dose-dependent effects on learning and memory via modulation of synaptic function and plasticity. Whereas physiological levels of CRH, acting over seconds to minutes, augment memory processes, exposure to presumed severe-stress levels of the peptide results in spine retraction and loss of synapses over more protracted time-frames. Loss of dendritic spines (and hence of synapses) takes place through actin cytoskeleton collapse downstream of CRHR(1) receptors that reside within excitatory synapses on spine heads. Chronic exposure to stress levels of CRH may promote dying-back (atrophy) of spine-carrying dendrites. Thus, the acute effects of CRH may contribute to stress-induced adaptive mechanisms, whereas chronic or excessive exposure to the peptide may promote learning problems and premature cognitive decline. PMID:22514519

Chen, Yuncai; Andres, Adrienne L; Frotscher, Michael; Baram, Tallie Z



Actions of BAX on mitochondrial channel activity and on synaptic transmission.  


Changes in mitochondrial architecture and permeability facilitate programmed cell death. The BCL-2 family protein BAX is implicated in the formation of large "death channels" in outer mitochondrial membranes. We found that BAX-induced channels on mitochondria may have alternative functions. By patch clamping mitochondrial membranes inside the presynaptic terminal of the living squid giant synapse, we made direct measurements of channel activity produced by BAX application. Only infrequently did BAX application result in large conductance channels similar to those produced by a proapoptotic BCL-xL fragment or by application of a BH3-only peptide. Instead, the majority of outer mitochondrial channels induced by BAX had much smaller conductances than those found previously for the proapoptotic protein. Injection of BAX into the presynaptic terminal did not abolish synaptic transmission, contrary to previous findings with the proapoptotic fragment of BCL-xL. Instead, injection of BAX caused an increase in neurotransmitter release, as has also been found for the full-length antiapoptotic BCL-xL protein. We suggest that BAX can act to enhance synaptic efficacy in a normal physiological setting. Furthermore, the occasional large openings may reflect the function of "activated" BAX either to facilitate cell death or to play a physiological role in decreasing synaptic activity. PMID:16115013

Jonas, Elizabeth A; Hardwick, J Marie; Kaczmarek, Leonard K


Stimulation of alpha2-adrenoceptors suppresses excitatory synaptic transmission in the medial prefrontal cortex of rat.  


Stimulation of alpha2-, especially alpha2A-adrenoceptor (AR), in the prefrontal cortex (PFC) produces a beneficial effect on cognitive functions such as working memory. Alpha2-adrenergic agonists like clonidine and guanfacine have been used experimentally and clinically for treatment of psychiatric disorders such as attention-deficit/hyperactivity disorder (ADHD) and schizophrenia. However, the neurophysiological actions of alpha2-ARs in the PFC are poorly understood. In the present study, we recorded field excitatory post-synaptic potential (fEPSP) and evoked excitatory post-synaptic current (eEPSC) in the medial prefrontal cortex (mPFC) of rats, using in vivo field-potential recording and in vitro whole-cell patch-clamp recording techniques, and examined the effects of the alpha2-AR agonist clonidine and the selective alpha2A-AR agonist guanfacine on fEPSP and eEPSC. Systemic or intra-mPFC application of clonidine or guanfacine significantly reduced fEPSP in the mPFC, either in anesthetized or freely moving rats. Consistently, bath-application of guanfacine suppressed eEPSC in layer V/VI pyramidal neurons, and this effect was blocked by the alpha2-AR antagonist yohimbine or the Gi inhibitor NF023. Moreover, treatment with guanfacine had no effect on paired-pulse facilitation (PPF) of fEPSP and eEPSC. The present study provides the first electrophysiological evidence that stimulation of alpha2A-AR inhibits excitatory synaptic transmission in the mPFC through a post-synaptic mechanism. PMID:17957212

Ji, Xiao-Hua; Ji, Jin-Zhao; Zhang, Hui; Li, Bao-Ming



Subtype-selective reconstitution of synaptic transmission in sympathetic ganglion neurons by expression of exogenous calcium channels  

PubMed Central

Fast cholinergic neurotransmission between superior cervical ganglion neurons (SCGNs) in cell culture is initiated by N-type Ca2+ currents through Cav2.2 channels. To test the ability of different Ca2+-channel subtypes to initiate synaptic transmission in these cells, SCGNs were injected with cDNAs encoding Cav1.2 channels, which conduct L-type currents, Cav2.1 channels, which conduct P/Q-type Ca2+ currents, and Cav2.3 channels, which conduct R-type Ca2+ currents. Exogenously expressed Cav2.1 channels were localized in nerve terminals, as assessed by immunocytochemistry with subtype-specific antibodies, and these channels effectively initiated synaptic transmission. Injection with cDNA encoding Cav2.3 channels yielded a lower level of presynaptic labeling and synaptic transmission, whereas injection with cDNA encoding Cav1.2 channels resulted in no presynaptic labeling and no synaptic transmission. Our results show that exogenously expressed Ca2+ channels can mediate synaptic transmission in SCGNs and that the specificity of reconstitution of neurotransmission (Cav2.1 > Cav2.3 ? Cav1.2) follows the same order as in neurons in vivo. The specificity of reconstitution of neurotransmission parallels the specificity of trafficking of these Cav channels to nerve terminals.

Mochida, Sumiko; Westenbroek, Ruth E.; Yokoyama, Charles T.; Itoh, Kanako; Catterall, William A.



Learning-induced modulation of SK channels-mediated effect on synaptic transmission.  


Although small conductance (SK)-mediated calcium-dependent potassium currents are usually mostly thought to modulate neuronal adaptation by suppressing repetitive spike firing, recent evidence suggests that these channels also modulate synaptic transmission. SK2 channels were shown to be activated in dendritic spines following calcium entry via N-methyl-d-aspartate (NMDA) receptor. Such activation of potassium currents terminates the NMDA-dependent postsynaptic potential (PSP). Synaptic potentials in pyramidal neurons in the piriform cortex from olfactory-discrimination-trained rats have enhanced rise time 3 days after learning, and their dendritic spines are significantly smaller at this time. In the present study we examined whether the SK channel-mediated effect on PSPs is modified after learning. The SK channels inhibitor, apamin, that selectively blocks the SK channels-mediated potassium currents enhanced the width of the PSP in neurons from trained rats only. This effect is abolished in the presence of the NMDA-channel blocker, APV. The learning-induced reduction in paired-pulse facilitation was not affected by apamin. Although the effect of the SK channels is increased after learning, the protein expression level of the SK2 channels, the type located in dendritic spines, was decreased after learning. The protein expression level of the SK3 channel, suggested to be located mainly in axon terminals, was not modified by learning. We suggest that the enhanced effect of the SK channels on NMDA-mediated synaptic transmission is the result of the reduction in the spine volume after learning. Moreover, these data indicate that spines are more excitable after learning, and are thus more predisposed to activity-dependent modifications. PMID:18005060

Brosh, Inbar; Rosenblum, Kobi; Barkai, Edi



Control of Excitatory Synaptic Transmission by C-terminal Src Kinase*S?  

PubMed Central

The induction of long-term potentiation at CA3-CA1 synapses is caused by an N-methyl-d-aspartate (NMDA) receptordependent accumulation of intracellular Ca2+, followed by Src family kinase activation and a positive feedback enhancement of NMDA receptors (NMDARs). Nevertheless, the amplitude of baseline transmission remains remarkably constant even though low frequency stimulation is also associated with an NMDAR-dependent influx of Ca2+ into dendritic spines. We show here that an interaction between C-terminal Src kinase (Csk) and NMDARs controls the Src-dependent regulation of NMDAR activity. Csk associates with the NMDAR signaling complex in the adult brain, inhibiting the Src-dependent potentiation of NMDARs in CA1 neurons and attenuating the Src-dependent induction of long-term potentiation. Csk associates directly with Src-phosphorylated NR2 subunits in vitro. An inhibitory antibody for Csk disrupts this physical association, potentiates NMDAR mediated excitatory postsynaptic currents, and induces long-term potentiation at CA3-CA1 synapses. Thus, Csk serves to maintain the constancy of baseline excitatory synaptic transmission by inhibiting Src kinase-dependent synaptic plasticity in the hippocampus.

Xu, Jindong; Weerapura, Manjula; Ali, Mohammad K.; Jackson, Michael F.; Li, Hongbin; Lei, Gang; Xue, Sheng; Kwan, Chun L.; Manolson, Morris F.; Yang, Kai; MacDonald, John F.; Yu, Xian-Min



Argiotoxin-636 blocks excitatory synaptic transmission in rat hippocampal CA1 pyramidal neurons.  


Argiotoxin 636, (AR636), a synaptic antagonist from orb weaver spider venom, is shown to produce reversible blockade of excitatory transmission in CA1 pyramidal neurons of the in vitro rat hippocampus. Microtopical application of AR636 (5-50 nM) resulted in a concentration-dependent suppression of the amplitude of the dendritic field EPSP recorded from stratum radiatum, and the amplitude of the population spike recorded from stratum pyramidale in response to stimulation of the Schaffer collaterals. The maximum effect of AR636 occurred at about 15-25 min. These effects were reversible after washing with toxin-free physiological solution with the rate of recovery having an inverse relationship to the concentration of AR636. In contrast to the effects observed with orthodromic stimulation, the amplitude of the antidromic spike was not affected by exposure to AR636. The temporal pattern of GABAergic paired-pulse inhibition was unaffected by exposure to AR636. Neuronal discharge elicited by pressure ejection of L-glutamate was abolished by AR636, whereas, responses to L-aspartate were not significantly affected. These data suggest that AR636 functions as a selective antagonist of glutamate-mediated synaptic transmission in rat hippocampus. PMID:2540876

Ashe, J H; Cox, C L; Adams, M E



Synaptic transmission in the auditory brainstem of normal and congenitally deaf mice  

PubMed Central

The deafness (dn/dn) mutant mouse provides a valuable model of human congenital deafness. We investigated the properties of synaptic transmission in the anteroventral cochlear nucleus (AVCN) of normal and congenitally deaf dn/dn mice. Excitatory postsynaptic currents (EPSCs) were evoked by focal stimulation of single auditory nerve fibres, and measured by whole-cell recordings from neurones in AVCN slices (mean postnatal age = P13). Absolute amplitudes of both AMPA- and NMDA-mediated components of evoked EPSCs were greater (170 %) in deaf versus control animals. Enhanced transmission in deaf mice was due to a presynaptic mechanism. Variance-mean analysis revealed that the probability of transmitter release was significantly greater in deaf (Pr = 0.8) versus control animals (Pr = 0.5). Following high frequency stimulation, deaf mice showed a greater depression of evoked EPSCs, and a significant increase in the frequency of delayed-release (asynchronous) miniature EPSCs (aEPSCs) (deaf 100 Hz vs. control 7 Hz). The acetoxymethyl ester of EGTA (EGTA-AM) blocked the increase in miniature aEPSCs and returned tetanic depression to control values. In deaf mice, reduction of mean Pr using cadmium caused an expected increase in paired-pulse ratio (PPR). However, in the same cells, a similar reduction in release by EGTA-AM did not result in a change in PPR, demonstrating that a change may occur in Pr without a concomitant change in PPR. In many respects, transmission in deaf mice was found to be remarkably similar to control mice, implying that many parameters of synaptic transmission develop normally in these animals. The two significant differences (higher Pr and asynchronous release in deaf mice) could both be reversed by the addition of EGTA-AM, suggesting that endogenous calcium buffering may be impaired or undeveloped in the presynaptic terminals of the auditory nerve in deaf mice.

Oleskevich, Sharon; Walmsley, Bruce



Alterations in information transmission in ensembles of primary muscle spindle afferents after muscle fatigue in heteronymous muscle  

Microsoft Academic Search

This study showed that fatigue of the ipsilateral medial gastrocnemius muscle caused a clear-cut reduction in the ability of ensembles of primary muscle spindle afferents from the lateral gastrocnemius muscle to discriminate between muscle stretches of varying amplitude. The results were probably caused by reflex-mediated effects from chemosensitive group III and IV afferents onto the ?-motoneurons projecting to lateral gastrocnemius

J Pedersen; M Ljubisavljevic; M Bergenheim; H Johansson



Excitatory amino acid-evoked membrane currents and excitatory synaptic transmission in lamprey reticulospinal neurons.  


The characteristics of excitatory amino acid-evoked currents and of excitatory synaptic events have been examined in lamprey Müller neurons using voltage clamp and current clamp recording techniques. Application of glutamate evoked depolarizations associated with a decrease in input resistance. The reversal potential of the responses was -35 mV. Under voltage clamp conditions, a series of excitatory amino acid agonists evoked inward currents associated with little or no increase in baseline current noise. The order of potency of the excitatory amino acid agonists was quisqualate greater than kainate greater than glutamate greater than aspartate, while N-methyl-D-aspartic acid (NMDA) was inactive. Inward currents evoked by glutamate, as well as by kainate and quisqualate were attenuated reversibly by 1 mM kynurenic acid (KYN). In contrast, glutamate-evoked currents were not affected by 100 microM D(-)-2-amino-5-phosphonovaleric acid (APV), a selective NMDA antagonist. Spontaneously occurring and stimulus-evoked excitatory postsynaptic events were antagonized reversibly by 1 mM KYN. At this concentration, KYN had no effect on membrane potential, input resistance, or excitability of the cells. In contrast, excitatory postsynaptic currents were unaffected by APV. It is concluded that both glutamate responses and excitatory synaptic transmission in lamprey Müller neurons are mediated by non-NMDA-type receptors and that these receptors are associated with ionic channels with a low elementary conductance. The combined pharmacological and biophysical characteristics of these responses are therefore different from those previously reported in other preparations. Spontaneous (but not stimulus-evoked) inhibitory synaptic events in Müller neurons were blocked reversibly by 1 mM KYN but not by 100 microM APV, suggesting that excitation of interneurons inhibitory to Müller cells was also mediated by non-NMDA receptors. PMID:2896054

Dryer, S E



Synaptojanin1 is required for temporal fidelity of synaptic transmission in hair cells.  


To faithfully encode mechanosensory information, auditory/vestibular hair cells utilize graded synaptic vesicle (SV) release at specialized ribbon synapses. The molecular basis of SV release and consequent recycling of membrane in hair cells has not been fully explored. Here, we report that comet, a gene identified in an ENU mutagenesis screen for zebrafish larvae with vestibular defects, encodes the lipid phosphatase Synaptojanin 1 (Synj1). Examination of mutant synj1 hair cells revealed basal blebbing near ribbons that was dependent on Cav1.3 calcium channel activity but not mechanotransduction. Synaptojanin has been previously implicated in SV recycling; therefore, we tested synaptic transmission at hair-cell synapses. Recordings of post-synaptic activity in synj1 mutants showed relatively normal spike rates when hair cells were mechanically stimulated for a short period of time at 20 Hz. In contrast, a sharp decline in the rate of firing occurred during prolonged stimulation at 20 Hz or stimulation at a higher frequency of 60 Hz. The decline in spike rate suggested that fewer vesicles were available for release. Consistent with this result, we observed that stimulated mutant hair cells had decreased numbers of tethered and reserve-pool vesicles in comparison to wild-type hair cells. Furthermore, stimulation at 60 Hz impaired phase locking of the postsynaptic activity to the mechanical stimulus. Following prolonged stimulation at 60 Hz, we also found that mutant synj1 hair cells displayed a striking delay in the recovery of spontaneous activity. Collectively, the data suggest that Synj1 is critical for retrieval of membrane in order to maintain the quantity, timing of fusion, and spontaneous release properties of SVs at hair-cell ribbon synapses. PMID:19424431

Trapani, Josef G; Obholzer, Nikolaus; Mo, Weike; Brockerhoff, Susan E; Nicolson, Teresa



A computational model to investigate astrocytic glutamate uptake influence on synaptic transmission and neuronal spiking.  


Over the past decades, our view of astrocytes has switched from passive support cells to active processing elements in the brain. The current view is that astrocytes shape neuronal communication and also play an important role in many neurodegenerative diseases. Despite the growing awareness of the importance of astrocytes, the exact mechanisms underlying neuron-astrocyte communication and the physiological consequences of astrocytic-neuronal interactions remain largely unclear. In this work, we define a modeling framework that will permit to address unanswered questions regarding the role of astrocytes. Our computational model of a detailed glutamatergic synapse facilitates the analysis of neural system responses to various stimuli and conditions that are otherwise difficult to obtain experimentally, in particular the readouts at the sub-cellular level. In this paper, we extend a detailed glutamatergic synaptic model, to include astrocytic glutamate transporters. We demonstrate how these glial transporters, responsible for the majority of glutamate uptake, modulate synaptic transmission mediated by ionotropic AMPA and NMDA receptors at glutamatergic synapses. Furthermore, we investigate how these local signaling effects at the synaptic level are translated into varying spatio-temporal patterns of neuron firing. Paired pulse stimulation results reveal that the effect of astrocytic glutamate uptake is more apparent when the input inter-spike interval is sufficiently long to allow the receptors to recover from desensitization. These results suggest an important functional role of astrocytes in spike timing dependent processes and demand further investigation of the molecular basis of certain neurological diseases specifically related to alterations in astrocytic glutamate uptake, such as epilepsy. PMID:23060782

Allam, Sushmita L; Ghaderi, Viviane S; Bouteiller, Jean-Marie C; Legendre, Arnaud; Ambert, Nicolas; Greget, Renaud; Bischoff, Serge; Baudry, Michel; Berger, Theodore W



ben Functions with Scamp during Synaptic Transmission and Long-Term Memory Formation in Drosophila  

PubMed Central

Genetic screens for Drosophila mutants defective in pavlovian olfactory memory have provided unique insight into the molecular basis of memory storage. Occasionally, these singular genetic lesions have been assembled into meaningful molecular pathways and neural circuitries. For the most part, however, these genes and their expression patterns in the CNS remain fragmented, demanding new clues from continued mutant screens. From a behavioral screen for long-term memory (LTM) mutants, we have identified ben (CG32594), which encodes a novel protein. Mutations of ben specifically disrupt LTM, leaving earlier memory phases intact. The role of ben appears physiological rather than developmental, because acutely induced expression of a ben+ transgene in adults rescues the mutant’s LTM defect. More interestingly, induced expression of ben+ specifically in mushroom bodies (MBs), but not in the ellipsoid body of the central complex, is sufficient to rescue the mutant LTM defect. This suggests a role for ben in the MB during olfactory memory formation. We also provide evidence that BEN interacts genetically in both synaptic transmission and LTM formation with SCAMP, a synaptic protein known to be involved in vesicle recycling.

Zhao, Hong; Zheng, Xingguo; Yuan, Xiaojing; Wang, Lei; Wang, Xin; Zhong, Yi; Xie, Zuoping; Tully, Tim



Slow synaptic transmission in myenteric AH neurons from the inflamed guinea pig ileum.  


We investigated the effect of inflammation on slow synaptic transmission in myenteric neurons in the guinea pig ileum. Inflammation was induced by the intraluminal injection of trinitrobenzene sulfonate, and tissues were taken for in vitro investigation 6-7 days later. Brief tetanic stimulation of synaptic inputs (20 Hz, 1 s) induced slow excitatory postsynaptic potentials (EPSPs) in 49% and maintained postsynaptic excitation that lasted from 27 min to 3 h in 13% of neurons from the inflamed ileum. These neurons were classified electrophysiologically as AH neurons; 10 were morphological type II neurons, and one was type I. Such long-term hyperexcitability after a brief stimulus is not encountered in enteric neurons of normal intestine. Electrophysiological properties of neurons with maintained postsynaptic excitation were similar to those of neurons with slow EPSPs. Another form of prolonged excitation, sustained slow postsynaptic excitation (SSPE), induced by 1-Hz, 4-min stimulation, in type II neurons from the inflamed ileum reached its peak earlier but had lower amplitude than that in control. Unlike slow EPSPs and similar to SSPEs, maintained excitation was not inhibited by neurokinin-1 or neurokinin-3 receptor antagonists. Maintained postsynaptic excitation was not influenced by PKC inhibitors, but the PKA inhibitor, H-89, caused further increase in neuronal excitability. In conclusion, maintained excitation, observed only in neurons from the inflamed ileum, may contribute to the dysmotility, pain, and discomfort associated with intestinal inflammation. PMID:19556360

Nurgali, Kulmira; Nguyen, Trung V; Thacker, Michelle; Pontell, Louise; Furness, John B



Glycine receptors involved in synaptic transmission are selectively regulated by the cytoskeleton in mouse spinal neurons.  


Using whole cell patch-clamp recordings, we examined the effect of colchicine, a microtubule disrupter, on the properties of glycine receptors (GlyRs) in cultured spinal cord neurons. Confocal microscopy revealed that colchicine treatment effectively altered microtubule bundles and neuronal morphology. Application of colchicine via the culture media or the patch-pipette, however, did not affect the whole cell current rundown (73 +/- 6% of control after 1 h), the sensitivity of the GlyR to glycine (EC(50) = 29 +/- 1 microM), or strychnine inhibition (47 +/- 5% of control after 100 nM strychnine). On the other hand, colchicine dialyzed for 25 min via the patch pipette selectively reduced the quantal amplitude of spontaneous glycinergic miniature inhibitory postsynaptic currents (mIPSCs) to 68 +/- 5% of control. This effect was specific for GlyRs since synaptic events mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and GABA(A) receptors were unchanged. In conclusion, this study indicates that microtubules can regulate the function of GlyRs involved in inhibitory synaptic transmission. PMID:11784780

van Zundert, Brigitte; Alvarez, Francisco J; Yevenes, Gonzalo E; Cárcamo, Juan G; Vera, Juan Carlos; Aguayo, Luis G



Analysis of synaptic efficacy in spinal motoneurones from `quantum' aspects  

PubMed Central

1. Synaptic responses of triceps surae motoneurones of the cat following stimulation of single afferent fibres were examined by intracellular recording techniques. 2. The mean quantum content (m) of monosynaptic excitatory postsynaptic potentials (EPSPs) was independent of the type of motoneurone recorded and of the afferent fibre stimulated. There was no significant difference in m value between homonymous and heteronymous synapses. 3. A positive correlation was found between the amplitude of unit EPSPs and the input resistance of motoneurones. The difference in the amplitude of unit EPSPs appears to be responsible for the higher synaptic efficacy in slow-conducting motoneurones than in fast-conducting motoneurones. 4. There was no significant difference in the time course of monosynaptic EPSPs evoked by impulses from homonymous and heteronymous afferent fibres. 5. The ratio of monosynaptic connexions from a given afferent fibre was significantly greater on to homonymous than to heteronymous motoneurones. It is concluded that the difference in efficacy between homonymous and heteronymous synaptic transmission is due to the difference in the number of afferent fibres converging upon these motoneurones.

Kuno, M.; Miyahara, J. T.



Neuronal Nogo-A negatively regulates dendritic morphology and synaptic transmission in the cerebellum  

PubMed Central

Neuronal signal integration as well as synaptic transmission and plasticity highly depend on the morphology of dendrites and their spines. Nogo-A is a membrane protein enriched in the adult central nervous system (CNS) myelin, where it restricts the capacity of axons to grow and regenerate after injury. Nogo-A is also expressed by certain neurons, in particular during development, but its physiological function in this cell type is less well understood. We addressed this question in the cerebellum, where Nogo-A is transitorily highly expressed in the Purkinje cells (PCs) during early postnatal development. We used general genetic ablation (KO) as well as selective overexpression of Nogo-A in PCs to analyze its effect on dendritogenesis and on the formation of their main input synapses from parallel (PFs) and climbing fibers (CFs). PC dendritic trees were larger and more complex in Nogo-A KO mice and smaller than in wild-type in Nogo-A overexpressing PCs. Nogo-A KO resulted in premature soma-to-dendrite translocation of CFs and an enlargement of the CF territory in the molecular layer during development. Although spine density was not influenced by Nogo-A, the size of postsynaptic densities of PF–PC synapses was negatively correlated with the Nogo-A expression level. Electrophysiological studies revealed that Nogo-A negatively regulates the strength of synaptic transmission at the PF–PC synapse. Thus, Nogo-A appears as a negative regulator of PC input synapses, which orchestrates cerebellar connectivity through regulation of synapse morphology and the size of the PC dendritic tree.

Petrinovic, Marija M.; Hourez, Raphael; Aloy, Elisabeth M.; Dewarrat, Gregoire; Gall, David; Weinmann, Oliver; Gaudias, Julien; Bachmann, Lukas C.; Schiffmann, Serge N.; Vogt, Kaspar E.; Schwab, Martin E.



Hyperoxic stimulation of synchronous orthodromic activity and induction of neural plasticity does not require changes in excitatory synaptic transmission  

PubMed Central

The first study, described in the companion article, reports that acute exposure of rat hippocampal slices to either hyperbaric oxygen (HBO: 2.84 and 4.54 atmospheres absolute, ATA) or normobaric reoxygenation (NBOreox; i.e., normobaric hyperoxia: 0.6 or 0.0 ? 0.95 ATA) stimulates synchronous orthodromic activity in CA1 neurons, which includes activation of O2-induced potentiation (OxIP) and, in some cases, hyperexcitability (secondary population spikes, sPS). In this second study we tested the hypothesis that HBO and NBOreox increase orthodromic activity of CA1 neurons (oPS, orthodromic population spike) and OxIP via a combination of both increased excitatory synaptic transmission (field excitatory postsynaptic potential, fEPSP) and intrinsic excitability (antidromic population spike, aPS). HBO and NBOreox increased the oPS but rarely increased or potentiated the fEPSP. HBO exposure produced epileptiform antidromic activity, which was abolished during inhibition of fast GABAergic and glutamatergic synaptic transmission. Decreasing O2 from 0.95 ATA (control) to 0.6 ATA (intermediate O2) or 0.0 ATA (hypoxia) reversibly abolished the fEPSP, and reoxygenation rarely induced potentiation of the fEPSP or aPS. Intracellular recordings and antidromic field potential recordings, however, revealed that synaptic transmission and neuronal excitability were preserved, albeit at lower levels, in 0.60 ATA O2. Together, these data indicate that 1) the changes in excitatory postsynaptic activity are not required for stimulation of the oPS during and HBO/NBOreox or for activation of OxIP, suggesting the latter is a form of intrinsic plasticity; 2) HBO disinhibits spontaneous synaptic transmission to induce epileptiform activity; and 3) although synchronous synaptic activation of the CA1 neuronal population requires hyperoxia (i.e., 0.95 ATA O2), synaptic activation of individual CA1 neurons does not.

Garcia, Alfredo J.; Putnam, Robert W.



New tools for targeted disruption of cholinergic synaptic transmission in Drosophila melanogaster.  


Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels. The ?7 subtype of nAChRs is involved in neurological pathologies such as Parkinson's disease, Alzheimer's disease, addiction, epilepsy and autism spectrum disorders. The Drosophila melanogaster ?7 (D?7) has the closest sequence homology to the vertebrate ?7 subunit and it can form homopentameric receptors just as the vertebrate counterpart. The D?7 subunits are essential for the function of the Giant Fiber circuit, which mediates the escape response of the fly. To further characterize the receptor function, we generated different missense mutations in the D?7 nAChR's ligand binding domain. We characterized the effects of targeted expression of two UAS-constructs carrying a single mutation, D197A and Y195T, as well as a UAS-construct carrying a triple D77T, L117Q, I196P mutation in a D?7 null mutant and in a wild type background. Expression of the triple mutation was able to restore the function of the circuit in D?7 null mutants and had no disruptive effects when expressed in wild type. In contrast, both single mutations severely disrupted the synaptic transmission of D?7-dependent but not glutamatergic or gap junction dependent synapses in wild type background, and did not or only partially rescued the synaptic defects of the null mutant. These observations are consistent with the formation of hybrid receptors, consisting of D197A or Y195T subunits and wild type D?7 subunits, in which the binding of acetylcholine or acetylcholine-induced conformational changes of the D?7 receptor are altered and causes inhibition of cholinergic responses. Thus targeted expression of D197A or Y195T can be used to selectively disrupt synaptic transmission of D?7-dependent synapses in neuronal circuits. Hence, these constructs can be used as tools to study learning and memory or addiction associated behaviors by allowing the manipulation of neuronal processing in the circuits without affecting other cellular signaling. PMID:23737994

Mejia, Monica; Heghinian, Mari D; Marí, Frank; Godenschwege, Tanja A



Differential Short-term Synaptic Plasticity and Transmission of Complex Spike Trains: to Depress or to Facilitate?  

Microsoft Academic Search

Experimental studies have revealed conspicuous short-term facil- itation and depression that are expressed differentially at distinct classes of cortical synapses. To explore computational implications of synaptic dynamics, we investigated transmission of complex spike trains through a stochastic model of cortical synapse endowed with short-term facilitation and vesicle depletion. Inputs to the synapse model were either real spike train data recorded

Victor Matveev; Xiao-Jing Wang



Constitutively active group I mGlu receptors and PKMzeta regulate synaptic transmission in developing perirhinal cortex.  


Synaptic transmission is essential for early development of the central nervous system. However, the mechanisms that regulate early synaptic transmission in the cerebral cortex are unclear. PKM? is a kinase essential for the maintenance of LTP. We show for the first time that inhibition of PKM? produces a profound depression of basal synaptic transmission in neonatal, but not adult, rat perirhinal cortex. This suggests that synapses in early development are in a constitutive LTP-like state. Furthermore, basal synaptic transmission in immature, but not mature, perirhinal cortex relies on persistent activity of metabotropic glutamate (mGlu) receptor, PI3Kinase and mammalian target of rapamycin (mTOR). Thus early in development, cortical synapses exist in an LTP-like state maintained by tonically active mGlu receptor-, mTOR- and PKM?- dependent cascades. These results provide new understanding of the molecular mechanisms that control synapses during development and may aid our understanding of developmental disorders such as autism and schizophrenia. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. PMID:23357951

Panaccione, Isabella; King, Rachel; Molinaro, Gemma; Riozzi, Barbara; Battaglia, Giuseppe; Nicoletti, Ferdinando; Bashir, Zafar I



Synaptic Transmission at Functionally Identified Synapses in the Enteric Nervous System: Roles for Both Ionotropic and Metabotropic Receptors  

PubMed Central

Digestion and absorption of nutrients and the secretion and reabsorption of fluid in the gastrointestinal tract are regulated by neurons of the enteric nervous system (ENS), the extensive peripheral nerve network contained within the intestinal wall. The ENS is an important physiological model for the study of neural networks since it is both complex and accessible. At least 20 different neurochemically and functionally distinct classes of enteric neurons have been identified in the guinea pig ileum. These neurons express a wide range of ionotropic and metabotropic receptors. Synaptic potentials mediated by ionotropic receptors such as the nicotinic acetylcholine receptor, P2X purinoceptors and 5-HT3 receptors are seen in many enteric neurons. However, prominent synaptic potentials mediated by metabotropic receptors, like the P2Y1 receptor and the NK1 receptor, are also seen in these neurons. Studies of synaptic transmission between the different neuron classes within the enteric neural pathways have shown that both ionotropic and metabotropic synaptic potentials play major roles at distinct synapses within simple reflex pathways. However, there are still functional synapses at which no known transmitter or receptor has been identified. This review describes the identified roles for both ionotropic and metabotropic neurotransmission at functionally defined synapses within the guinea pig ileum ENS. It is concluded that metabotropic synaptic potentials act as primary transmitters at some synapses. It is suggested identification of the interactions between different synaptic potentials in the production of complex behaviours will require the use of well validated computer models of the enteric neural circuitry.

Gwynne, RM; Bornstein, JC



Inhibition of synaptic transmission and G protein modulation by synthetic CaV2.2 Ca2+ channel peptides  

PubMed Central

Abstract Modulation of presynaptic voltage-dependent Ca2+ channels is a major means of controlling neurotransmitter release. The CaV2.2 Ca2+ channel subunit contains several inhibitory interaction sites for G?? subunits, including the amino terminal (NT) and I–II loop. The NT and I–II loop have also been proposed to undergo a G protein-gated inhibitory interaction, whilst the NT itself has also been proposed to suppress CaV2 channel activity. Here, we investigate the effects of an amino terminal (CaV2.2[45–55]) ‘NT peptide’ and a I–II loop alpha interaction domain (CaV2.2[377–393]) ‘AID peptide’ on synaptic transmission, Ca2+ channel activity and G protein modulation in superior cervical ganglion neurones (SCGNs). Presynaptic injection of NT or AID peptide into SCGN synapses inhibited synaptic transmission and also attenuated noradrenaline-induced G protein modulation. In isolated SCGNs, NT and AID peptides reduced whole-cell Ca2+ current amplitude, modified voltage dependence of Ca2+ channel activation and attenuated noradrenaline-induced G protein modulation. Co-application of NT and AID peptide negated inhibitory actions. Together, these data favour direct peptide interaction with presynaptic Ca2+ channels, with effects on current amplitude and gating representing likely mechanisms responsible for inhibition of synaptic transmission. Mutations to residues reported as determinants of Ca2+ channel function within the NT peptide negated inhibitory effects on synaptic transmission, Ca2+ current amplitude and gating and G protein modulation. A mutation within the proposed QXXER motif for G protein modulation did not abolish inhibitory effects of the AID peptide. This study suggests that the CaV2.2 amino terminal and I–II loop contribute molecular determinants for Ca2+ channel function; the data favour a direct interaction of peptides with Ca2+ channels to inhibit synaptic transmission and attenuate G protein modulation.

Bucci, Giovanna; Mochida, Sumiko; Stephens, Gary J



Bcl-xL Inhibitor ABT-737 Reveals a Dual Role for Bcl-xL in Synaptic Transmission  

PubMed Central

A role for BCL-xL in regulating neuronal activity is suggested by its dramatic effects on synaptic function and mitochondrial channel activity. When recombinant BCL-xL is injected into the giant presynaptic terminal of squid stellate ganglion or applied directly to mitochondrial outer membranes within the living terminal, it potentiates synaptic transmission acutely, and it produces mitochondrial channel activity. The squid, however, is a genetically intractable model, making it difficult to apply genetic tools in squid to explore the role of endogenous BCL-xL in synaptic function. Therefore the small molecule inhibitor ABT-737, a mimetic of the BH3-only protein BAD, binding to the BH3-binding domain pocket, was tested in squid, revealing a dual role for BCL-xL. ABT-737 slowed recovery of synaptic responses after repetitive synaptic activity, indicating that endogenous BCL-xL is necessary for timely recovery of rapidly firing synapses. Unexpectedly, however, ABT-737 also protected neurons from hypoxia-induced synaptic rundown and from increased permeability of the mitochondrial outer membrane during hypoxia. This implies that endogenous BCL-xL or a modified form of BCL-xL, such as the N-truncated, proteolytic, pro-apoptotic cleavage product, ?N BCL-xL, contributes to injurious responses of the hypoxic synapse. To determine if ABT-737 is also an inhibitor of ?N BCL-xL, recombinant ?N BCL-xL protein was injected into the synapse. ABT-737 potently inhibited synaptic rundown induced by recombinant ?N BCL-xL. These observations support the possibility that endogenous proteolysis or a functionally equivalent modification of BCL-xL is responsible for the deleterious effects of hypoxia on synaptic activity.

Hickman, John A.; Hardwick, J. Marie; Kaczmarek, Leonard K.; Jonas, Elizabeth A.



Distinct Neuronal Coding Schemes in Memory Revealed by Selective Erasure of Fast Synchronous Synaptic Transmission  

PubMed Central

Neurons encode information by firing spikes in isolation or bursts, and propagate information by spike-triggered neurotransmitter release that initiates synaptic transmission. Isolated spikes trigger neurotransmitter release unreliably but with high temporal precision, whereas bursts of spikes boost transmission fidelity by overcoming the unreliability of spike-triggered release but are temporally imprecise. However, the relative physiological importance of different spike firing modes remains unclear. Here, we show that knockdown of synaptotagmin-1, the major Ca2+-sensor for neurotransmitter release, abrogated neurotransmission evoked by isolated spikes, but only delayed without abolishing neurotransmission evoked by bursts of spikes. Nevertheless, knockdown of synaptotagmin-1 in the hippocampal CA1 region did not impede acquisition of recent contextual fear memories, although it did impair the precision of such memories. In contrast, knockdown of synaptotagmin-1 in the prefrontal cortex impaired all remote fear memories. These results indicate that different brain circuits and types of memory employ distinct spike-coding schemes to encode and transmit information.

Xu, Wei; Morishita, Wade; Buckmaster, Paul S.; Pang, Zhiping P.; Malenka, Robert C.; Sudhof, Thomas C.



Astrocyte activation of presynaptic metabotropic glutamate receptors modulates hippocampal inhibitory synaptic transmission  

PubMed Central

In the CNS, fine processes of astrocytes often wrap around dendrites, axons and synapses, which provides an interface where neurons and astrocytes might interact. We have reported previously that selective Ca2+ elevation in astrocytes, by photolysis of caged Ca2+ by o-nitrophenyl-EGTA (NP-EGTA), causes a kainite receptor-dependent increase in the frequency of spontaneous inhibitory post-synaptic potentials (sIPSCs) in neighboring interneurons in hippocampal slices. However, tetrodotoxin (TTX), which blocks action potentials, reduces the frequency of miniature IPSCs (mIPSCs) in interneurons during Ca2+ uncaging by an unknown presynaptic mechanism. In this study we investigate the mechanism underlying the presynaptic inhibition. We show that Ca2+ uncaging in astrocytes is accompanied by a decrease in the amplitude of evoked IPSCs (eIPSCs) in neighboring interneurons. The decreases in eIPSC amplitude and mIPSC frequency are prevented by CPPG, a group II/III metabotropic glutamate receptor (mGluR) antagonist, but not by the AMPA/kainate and NMDA receptor antagonists CNQX/CPP. Application of either the group II mGluR agonist DCG IV or the group III mGluR agonist L-AP4 decreased the amplitude of eIPSCs by a presynaptic mechanism, and both effects are blocked by CPPG. Thus, activation of mGluRs mediates the effects of Ca2+ uncaging on mIPSCs and eIPSCs. Our results indicate that Ca2+-dependent release of glutamate from astrocytes can activate distinct classes of glutamate receptors and differentially modulate inhibitory synaptic transmission in hippocampal interneurons.

Liu, Qing-Song; Xu, Qiwu; Kang, Jian; Nedergaard, Maiken



Synaptic Transmission from Horizontal Cells to Cones Is Impaired by Loss of Connexin Hemichannels  

PubMed Central

In the vertebrate retina, horizontal cells generate the inhibitory surround of bipolar cells, an essential step in contrast enhancement. For the last decades, the mechanism involved in this inhibitory synaptic pathway has been a major controversy in retinal research. One hypothesis suggests that connexin hemichannels mediate this negative feedback signal; another suggests that feedback is mediated by protons. Mutant zebrafish were generated that lack connexin 55.5 hemichannels in horizontal cells. Whole cell voltage clamp recordings were made from isolated horizontal cells and cones in flat mount retinas. Light-induced feedback from horizontal cells to cones was reduced in mutants. A reduction of feedback was also found when horizontal cells were pharmacologically hyperpolarized but was absent when they were pharmacologically depolarized. Hemichannel currents in isolated horizontal cells showed a similar behavior. The hyperpolarization-induced hemichannel current was strongly reduced in the mutants while the depolarization-induced hemichannel current was not. Intracellular recordings were made from horizontal cells. Consistent with impaired feedback in the mutant, spectral opponent responses in horizontal cells were diminished in these animals. A behavioral assay revealed a lower contrast-sensitivity, illustrating the role of the horizontal cell to cone feedback pathway in contrast enhancement. Model simulations showed that the observed modifications of feedback can be accounted for by an ephaptic mechanism. A model for feedback, in which the number of connexin hemichannels is reduced to about 40%, fully predicts the specific asymmetric modification of feedback. To our knowledge, this is the first successful genetic interference in the feedback pathway from horizontal cells to cones. It provides direct evidence for an unconventional role of connexin hemichannels in the inhibitory synapse between horizontal cells and cones. This is an important step in resolving a long-standing debate about the unusual form of (ephaptic) synaptic transmission between horizontal cells and cones in the vertebrate retina.

Klaassen, Lauw J.; Sun, Ziyi; Steijaert, Marvin N.; Bolte, Petra; Fahrenfort, Iris; Sjoerdsma, Trijntje; Klooster, Jan; Claassen, Yvonne; Shields, Colleen R.; Ten Eikelder, Huub M. M.; Janssen-Bienhold, Ulrike; Zoidl, Georg; McMahon, Douglas G.; Kamermans, Maarten



The projection and synaptic organisation of NTS afferent connections with presympathetic neurons, GABA and nNOS neurons in the paraventricular nucleus of the hypothalamus  

PubMed Central

Elevated sympathetic nerve activity, strongly associated with cardiovascular disease, is partly generated from the presympathetic neurons of the paraventricular nucleus of the hypothalamus (PVN). The PVN-presympathetic neurons regulating cardiac and vasomotor sympathetic activity receive information about cardiovascular status from receptors in the heart and circulation. These receptors signal changes via afferent neurons terminating in the nucleus tractus solitarius (NTS), some of which may result in excitation or inhibition of PVN-presympathetic neurons. Understanding the anatomy and neurochemistry of NTS afferent connections within the PVN could provide important clues to the impairment in homeostasis cardiovascular control associated with disease. Transynaptic labelling has shown the presence of neuronal nitric oxide synthase (nNOS)-containing neurons and GABA interneurons that terminate on presympathetic PVN neurons any of which may be the target for NTS afferents. So far NTS connections to these diverse neuronal pools have not been demonstrated and were investigated in this study. Anterograde (biotin dextran amine – BDA) labelling of the ascending projection from the NTS and retrograde (fluorogold – FG or cholera toxin B subunit – CTB) labelling of PVN presympathetic neurons combined with immunohistochemistry for GABA and nNOS was used to identify the terminal neuronal targets of the ascending projection from the NTS. It was shown that NTS afferent terminals are apposed to either PVN-GABA interneurons or to nitric oxide producing neurons or even directly to presympathetic neurons. Furthermore, there was evidence that some NTS axons were positive for vesicular glutamate transporter 2 (vGLUT2). The data provide an anatomical basis for the different functions of cardiovascular receptors that mediate their actions via the NTS–PVN pathways.

Affleck, V.S.; Coote, J.H.; Pyner, S.



Plasticity of synaptic connections in sensory-motor pathways of the adult locust flight system.  


We investigated possible roles of retrograde signals and competitive interactions in the lesion-induced reorganization of synaptic contacts in the locust CNS. Neuronal plasticity is elicited in the adult flight system by removal of afferents from the tegula, a mechanoreceptor organ at the base of the wing. We severed one hindwing organ and studied the resulting rearrangement of synaptic contacts between flight interneurons and afferent neurons from the remaining three tegulae (2 forewing, 1 hindwing). This was done by electric stimulation of afferents and intracellular recording from interneurons (and occasionally motoneurons). Two to three weeks after unilateral tegula lesion, connections between tegula afferents and flight interneurons were altered in the following way. 1) Axons from the forewing tegula on the operated side had established new synaptic contacts with metathoracic elevator interneurons. In addition, the amplitude of compound excitatory postsynaptic potentials elicited by electric stimulation was increased, indicating that a larger number of afferents connected to any given interneuron. 2) On the side contralateral to the lesion, connectivity between axons from the forewing tegula and elevator interneurons was decreased. 3) The efficacy of the (remaining) hindwing afferents appeared to be increased with regard to both synaptic transmission to interneurons and impact on flight motor pattern. 4) Flight motoneurons, which are normally restricted to the ipsilateral hemiganglion, sprouted across the ganglion midline after unilateral tegula removal and apparently established new synaptic contacts with tegula afferents on that side. The changes on the operated side are interpreted as occupation of synaptic space vacated on the interneurons by the severed hindwing afferents. On the contralateral side, the changes in synaptic contact must be elicited by retrograde signals from bilaterally arborizing flight interneurons, because tegula projections remain strictly ipsilateral. The pattern of changes suggests competitive interactions between forewing and hindwing afferents. The present investigation thus presents evidence that the CNS of the mature locust is capable of extensive synaptic rearrangement in response to injury and indicates for the first time the action of retrograde signals from interneurons. PMID:9310419

Wolf, H; Büschges, A



The BDNF Val66Met polymorphism impairs synaptic transmission and plasticity in the infralimbic medial prefrontal cortex  

PubMed Central

The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is a common human single nucleotide polymorphism (SNP) that affects the regulated release of BDNF, and has been implicated in affective disorders and cognitive dysfunction. A decreased activation of the infralimbic medial prefrontal cortex (IL-mPFC), a brain region critical for the regulation of affective behaviors, has been described in BDNFMet carriers. However, it is unclear whether and how the Val66Met polymorphism affects the IL-mPFC synapses. Here we report that spike timing-dependent plasticity (STDP) was absent in the IL-mPFC pyramidal neurons from BDNFMet/Met mice, a mouse that recapitulates the specific phenotypic properties of the human BDNF Val66Met polymorphism. Also, we observed a decrease in N-methyl-D-aspartic acid (NMDA) and ?-aminobutyric acid (GABA) receptor-mediated synaptic transmission in the pyramidal neurons of BDNFMet/Met mice. While BDNF enhanced non-NMDA receptor transmission and depressed GABA receptor transmission in the wild-type mice, both effects were absent in BDNFMet/Met mice after BDNF treatment. Indeed, exogenous BDNF reversed the deficits in STDP and NMDA receptor transmission in BDNFMet/Met neurons. BDNF-mediated selective reversal of the deficit in plasticity and NMDA receptor transmission, but its lack of effect on GABA and non-NMDA receptor transmission in BDNFMet/Met mice, suggests separate mechanisms of Val66Met polymorphism upon synaptic transmission. The effect of the Val66Met polymorphism on synaptic transmission and plasticity in the IL-mPFC represents a mechanism to account for this SNP's impact on affective disorders and cognitive dysfunction.

Pattwell, Siobhan S.; Bath, Kevin G.; Perez-Castro, Rosalia; Lee, Francis S.; Chao, Moses V.; Ninan, Ipe



Adrenergic receptors modulate motoneuron excitability, sensory synaptic transmission and muscle spasms after chronic spinal cord injury.  


The brain stem provides most of the noradrenaline (NA) present in the spinal cord, which functions to both increase spinal motoneuron excitability and inhibit sensory afferent transmission to motoneurons (excitatory postsynaptic potentials; EPSPs). NA increases motoneuron excitability by facilitating calcium-mediated persistent inward currents (Ca PICs) that are crucial for sustained motoneuron firing. Spinal cord transection eliminates most NA and accordingly causes an immediate loss of PICs and emergence of exaggerated EPSPs. However, with time PICs recover, and thus the exaggerated EPSPs can then readily trigger these PICs, which in turn produce muscle spasms. Here we examined the contribution of adrenergic receptors to spasms in chronic spinal rats. Selective activation of the ?(1A) adrenergic receptor with the agonists methoxamine or A61603 facilitated Ca PIC and spasm activity, recorded both in vivo and in vitro. In contrast, the ?(2) receptor agonists clonidine and UK14303 did not facilitate Ca PICs, but did decrease the EPSPs that trigger spasms. Moreover, in the absence of agonists, spasms recorded in vivo were inhibited by the ?(1) receptor antagonists WB4010, prazosin, and REC15/2739, and increased by the ?(2) receptor antagonist RX821001, suggesting that both adrenergic receptors were endogenously active. In contrast, spasm activity recorded in the isolated in vitro cord was inhibited only by the ?(1) antagonists that block constitutive receptor activity (activity in the absence of NA; inverse agonists, WB4010 and prazosin) and not by the neutral antagonist REC15/2739, which only blocks conventional NA-mediated receptor activity. RX821001 had no effect in vitro even though it is an ?(2) receptor inverse agonist. Our results suggest that after chronic spinal cord injury Ca PICs and spasms are facilitated, in part, by constitutive activity in ?(1) adrenergic receptors. Additionally, peripherally derived NA (or similar ligand) activates both ?(1) and ?(2) adrenergic receptors, controlling PICs and EPSPs, respectively. PMID:21047936

Rank, M M; Murray, K C; Stephens, M J; D'Amico, J; Gorassini, M A; Bennett, D J



Delayed Reduction of Hippocampal Synaptic Transmission and Spines Following Exposure to Repeated Subclinical Doses of Organophosphorus Pesticide in Adult Mice  

PubMed Central

Agricultural and household organophosphorus (OP) pesticides inhibit acetylcholinesterase (AchE), resulting in increased acetylcholine (Ach) in the central nervous system. In adults, acute and prolonged exposure to high doses of AchE inhibitors causes severe, clinically apparent symptoms, followed by lasting memory impairments and cognitive dysfunction. The neurotoxicity of repeated environmental exposure to lower, subclinical doses of OP pesticides in adults is not as well studied. However, repeated exposure to acetylcholinesterase inhibitors, such as chlorpyrifos (CPF), pyridostigmine, and sarin nerve agent, has been epidemiologically linked to delayed onset symptoms in Gulf War Illness and may be relevant to environmental exposure in farm workers among others. We treated adult mice with a subclinical dose (5 mg/kg) of CPF for 5 consecutive days and investigated hippocampal synaptic transmission and spine density early (2–7 days) and late (3 months) after CPF administration. No signs of cholinergic toxicity were observed at any time during or after treatment. At 2–7 days after the last injection, we found increased synaptic transmission in the CA3-CA1 region of the hippocampus of CPF-treated mice compared with controls. In contrast, at 3 months after CPF administration, we observed a 50% reduction in synaptic transmission likely due to a corresponding 50% decrease in CA1 pyramidal neuron synaptic spine density. This study is the first to identify a biphasic progression of synaptic abnormalities following repeated OP exposure and suggests that even in the absence of acute cholinergic toxicity, repeated exposure to CPF causes delayed persistent damage to the adult brain in vivo.

Speed, Haley E.; Blaiss, Cory A.; Kim, Ahleum; Haws, Michael E.; Melvin, Neal R.; Jennings, Michael; Eisch, Amelia J.; Powell, Craig M.



Delayed reduction of hippocampal synaptic transmission and spines following exposure to repeated subclinical doses of organophosphorus pesticide in adult mice.  


Agricultural and household organophosphorus (OP) pesticides inhibit acetylcholinesterase (AchE), resulting in increased acetylcholine (Ach) in the central nervous system. In adults, acute and prolonged exposure to high doses of AchE inhibitors causes severe, clinically apparent symptoms, followed by lasting memory impairments and cognitive dysfunction. The neurotoxicity of repeated environmental exposure to lower, subclinical doses of OP pesticides in adults is not as well studied. However, repeated exposure to acetylcholinesterase inhibitors, such as chlorpyrifos (CPF), pyridostigmine, and sarin nerve agent, has been epidemiologically linked to delayed onset symptoms in Gulf War Illness and may be relevant to environmental exposure in farm workers among others. We treated adult mice with a subclinical dose (5 mg/kg) of CPF for 5 consecutive days and investigated hippocampal synaptic transmission and spine density early (2-7 days) and late (3 months) after CPF administration. No signs of cholinergic toxicity were observed at any time during or after treatment. At 2-7 days after the last injection, we found increased synaptic transmission in the CA3-CA1 region of the hippocampus of CPF-treated mice compared with controls. In contrast, at 3 months after CPF administration, we observed a 50% reduction in synaptic transmission likely due to a corresponding 50% decrease in CA1 pyramidal neuron synaptic spine density. This study is the first to identify a biphasic progression of synaptic abnormalities following repeated OP exposure and suggests that even in the absence of acute cholinergic toxicity, repeated exposure to CPF causes delayed persistent damage to the adult brain in vivo. PMID:21948870

Speed, Haley E; Blaiss, Cory A; Kim, Ahleum; Haws, Michael E; Melvin, Neal R; Jennings, Michael; Eisch, Amelia J; Powell, Craig M



Trans-synaptic transmission of vesicular Wnt signals through Evi/Wntless.  


Wnts play pivotal roles during development and in the mature nervous system. However, the mechanism by which Wnts traffic between cells has remained elusive. Here we demonstrate a mechanism of Wnt transmission through release of exosome-like vesicles containing the Wnt-binding protein Evenness Interrupted/Wntless/Sprinter (Evi/Wls/Srt). We show that at the Drosophila larval neuromuscular junction (NMJ), presynaptic vesicular release of Evi is required for the secretion of the Wnt, Wingless (Wg). We also show that Evi acts cell-autonomously in the postsynaptic Wnt-receiving cell to target dGRIP, a Wg-receptor-interacting protein, to postsynaptic sites. Upon Evi loss of function, dGRIP is not properly targeted to synaptic sites, interfering with postsynaptic Wnt signal transduction. These findings uncover a previously unknown cellular mechanism by which a secreted Wnt is transported across synapses by Evi-containing vesicles and reveal trafficking functions of Evi in both the Wnt-producing and the Wnt-receiving cells. For a video summary of this article, see the PaperFlick file with the Supplemental Data available online. PMID:19837038

Korkut, Ceren; Ataman, Bulent; Ramachandran, Preethi; Ashley, James; Barria, Romina; Gherbesi, Norberto; Budnik, Vivian



Forskolin Enhances Synaptic Transmission in Rat Dorsal Striatum through NMDA Receptors and PKA in Different Phases  

PubMed Central

The effect of forskolin on corticostriatal synaptic transmission was examined by recording excitatory postsynaptic currents (EPSCs) in rat brain slices using the whole-cell voltage-clamp technique. Forskolin produced a dose-dependent increase of corticostriatal EPSCs (1, 3, 10, and 30 µM) immediately after its treatment, and the increase at 10 and 30 µM was maintained even after its washout. When the brain slices were pre-treated with (DL)-2-amino-5-phosphonovaleric acid (AP-V, 100 µM), an NMDA receptor antagonist, the acute effect of forskolin (10 µM) was blocked. However, after washout of forskolin, an increase of corticostriatal EPSCs was still observed even in the presence of AP-V. When KT 5720 (5 µM), a protein kinase A (PKA) inhibitor, was applied through the patch pipette, forskolin (10 µM) increased corticostriatal EPSCs, but this increase was not maintained. When forskolin was applied together with AP-V and KT 5720, both the increase and maintenance of the corticostriatal EPSCs were blocked. These results suggest that forskolin activates both NMDA receptors and PKA, however, in a different manner.

Cho, Hyeong Seok; Lee, Hyun Ho; Choi, Se Joon; Kim, Ki Jung; Jeun, Seung Hyun; Li, Qing-Zhong



Hippocampal synaptic transmission and LTP in vivo are intact following bilateral vestibular deafferentation in the rat.  


Numerous studies in animals and humans have shown that damage to the vestibular system in the inner ear results in spatial memory deficits, presumably because areas of the brain such as the hippocampus require vestibular input to accurately represent the spatial environment. Consistent with this hypothesis, studies in animals have demonstrated that complete bilateral vestibular deafferentation (BVD) causes a disruption of place cell firing as well as theta activity. The aim of this study was to investigate whether BVD in rats affects baseline field potentials (field excitatory postsynaptic potentials and population spikes) and long-term potentiation (LTP) in CA1 and the dentate gyrus (DG) of awake freely moving rats up to 43 days post-BVD and of anesthetized rats at 7 months post-BVD. Compared to sham controls, BVD had no significant effect on either baseline field potentials or LTP in either condition. These results suggest that although BVD interferes with the encoding, consolidation, and/or retrieval of spatial memories and the function of place cells, these changes are not related to detectable in vivo decrements in basal synaptic transmission or LTP, at least in the investigated pathways. PMID:19533678

Zheng, Yiwen; Mason-Parker, Sara E; Logan, Barbara; Darlington, Cynthia L; Smith, Paul F; Abraham, Wickliffe C



Loss and gain of FUS function impair neuromuscular synaptic transmission in a genetic model of ALS.  


Amyotrophic lateral sclerosis (ALS) presents clinically in adulthood and is characterized by the loss of motoneurons in the spinal cord and cerebral cortex. Animal models of the disease suggest that significant neuronal abnormalities exist during preclinical stages of the disease. Mutations in the gene fused in sarcoma (FUS) are associated with ALS and cause impairment in motor function in animal models. However, the mechanism of neuromuscular dysfunction underlying pathophysiological deficits causing impairment in locomotor function resulting from mutant FUS expression is unknown. To characterize the cellular pathophysiological defect, we expressed the wild-type human gene (wtFUS) or the ALS-associated mutation R521H (mutFUS) gene in zebrafish larvae and characterized their motor (swimming) activity and function of their neuromuscular junctions (NMJs). Additionally, we tested knockdown of zebrafish fus with an antisense morpholino oligonucleotide (fus AMO). Expression of either mutFUS or knockdown of fus resulted in impaired motor activity and reduced NMJ synaptic fidelity with reduced quantal transmission. Primary motoneurons expressing mutFUS were found to be more excitable. These impairments in neuronal function could be partially restored in fus AMO larvae also expressing wtFUS (fus AMO+wtFUS) but not mutFUS (fus AMO+mutFUS). These results show that both a loss and gain of FUS function result in defective presynaptic function at the NMJ. PMID:23771027

Armstrong, Gary A B; Drapeau, Pierre



Modulation by melatonin of glutamatergic synaptic transmission in the carp retina  

PubMed Central

Melatonin is involved in a variety of physiological functions through activating specific receptors coupled to GTP-binding protein. Melatonin and its receptors are abundant in the retina. Here we show for the first time that melatonin modulates glutamatergic synaptic transmission from cones to horizontal cells (HCs) in carp retina. Immunocytochemical data revealed the expression of the MT1 receptor on carp HCs. Whole-cell recordings further showed that melatonin of physiological concentrations potentiated glutamate-induced currents from isolated cone-driven HCs (H1 cells) in a dose-dependent manner, by increasing the efficacy and apparent affinity of the glutamate receptor. The effects of melatonin were reversed by luzindole, but not by K 185, indicating the involvement of the MT1 receptor. Like melatonin, methylene blue (MB), a guanylate cyclase inhibitor, also potentiated the glutamate currents, but internal infusion of cGMP suppressed them. The effects of melatonin were not observed in cGMP-filled and MB-incubated HCs. These results suggest that the melatonin effects may be mediated by decreasing the intracellular concentration of cGMP. Consistent with these observations, melatonin depolarized the membrane potential of H1 cells and reduced their light responses, which could also be blocked by luzindole. These effects of melatonin persisted in the presence of the antagonists of receptors for dopamine, GABA and glycine, indicating a direct action of melatonin on H1 cells. Such modulation by melatonin of glutamatergic transmission from cones to HCs is thought to be in part responsible for circadian changes in light responsiveness of cone HCs in teleost retina.

Huang, Hai; Lee, Shu-Chen; Yang, Xiong-Li



Transmission from group II muscle afferents is depressed by stimulation of locus coeruleus/subcoeruleus, Kölliker-Fuse and raphe nuclei in the cat.  


The effects of brief trains of electrical stimuli applied within the locus coeruleus and subcoeruleus, the Kölliker-Fuse nucleus and the raphe magnus, obscurus and pallidus nuclei were tested on transmission from group I and group II muscle afferent fibres in mid-lumbar spinal segments of chloralose anaesthetized cats. Changes in the effectiveness of transmission from these afferents were assessed from changes in the size of monosynaptic extracellular field potentials evoked by them. The depression of group II field potentials occurred at conditioning-testing intervals of 20-400 ms, and was maximal at intervals of 40-100 ms and 30-60 ms for potentials recorded in the intermediate zone and dorsal horn, respectively. At intervals up to about 30 ms it was combined with the depression of group I components of the intermediate zone field potentials. However, at longer intervals the conditioning stimuli depressed group II components of these potentials as selectively as monoamines applied ionophoretically at the recording site (Bras et al., 1989a, 1990). Thus, only the late depressive actions are considered as being possibly mediated by impulses in descending noradrenergic and/or serotonergic fibres. No major differences were found in the relative degree of depression of transmission from group II afferents by stimulation of the locus coeruleus/subcoeruleus, Kölliker-Fuse or raphe nuclei, either in the dorsal horn or in the intermediate zone. Since field potentials at these locations are preferentially depressed by ionophoretic application of serotonin and noradrenaline (Bras et al., 1990), and since the locus coeruleus/subcoeruleus, Kölliker-Fuse and raphe nuclei are interconnected, the study leads to the conclusion that both noradrenergic and serotonergic descending pathways can be activated by stimuli applied within either of them. Selective depression of field potentials of group II origin was also evoked by stimulation at other sites, e.g. the periaqueductal grey and medullary reticular formation, when conditioning-testing intervals were sufficiently long. Such a depression is considered to be secondary to activation of neurones of the locus coeruleus/subcoeruleus, Kölliker-Fuse or raphe nuclei and attributed to the spread of current or transsynaptic activation of these neurones, or to stimulation of their axon collaterals outside the nuclei rather than to other descending medullo-spinal systems. The non-selective depression of field potentials evoked by group I and group II afferents at shorter conditioning-testing intervals is proposed to be due to actions of reticulo-spinal pathways. PMID:1316845

Noga, B R; Bras, H; Jankowska, E



Levetiracetam (ucb LO59) affects in vitro models of epilepsy in CA3 pyramidal neurons without altering normal synaptic transmission  

Microsoft Academic Search

Previous behavioural and electrophysiological studies have indicated that levetiracetam (ucb LO59) acts as an anticonvulsant\\u000a drug in vivo. The purpose of the present study was to investigate the effects of levetiracetam on normal synaptic transmission\\u000a and epileptiform activity in vitro. Intracellular recordings were obtained from the CA3 subfield of the rat hippocampal slice\\u000a preparation. Levetiracetam in a concentration of 10

Susanne Birnstiel; Ernst Wülfert; Sheryl G. Beck



Compensatory increase in P\\/Q-calcium current-mediated synaptic transmission following chronic block of N-type channels  

Microsoft Academic Search

Synaptic transmission is triggered by presynaptic calcium influx through voltage-gated calcium channels. Axon terminals of central neurons express a diverse set of homologous calcium channels, giving rise to P\\/Q-, N-, and R-type calcium currents. The relative contribution of these components to presynaptic calcium signalling is heterogeneous and incompletely understood. Here we report that chronic block of N-type calcium channels in

Christiane Grimm; Nadine I. Holter; Andreas Draguhn; Claus Bruehl



NMDA depresses glutamatergic synaptic transmission in the striatum through the activation of adenosine A 1 receptors: Evidence from knockout mice  

Microsoft Academic Search

N-methyl-d-aspartate (NMDA) receptors play several essential roles in the physiology and pathophysiology of the brain. Their activation results in long-term changes in glutamatergic synaptic transmission in several brain areas, but excessive activation of these receptors induces neurotoxicity. Some of NMDA-mediated actions are critically dependent on functional interactions with the neuromodulator adenosine. In the present study, we have examined whether pharmacological

Sietske M. Schotanus; Bertil B. Fredholm; Karima Chergui



Alterations in synaptic transmission and long-term potentiation in hippocampal slices from young and aged PDAPP mice  

Microsoft Academic Search

Synaptic transmission and plasticity were studied in the CA1 field of hippocampal slices from young and aged transgenic mice over-expressing a mutant form of the human amyloid precursor protein (PDAPP mice). The transgenic mice at 4–5 months of age, prior to the formation of amyloid-? peptide deposits in these animals, differed from non-transgenic control mice in three respects: (1) paired-pulse

John Larson; Gary Lynch; Dora Games; Peter Seubert



Cannabinoid receptor type 1 located on presynaptic terminals of principal neurons in the forebrain controls glutamatergic synaptic transmission.  


It is widely accepted that cannabinoids regulate GABA release by activation of cannabinoid receptor type 1 (CB1). Results obtained from a variety of brain regions consistently indicate that cannabinoid agonists can also reduce glutamatergic synaptic transmission. However, there are still conflicting data concerning the role of CB1 in cannabinoid-induced inhibition of glutamatergic transmission in cortical areas. Here, we provide direct evidence that activation of CB1 on terminals of principal neurons controls excitatory synaptic responses in the forebrain. In slices of the basolateral amygdala, the CA1 region of the hippocampus, and the primary somatosensory cortex of wild-type mice, application of the CB1 agonist (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (WIN55,212-2; WIN) (5 mum) reduced evoked excitatory postsynaptic responses. In contrast, in slices obtained from conditional mouse mutants lacking CB1 in all principal forebrain neurons but not in GABAergic interneurons (CB1(f/f;CaMKIIalphaCre)), WIN no longer affected glutamatergic synaptic transmission in any of the brain regions tested. Compatible with a presynaptic mechanism, WIN did not change the sensitivity to focally uncaged l-glutamate. WIN reduced glutamatergic responses in slices obtained from mice lacking CB1 exclusively in GABAergic neurons (CB1(f/f;Dlx5/6-Cre)), thus excluding the involvement of CB1 expressed on GABAergic neurons in this effect of the drug. The present data strongly indicate that excitatory synaptic transmission in forebrain areas is directly modulated by CB1 expressed on presynaptic axon terminals originating from glutamatergic neurons. PMID:16723537

Domenici, Maria R; Azad, Shahnaz C; Marsicano, Giovanni; Schierloh, Anja; Wotjak, Carsten T; Dodt, Hans-Ulrich; Zieglgänsberger, Walter; Lutz, Beat; Rammes, Gerhard



Firing properties of respiratory rhythm generating neurons in the absence of synaptic transmission in rat medulla in vitro  

Microsoft Academic Search

It has previously been demonstrated that Pre-I neurons, localized in the rostral ventrolateral medulla, are important in the generation of the primary respiratory rhythm in brainstemspinal cord preparations from newborn rats. To investigate whether or not Pre-I neurons have endogenous pacemaker properties, we examined Pre-I neuron activity before and after chemical synaptic transmission was blocked by incubation in a low

H. Onimaru; A. Arata; I. Homma



Synaptic effects in lumbar alpha-motoneurones evoked from group II muscle afferents via two different interneuronal pathways in the cat.  


Conditioning of monosynaptic reflexes was used to investigate group II excitation from quadriceps (Q) and sartorius (Sart) in posterior biceps-semitendinosus (PBSt) motoneurones and different lesions were made to analyze the interneuronal pathways. The purpose of the investigation was to find if the excitation from group II Q and Sart afferents, which enter the spinal cord in L4-L6, is relayed to motoneurones by interneurones located in these segments and/or in the same segments (L7-S1) as the PBSt motoneurones. In some experiments a transection of the dorsal column in L6, which interrupts the group II input from Sart and Q to interneurones in the L7-S1 segments, resulted in a marked decrease (by about 2/3) of group II excitation from these nerves. In other experiments the same lesion did not reduce the group II effect. In the latter cases the effect could be abolished by a second lesion of the lateral funiculus (LF) in L5-L6. It is postulated that potent effects from Q and Sart group II afferents can be evoked by interneurones located in L7-S1, i.e. in the same segments as the PBSt motoneurones (L7-S1), and/or via interneurones in more rostral segments. The axons of the more rostrally located group II interneurones appear to descend mainly in the middle part of the LF. PMID:1745404

Cavallari, P; Pettersson, L G



Liprin-?2 promotes the presynaptic recruitment and turnover of RIM1/CASK to facilitate synaptic transmission.  


The presynaptic active zone mediates synaptic vesicle exocytosis, and modulation of its molecular composition is important for many types of synaptic plasticity. Here, we identify synaptic scaffold protein liprin-?2 as a key organizer in this process. We show that liprin-?2 levels were regulated by synaptic activity and the ubiquitin-proteasome system. Furthermore, liprin-?2 organized presynaptic ultrastructure and controlled synaptic output by regulating synaptic vesicle pool size. The presence of liprin-?2 at presynaptic sites did not depend on other active zone scaffolding proteins but was critical for recruitment of several components of the release machinery, including RIM1 and CASK. Fluorescence recovery after photobleaching showed that depletion of liprin-?2 resulted in reduced turnover of RIM1 and CASK at presynaptic terminals, suggesting that liprin-?2 promotes dynamic scaffolding for molecular complexes that facilitate synaptic vesicle release. Therefore, liprin-?2 plays an important role in maintaining active zone dynamics to modulate synaptic efficacy in response to changes in network activity. PMID:23751498

Spangler, Samantha A; Schmitz, Sabine K; Kevenaar, Josta T; de Graaff, Esther; de Wit, Heidi; Demmers, Jeroen; Toonen, Ruud F; Hoogenraad, Casper C



Optogenetic analysis of synaptic transmission in the central nervous system of the nematode Caenorhabditis elegans  

Microsoft Academic Search

A reliable method for recording evoked synaptic events in identified neurons in Caenorhabditis elegans would greatly accelerate our understanding of its nervous system at the molecular, cellular and network levels. Here we describe a method for recording synaptic currents and potentials from identified neurons in nearly intact worms. Dissection and exposure of postsynaptic neurons is facilitated by microfabricated agar substrates,

Theodore H. Lindsay; Tod R. Thiele; Shawn R. Lockery



Determinants of Spatial and Temporal Coding by Semicircular Canal Afferents  

PubMed Central

The vestibular semicircular canals are internal sensors that signal the magnitude, direction, and temporal properties of angular head motion. Fluid mechanics within the 3-canal labyrinth code the direction of movement and integrate angular acceleration stimuli over time. Directional coding is accomplished by decomposition of complex angular accelerations into 3 biomechanical components—one component exciting each of the 3 ampullary organs and associated afferent nerve bundles separately. For low-frequency angular motion stimuli, fluid displacement within each canal is proportional to angular acceleration. At higher frequencies, above the lower corner frequency, real-time integration is accomplished by viscous forces arising from the movement of fluid within the slender lumen of each canal. This results in angular velocity sensitive fluid displacements. Reflecting this, a subset of afferent fibers indeed report angular acceleration to the brain for low frequencies of head movement and report angular velocity for higher frequencies. However, a substantial number of afferent fibers also report angular acceleration, or a signal between acceleration and velocity, even at frequencies where the endolymph displacement is known to follow angular head velocity. These non-velocity-sensitive afferent signals cannot be attributed to canal biomechanics alone. The responses of non-velocity-sensitive cells include a mathematical differentiation (first-order or fractional) imparted by hair-cell and/or afferent complexes. This mathematical differentiation from velocity to acceleration cannot be attributed to hair cell ionic currents, but occurs as a result of the dynamics of synaptic transmission between hair cells and their primary afferent fibers. The evidence for this conclusion is reviewed below.

Highstein, Stephen M.; Rabbitt, Richard D.; Holstein, Gay R.; Boyle, Richard D.



Differential characteristics of endogenous serotonin-mediated synaptic transmission in the hippocampal CA1 and CA3 fields of anaesthetized rats  

Microsoft Academic Search

The characteristics of endogenous serotonin (5-HT)-mediated synaptic transmission were investigated in the hippocampal CA1 and CA3 fields of anaesthetized rats. Electrophysiological approaches were used to elucidate the effects of a selective 5-HT reuptake inhibitor, fluvoxamine, on synaptic transmission by determining the population spike amplitude (PSA). Fluvoxamine (10 or 30 mg\\/kg i.p.) increased the PSA in the CA1 and CA3 fields

Machiko Matsumoto; Taku Kojima; Hiroko Togashi; Kiyoshi Mori; Satoshi Ohashi; Ken-ichi Ueno; Mitsuhiro Yoshioka



A novel component of cannabis extract potentiates excitatory synaptic transmission in rat olfactory cortex in vitro.  


Cannabis is a potential treatment for epilepsy, although the few human studies supporting this use have proved inconclusive. Previously, we showed that a standardized cannabis extract (SCE), isolated Delta9-tetrahydrocannabinol (Delta9-THC), and even Delta9-THC-free SCE inhibited muscarinic agonist-induced epileptiform bursting in rat olfactory cortical brain slices, acting via CB1 receptors. The present work demonstrates that although Delta9-THC (1 microM) significantly depressed evoked depolarizing postsynaptic potentials (PSPs) in rat olfactory cortex neurones, both SCE and Delta9-THC-free SCE significantly potentiated evoked PSPs (all results were fully reversed by the CB1 receptor antagonist SR141716A, 1 microM); interestingly, the potentiation by Delta9-THC-free SCE was greater than that produced by SCE. On comparing the effects of Delta9-THC-free SCE upon evoked PSPs and artificial PSPs (aPSPs; evoked electrotonically following brief intracellular current injection), PSPs were enhanced, whereas aPSPs were unaffected, suggesting that the effect was not due to changes in background input resistance. Similar recordings made using CB1 receptor-deficient knockout mice (CB1-/-) and wild-type littermate controls revealed cannabinoid or extract-induced changes in membrane resistance, cell excitability and synaptic transmission in wild-type mice that were similar to those seen in rat neurones, but no effect on these properties were seen in CB1-/- cells. It appears that the unknown extract constituent(s) effects over-rode the suppressive effects of Delta9-THC on excitatory neurotransmitter release, which may explain some patients' preference for herbal cannabis rather than isolated Delta9-THC (due to attenuation of some of the central Delta9-THC side effects) and possibly account for the rare incidence of seizures in some individuals taking cannabis recreationally. PMID:15234473

Whalley, Benjamin J; Wilkinson, Jonathan D; Williamson, Elizabeth M; Constanti, Andrew



Multiplicative Synaptic Normalization and a Nonlinear Hebb Rule Underlie a Neurotrophic Model of Competitive Synaptic Plasticity  

Microsoft Academic Search

Synaptic normalization is used to enforce competitive dynamics in many models of developmental synaptic plasticity. In linear and semilinear Hebbian models, multiplicative synaptic normalization fails to segregate afferents whose activity patterns are positively correlated. To achieve this, the biologically problematic device of subtractive synaptic normalization must be used instead. Our own model of competition for neurotrophic support, which can segregate

Terry Elliott; Nigel Shadbolt



Hemodynamic Responses Evoked by Neuronal Stimulation via Channelrhodopsin-2 Can Be Independent of Intracortical Glutamatergic Synaptic Transmission  

PubMed Central

Maintenance of neuronal function depends on the delivery of oxygen and glucose through changes in blood flow that are linked to the level of ongoing neuronal and glial activity, yet the underlying mechanisms remain unclear. Using transgenic mice expressing the light-activated cation channel channelrhodopsin-2 in deep layer pyramidal neurons, we report that changes in intrinsic optical signals and blood flow can be evoked by activation of a subset of channelrhodopsin-2-expressing neurons in the sensorimotor cortex. We have combined imaging and pharmacology to examine the importance of glutamatergic synaptic transmission in this form of neurovascular coupling. Blockade of ionotropic glutamate receptors with the antagonists CNQX and MK801 significantly reduced forepaw-evoked hemodynamic responses, yet resulted in no significant reduction of channelrhodopsin-evoked hemodynamic responses, suggesting that stimulus-dependent coupling of neuronal activity to blood flow can be independent of local excitatory synaptic transmission. Together, these results indicate that channelrhodopsin-2 activation of sensorimotor excitatory neurons produces changes in intrinsic optical signals and blood flow that can occur under conditions where synaptic activation of neurons or other cells through ionotropic glutamate receptors would be blocked.

Scott, Nadia A.; Murphy, Timothy H.



Increased Gene Dosage of Ube3a Results in Autism Traits and Decreased Glutamate Synaptic Transmission in Mice  

PubMed Central

People with autism spectrum disorder are characterized by impaired social interaction, reduced communication, and increased repetitive behaviors. The disorder has a substantial genetic component, and recent studies have revealed frequent genome copy number variations (CNVs) in some individuals. A common CNV that occurs in 1 to 3% of those with autism—maternal 15q11-13 duplication (dup15) and triplication (isodicentric extranumerary chromosome, idic15)—affects several genes that have been suggested to underlie autism behavioral traits. To test this, we tripled the dosage of one of these genes, the ubiquitin protein ligase Ube3a, which is expressed solely from the maternal allele in mature neurons, and reconstituted the three core autism traits in mice: defective social interaction, impaired communication, and increased repetitive stereotypic behavior. The penetrance of these autism traits depended on Ube3a gene copy number. In animals with increased Ube3a gene dosage, glutamatergic, but not GABAergic, synaptic transmission was suppressed as a result of reduced presynaptic release probability, synaptic glutamate concentration, and postsynaptic action potential coupling. These results suggest that Ube3a gene dosage may contribute to the autism traits of individuals with maternal 15q11-13 duplication and support the idea that increased E3A ubiquitin ligase gene dosage results in reduced excitatory synaptic transmission.

Smith, Stephen E. P.; Zhou, Yu-Dong; Zhang, Guangping; Jin, Zhe; Stoppel, David C.; Anderson, Matthew P.



Lipid rafts, synaptic transmission and plasticity: impact in age-related neurodegenerative diseases.  


The synapse is a crowded area. In the last years, the concept that proteins can be organized in different membrane domains according to their structure has emerged. Cholesterol-rich membrane domains, or lipid rafts, form an organized portion of the membrane that is thought to concentrate signaling molecules. Accumulating evidence has shown that both the pre-synaptic and post-synaptic sites are highly enriched in lipid rafts, which are likely to organize and maintain synaptic proteins in their precise localization. Here we review recent studies highlighting the importance of lipid rafts for synaptic function and plasticity, as well as their relevance for age or disease-related cognitive impairment. This article is part of a Special Issue entitled 'Cognitive Enhancers'. PMID:22820274

Sebastiăo, Ana M; Colino-Oliveira, Mariana; Assaife-Lopes, Natália; Dias, Raquel B; Ribeiro, Joaquim A



Long-term enhancement of synaptic transmission between antennal lobe and mushroom body in cultured Drosophila brain.  


In Drosophila, the mushroom body (MB) is a critical brain structure for olfactory associative learning. During aversive conditioning, the MBs are thought to associate odour signals, conveyed by projection neurons (PNs) from the antennal lobe (AL), with shock signals conveyed through ascending fibres of the ventral nerve cord (AFV). Although synaptic transmission between AL and MB might play a crucial role for olfactory associative learning, its physiological properties have not been examined directly. Using a cultured Drosophila brain expressing a Ca(2+) indicator in the MBs, we investigated synaptic transmission and plasticity at the AL-MB synapse. Following stimulation with a glass micro-electrode, AL-induced Ca(2+) responses in the MBs were mediated through Drosophila nicotinic acetylcholine receptors (dnAChRs), while AFV-induced Ca(2+) responses were mediated through Drosophila NMDA receptors (dNRs). AL-MB synaptic transmission was enhanced more than 2 h after the simultaneous 'associative-stimulation' of AL and AFV, and such long-term enhancement (LTE) was specifically formed at the AL-MB synapses but not at the AFV-MB synapses. AL-MB LTE was not induced by intense stimulation of the AL alone, and the LTE decays within 60 min after subsequent repetitive AL stimulation. These phenotypes of associativity, input specificity and persistence of AL-MB LTE are highly reminiscent of olfactory memory. Furthermore, similar to olfactory aversive memory, AL-MB LTE formation required activation of the Drosophila D1 dopamine receptor, DopR, along with dnAChR and dNR during associative stimulations. These physiological and genetic analogies indicate that AL-MB LTE might be a relevant cellular model for olfactory memory. PMID:23027817

Ueno, Kohei; Naganos, Shintaro; Hirano, Yukinori; Horiuchi, Junjiro; Saitoe, Minoru



Tumor necrosis factor-alpha impairs the recovery of synaptic transmission from hypoxia in rat hippocampal slices.  


Cerebral ischaemia is a common occurrence in a range of pathological conditions, including stroke and traumatic brain injury. Two of the components in ischaemia are tissue hypoxia and the release of pro-inflammatory agents such as TNF-alpha. The role of TNF-alpha in an ischaemic/hypoxic episode is still controversial, although deleterious effects of pro-inflammatory cytokines in the area of injury are well documented. One of the prime adaptive mechanisms in response to hypoxia is the cellular activation of adenosine 1 receptors (A1Rs), which inhibits excitatory synaptic transmission. In the present study we have examined the effect of TNF-alpha application on synaptic transmission during hypoxic exposure and re-oxygenation using extracellular recordings in the CA1 region of the rat hippocampal slice. Hypoxia caused a reversible depression of the field EPSP (29.6+/-9.7% of control, n=5), which was adenosine A(1) receptor-dependent (85.7+/-4.3%, in the presence of DPCPX (200 nM), the adenosine A(1) receptor antagonist). DPCPX inhibited the maintenance of long-term potentiation obtained 30 min post hypoxia (143.8+/-8.2% versus 96.4+/-10.6% respectively, 1h post tetanus; n=5; p<0.005). In TNF-alpha (150 pM) treated slices hypoxic depression was similar to controls but a reduction in fEPSP slope was observed during re-oxygenation (66.8+/-1.4%, n=5). This effect was reversed by pre-treatment with SB 203580 (1 microM), a p38 MAP kinase inhibitor (91.8+/-6.9%, n=5). These results demonstrate a novel p38 MAPK dependent role for TNF-alpha in attenuating synaptic transmission after a hypoxic episode. PMID:19942300

Batti, Laura; O'Connor, John J



Maternal infection and fever during late gestation are associated with altered synaptic transmission in the hippocampus of juvenile offspring rats.  


Prenatal exposure to infection is known to affect brain development and has been linked to increased risk for schizophrenia. The goal of this study was to investigate whether maternal infection and associated fever near term disrupts synaptic transmission in the hippocampus of the offspring. We used LPS to mimic bacterial infection and trigger the maternal inflammatory response in near-term rats. LPS was administered to rats on embryonic days 15 and 16 and hippocampal synaptic transmission was evaluated in the offspring on postnatal days 20-25. Only offspring from rats that showed a fever in response to LPS were tested. Schaffer collateral-evoked field excitatory postsynaptic potentials (fEPSPs) and fiber volleys in CA1 of hippocampal slices appeared smaller in offspring from the LPS group compared with controls, but, when the fEPSPs were normalized to the amplitude of fiber volleys, they were larger in the LPS group. In addition, intrinsic excitability of CA1 pyramidal neurons was heightened, as antidromic field responses in the LPS group were greater than those from control. Short-, but not long-term plasticity was impaired since paired-pulse facilitation of the fEPSP was attenuated in the LPS group, whereas no differences in long-term potentiation were noted. These results suggest that LPS-induced inflammation during pregnancy produces in the offspring a reduction in presynaptic input to CA1 with compensatory enhancements in postsynaptic glutamatergic response and pyramidal cell excitability. Neurodevelopmental disruption triggered by prenatal infection can have profound effects on hippocampal synaptic transmission, likely contributing to the memory and cognitive deficits observed in schizophrenia. PMID:18753265

Lowe, Germaine C; Luheshi, Giamal N; Williams, Sylvain



Subtype-selective reconstitution of synaptic transmission in sympathetic ganglion neurons by expression of exogenous calcium channels  

Microsoft Academic Search

Fast cholinergic neurotransmission between superior cervical ganglion neurons (SCGNs) in cell culture is initiated by N-type Ca2+ currents through Cav2.2 channels. To test the ability of different Ca2+-channel subtypes to initiate synaptic transmission in these cells, SCGNs were injected with cDNAs encoding Cav1.2 channels, which conduct L-type currents, Cav2.1 channels, which conduct P\\/Q-type Ca2+ currents, and Cav2.3 channels, which conduct

Sumiko Mochida; Ruth E. Westenbroek; Charles T. Yokoyama; Kanako Itoh; William A. Catterall



Bistability and Spatiotemporal Irregularity in Neuronal Networks with Nonlinear Synaptic Transmission  

NASA Astrophysics Data System (ADS)

We present a mean-field theory for spiking networks operating in the balanced excitation-inhibition regime, with synapses displaying short-term plasticity. The theory reveals a novel mechanism for bistability which relies on the nonlinearity of the synaptic interactions. As synaptic nonlinearity is mainly controlled by the spiking rates, the different states are stabilized by dynamically generated changes in the noise level. Thus, in both states, the network operates in the fluctuation-driven regime, producing activity patterns characterized by strong spatiotemporal irregularity.

Mongillo, Gianluigi; Hansel, David; van Vreeswijk, Carl



Ubiquitin ligase RNF167 regulates AMPA receptor-mediated synaptic transmission.  


AMPA receptors (AMPARs) mediate the majority of fast excitatory neurotransmission, and their density at postsynaptic sites determines synaptic strength. Ubiquitination is a posttranslational modification that dynamically regulates the synaptic expression of many proteins. However, very few of the ubiquitinating enzymes implicated in the process have been identified. In a screen to identify transmembrane RING domain-containing E3 ubiquitin ligases that regulate surface expression of AMPARs, we identified RNF167. Predominantly lysosomal, a subpopulation of RNF167 is located on the surface of cultured neurons. Using a RING mutant RNF167 or a specific shRNA to eliminate endogenous RNF167, we demonstrate that AMPAR surface expression increases in hippocampal neurons with disrupted RNF167 activity and that RNF167 is involved in activity-dependent ubiquitination of AMPARs. In addition, RNF167 regulates synaptic AMPAR currents, whereas synaptic NMDAR currents are unaffected. Therefore, our study identifies RNF167 as a selective regulator of AMPAR-mediated neurotransmission and expands our understanding of how ubiquitination dynamically regulates excitatory synapses. PMID:23129617

Lussier, Marc P; Herring, Bruce E; Nasu-Nishimura, Yukiko; Neutzner, Albert; Karbowski, Mariusz; Youle, Richard J; Nicoll, Roger A; Roche, Katherine W



Synaptic Transmission from Horizontal Cells to Cones Is Impaired by Loss of Connexin Hemichannels  

Microsoft Academic Search

In the vertebrate retina, horizontal cells generate the inhibitory surround of bipolar cells, an essential step in contrast enhancement. For the last decades, the mechanism involved in this inhibitory synaptic pathway has been a major controversy in retinal research. One hypothesis suggests that connexin hemichannels mediate this negative feedback signal; another suggests that feedback is mediated by protons. Mutant zebrafish

Lauw J. Klaassen; Ziyi Sun; Marvin N. Steijaert; Petra Bolte; Iris Fahrenfort; Trijntje Sjoerdsma; Jan Klooster; Yvonne Claassen; Colleen R. Shields; Huub M. M. Ten Eikelder; Ulrike Janssen-Bienhold; Georg Zoidl; Douglas G. McMahon; Maarten Kamermans



Effect of repeated ipsapirone treatment on hippocampal excitatory synaptic transmission in the freely behaving rat: role of 5HT 1A receptors and relationship to anxiolytic effect  

Microsoft Academic Search

The effects of acute and repeated treatment with the 5-HT1A receptor ligand ipsapirone on hippocampal excitatory synaptic transmission and in an ultrasonic vocalization anxiety test were investigated in the rat. Synaptic responses in the CA1 region of the dorsal hippocampus of alert, freely behaving male Wistar rats were reduced after acute injection of ipsapirone (1 or 2 mg\\/kg, i.p.). This

Lin Xu; Roger Anwyl; Jean De Vry; Michael J Rowan



Lactational alcohol exposure elicits long-term immune deficits and increased noradrenergic synaptic transmission in lymphoid organs  

SciTech Connect

Increasing evidence suggests that the sympathetic nervous system plays an important role in immunomodulation. While chronic alcohol consumption has been associated with immune deficits, the effects of exposure to alcohol during early postnatal life on subsequent immunocompetence and activity of sympathetic neurons in lymphoid organs are not known. This study examined the long-term effects of lactational alcohol consumption on cellular immune responses and noradrenergic synaptic transmission in lymphoid and other organs of the young adult C57BL/6 mouse. The data show that exposure to alcohol via the mother's milk was associated with long-term deficits in cellular immunity, including suppression of the local graft vs host and contact hypersensitive responses. The animals also displayed enhanced noradrenergic synaptic transmission and decreased {beta}-adrenoceptor density selectively in lymphoid organs. These neuroimmune changes are particularly striking since body weight-gain of the suckling pups was normal and their blood alcohol concentration was considerably lower than that of the alcohol-consuming dam. This suggests an increased sensitivity of the nascent immune and nervous systems during the critical period of early postnatal development.

Gottesfeld, Z. (Univ. of Texas Medical School, Houston (USA)); LeGrue, S.J. (Univ. of Texas M.D. Anderson Cancer Center, Houston (USA))



Transient reversal of the sodium/calcium exchanger boosts presynaptic calcium and synaptic transmission at a cerebellar synapse.  


The sodium/calcium exchanger (NCX) is a widespread transporter that exchanges sodium and calcium ions across excitable membranes. Normally, NCX mainly operates in its "forward" mode, harnessing the electrochemical gradient of sodium ions to expel calcium. During membrane depolarization or elevated internal sodium levels, NCX can instead switch the direction of net flux to expel sodium and allow calcium entry. Such "reverse"-mode NCX operation is frequently implicated during pathological or artificially extended periods of depolarization, not during normal activity. We have used fast calcium imaging, mathematical simulation, and whole cell electrophysiology to study the role of NCX at the parallel fiber-to-Purkinje neuron synapse in the mouse cerebellum. We show that nontraditional, reverse-mode NCX activity boosts the amplitude and duration of parallel fiber calcium transients during short bursts of high-frequency action potentials typical of their behavior in vivo. Simulations, supported by experimental manipulations, showed that accumulation of intracellular sodium drove NCX into reverse mode. This mechanism fueled additional calcium influx into the parallel fibers that promoted synaptic transmission to Purkinje neurons for up to 400 ms after the burst. Thus we provide the first functional demonstration of transient and fast NCX-mediated calcium entry at a major central synapse. This unexpected contribution from reverse-mode NCX appears critical for shaping presynaptic calcium dynamics and transiently boosting synaptic transmission, and is likely to optimize the accuracy of cerebellar information transfer. PMID:23255722

Roome, Chris J; Power, Emmet M; Empson, Ruth M



Exendin (5-39), an antagonist of GLP-1 receptor, modulates synaptic transmission via glutamate uptake in the dentate gyrus.  


Extracellular concentrations of glutamate are mainly controlled by an astrocytic glutamate transporter, GLT-1. We previously reported that exendin (5-39) (Ex), an antagonist of the GLP-1 receptor, improved memory impairment in ?-amyloid protein-treated rats. In this study, we investigated effects of Ex on synaptic transmission through astrocytic GLT-1 in the hippocampus. Continuous intracerebroventricular (i.c.v.) administration of Ex for 1-week increased GLT-1 protein levels in the hippocampus of 4-week-old male Wistar rats. For electrophysiological studies, hippocampal slices were prepared from these Ex-treated rats or vehicle-treated rats. Ex decreased fEPSP decay time, and increased the input-output relation and decreased the paired-pulse ratio in the dentate gyrus (DG). Furthermore, Ex inhibited long-term depression but not long-term potentiation in the DG. These effects were prevented by DHK, a specific GLT-1 inhibitor. In addition, glutamate uptake was significantly increased by Ex-treatment in cultured astrocytes. These results suggest that Ex modulates synaptic transmission and plasticity through astrocytic glutamate uptake in the DG. PMID:23318256

Kobayashi, Kazuma; Iwai, Takashi; Sasaki-Hamada, Sachie; Kamanaka, Gaku; Oka, Jun-Ichiro



The physiological role of three acetylcholine receptors in synaptic transmission in Aplysia  

PubMed Central

1. It is shown that a single presumably cholinergic presynaptic neurone can mediate, monosynaptically, multicomponent responses in a given cell and different responses in different cells. 2. Complex responses (whether evoked synaptically or by ACh injection) are shown to be the result of the coexistence on a given post-synaptic neurone of more than one of three cholinergic receptor types previously described. Likewise, different responses in different cells are due to the fact that different post-synaptic neurones bear different combinations of these three receptors. 3. Pharmacological analysis shows that the multicomponent nature of many of the responses is not always evident: what appears, under normal conditions, to be a single-component excitatory potential can be shown often to be a complex response consisting of superimposed e.p.s.p.s and rapid i.p.s.p.s which are sometimes, though not always, accompanied by a slow i.p.s.p. 4. Although which and how many of the three receptor types is the major factor contributing to the type of response observed, in the case of some of the synaptic potentials certain other factors were found to contribute to the final response form. First, in the large cells of the visceral ganglion, as well as in the left giant cell of the pleural ganglion, there is a marked `electrical separation' between the region in which the synaptic currents are generated and the point of recording. This `electrical distance' often altered the inversion potential, and sometimes the form of the responses. Secondly, in some visceral neurones, activation of the cholinergic presynaptic neurone L10 causes (either directly or indirectly) a potential change which cannot be accounted for in terms of the activation of cholinergic receptors. This `non-cholinergic' response (not imitated by an ionophoretic injection of ACh) is unmasked by the blocking of all three cholinergic receptors. It contributes differentially in different cells to the total response pattern produced by L10 under normal conditions, but its contribution is often characterized by a late hyperpolarizing phase which appears to be impossible to invert. This phase has been shown, however, to be dependent upon the potassium concentration in the extracellular space surrounding the synapse. 4. It is tentatively suggested that this residual, non-cholinergic element of the synaptic response in some visceral cells be the result of the activation of an electrical synapse.

Kehoe, Jacsue



Structural and functional analysis of synaptic transmission between identified leech neurones in culture.  

PubMed Central

The fine structure and physiological properties of chemical synapses that develop between identified leech neurones in culture have been studied by electron microscopy and by quantal analysis. Earlier work has shown that the transmitter liberated by isolated Retzius cells, serotonin, evokes chloride-dependent inhibitory post-synaptic potentials (i.p.s.p.s) in P sensory cells, and also in Retzius cells. When pairs of Retzius cells or Retzius and P sensory cells were placed in close apposition in culture for a few days, their somata extended numerous fine processes which came into contact and interdigitated. In the region of interdigitation, only narrow spaces, approximately 20-25 nm wide separated the membranes. The appearance of the cytoplasm of the two neurones was distinctive: in particular, Retzius cells contained agranular vesicles, as well as abundant dense core vesicles which were not as prevalent in P cells. Structures resembling synapses developed by 4 days, with characteristic vesicles clustered in terminals of the Retzius cell apposed to the post-synaptic membrane. In the presence of raised Mg or lowered Ca in the culture medium, the i.p.s.p. in the P cell evoked by an impulse in the Retzius cell became diminished in amplitude. The time-to-peak and half-time of decay were unchanged. Under these conditions, with repeated stimulation, quantal fluctuations of these post-synaptic potentials and failures were observed. In addition, there occurred spontaneous events which resembled miniature synaptic potentials and had amplitudes and time courses similar to those of the unitary events evoked by presynaptic impulses. The amplitudes of evoked synaptic potentials in raised Mg were distributed in accord with the Poisson equation. The agreement was good when either the spontaneous miniature potentials or the failures of evoked release were used to calculate m, the mean number of quanta per trial. With larger values of m the results were distributed as predicted by the binomial equation. These morphological and electrophysiological experiments together indicate that the inhibitory potentials observed in P cells result from quantal units of transmitter released by presynaptic terminals of the Retzius cell which are in close apposition to the post-synaptic membrane. Images Plate 1 Plate 2

Henderson, L P; Kuffler, D P; Nicholls, J; Zhang, R



A comparison of chemical and electrical synaptic transmission between single sensory cells and a motoneurone in the central nervous system of the leech  

PubMed Central

In leech ganglia, three sensory cells of different modality converge on a motoneurone, where they form chemical and electrical synapses. Each of these synapses behaves in a characteristic manner and the nature of the transmission mechanism has significant functional consequences for the operation of the reflexes. An analysis has been made of the effects of trains of impulses on synaptic transmission through these pathways, using frequencies that correspond to natural firing. 1. At the chemical synapse between the nociceptive sensory cell and the motoneurone, two opposing events occur: facilitation and depression. Thus, with trains of impulses, the synaptic potentials first increase in amplitude and then decrease. The two processes could be separated by altering the Mg and Ca content of the bathing fluid. In concentrations of Mg that reduced the amplitude of a single control chemical synaptic potential, pure facilitation occurred during a train. Depression predominated during brief trains in raised concentrations of Ca, although synaptic potentials were initially larger. These results suggest that changes in the amount of transmitter released by each presynaptic action potential can account for the changes observed in chemical synaptic transmission. 2. In contrast, electrical transmission between the sensory cell responding to touch and the same motoneurone did not show facilitation or depression. The electrical coupling potential in the motoneurone was relatively constant when the touch cell fired at high or low frequencies in normal Ringer fluid, high Mg, or high Ca fluid. 3. Further differences between chemical and electrical synapses were apparent when the preparation was cooled to 4° C. In the cold the latency of chemically evoked synaptic potentials in the motoneurone increased and their amplitude declined drastically with repetitive stimulation, while electrical coupling potentials were unaffected. 4. A brief hyperpolarization of the presynaptic cell by injected current produced a marked and prolonged increase in chemically evoked synaptic potentials, but did not influence electrical synaptic transmission. 5. The synapses of the sensory cell responding to pressure, which are both chemical and electrical, behaved as expected: the chemical synaptic potentials showed facilitation and depression while electrical transmission remained relatively constant. 6. These experiments emphasize the different functional consequences of electrical or chemical synapses in reflex pathways for the transmission of signals that arise as a result of natural sensory stimuli. ImagesPlate 1

Nicholls, J. G.; Purves, D.



A comparison of chemical and electrical synaptic transmission between single sensory cells and a motoneurone in the central nervous system of the leech.  


In leech ganglia, three sensory cells of different modality converge on a motoneurone, where they form chemical and electrical synapses. Each of these synapses behaves in a characteristic manner and the nature of the transmission mechanism has significant functional consequences for the operation of the reflexes. An analysis has been made of the effects of trains of impulses on synaptic transmission through these pathways, using frequencies that correspond to natural firing.1. At the chemical synapse between the nociceptive sensory cell and the motoneurone, two opposing events occur: facilitation and depression. Thus, with trains of impulses, the synaptic potentials first increase in amplitude and then decrease. The two processes could be separated by altering the Mg and Ca content of the bathing fluid. In concentrations of Mg that reduced the amplitude of a single control chemical synaptic potential, pure facilitation occurred during a train. Depression predominated during brief trains in raised concentrations of Ca, although synaptic potentials were initially larger. These results suggest that changes in the amount of transmitter released by each presynaptic action potential can account for the changes observed in chemical synaptic transmission.2. In contrast, electrical transmission between the sensory cell responding to touch and the same motoneurone did not show facilitation or depression. The electrical coupling potential in the motoneurone was relatively constant when the touch cell fired at high or low frequencies in normal Ringer fluid, high Mg, or high Ca fluid.3. Further differences between chemical and electrical synapses were apparent when the preparation was cooled to 4 degrees C. In the cold the latency of chemically evoked synaptic potentials in the motoneurone increased and their amplitude declined drastically with repetitive stimulation, while electrical coupling potentials were unaffected.4. A brief hyperpolarization of the presynaptic cell by injected current produced a marked and prolonged increase in chemically evoked synaptic potentials, but did not influence electrical synaptic transmission.5. The synapses of the sensory cell responding to pressure, which are both chemical and electrical, behaved as expected: the chemical synaptic potentials showed facilitation and depression while electrical transmission remained relatively constant.6. These experiments emphasize the different functional consequences of electrical or chemical synapses in reflex pathways for the transmission of signals that arise as a result of natural sensory stimuli. PMID:4342522

Nicholls, J G; Purves, D



Regulation of Synaptic Transmission by Presynaptic CaMKII and BK channels  

PubMed Central

Ca2+/calmodulin-dependent protein kinase II (CaMKII) and the BK channel are enriched at the presynaptic nerve terminal, where CaMKII associates with synaptic vesicles whereas the BK channel colocalizes with voltage-sensitive Ca2+ channels (VSCCs) in the plasma membrane. Mounting evidence suggests that these two proteins play important roles in controlling neurotransmitter release. Presynaptic BK channels primarily serve as a negative regulator of neurotransmitter release. In contrast, presynaptic CaMKII either enhances or inhibits neurotransmitter release and synaptic plasticity depending on experimental/physiological conditions and properties of specific synapses. The different functions of presynaptic CaMKII appear to be mediated by distinct downstream proteins, including the BK channel.

Wang, Zhao-Wen



Nitric Oxide Enhances Inhibitory Synaptic Transmission and Neuronal Excitability in Guinea-Pig Submucous Plexus  

PubMed Central

Varicosities immunoreactive for nitric oxide synthase (NOS) make synaptic connections with submucosal neurons in the guinea-pig small intestine, but the effects of nitric oxide (NO) on these neurons are unknown. We used intracellular recording to characterize effects of sodium nitroprusside (SNP, NO donor) and nitro-l-arginine (NOLA, NOS inhibitor), on inhibitory synaptic potentials (IPSPs), slow excitatory synaptic potentials (EPSPs) and action potential firing in submucosal neurons of guinea-pig ileum in vitro. Recordings were made from neurons with the characteristic IPSPs of non-cholinergic secretomotor neurons. SNP (100 ?M) markedly enhanced IPSPs evoked by single stimuli applied to intermodal strands and IPSPs evoked by trains of 2–10 pulses (30 Hz). Both noradrenergic (idazoxan-sensitive) and non-adrenergic (idazoxan-insensitive) IPSPs were affected. SNP enhanced hyperpolarizations evoked by locally applied noradrenaline or somatostatin. SNP did not affect slow EPSPs evoked by single stimuli, but depressed slow EPSPs evoked by stimulus trains. NOLA (100 ?M) depressed IPSPs evoked by one to three stimulus pulses and enhanced slow EPSPs evoked by trains of two to three stimuli (30 Hz). SNP also increased the number of action potentials and the duration of firing evoked by prolonged (500 or 1000?ms) depolarizing current pulses, but NOLA had no consistent effect on action potential firing. We conclude that neurally released NO acts post-synaptically to enhance IPSPs and depress slow EPSPs, but may enhance the intrinsic excitability of these neurons. Thus, NOS neurons may locally regulate several secretomotor pathways ending on common neurons.

Bornstein, Joel C.; Marks, Kathryn A.; Foong, Jaime Pei Pei; Gwynne, Rachel M.; Wang, Zhi Hong



Retrograde Control of Synaptic Transmission by Postsynaptic CaMKII at the Drosophila Neuromuscular Junction  

Microsoft Academic Search

Retrograde signaling plays an important role in synaptic homeostasis, growth, and plasticity. A retrograde signal at the neuromuscular junction (NMJ) of Drosophila controls the homeostasis of neurotransmitter release. Here, we show that this retrograde signal is regulated by the postsynaptic activity of Ca2+\\/calmodulin-dependent protein kinase II (CaMKII). Reducing CaMKII activity in muscles enhances the signal and increases neurotransmitter release, while

A. Pejmun Haghighi; Brian D. McCabe; Richard D. Fetter; Jessica E. Palmer; Sabrina Hom; Corey S. Goodman



GABA Receptors Containing Rdl Subunits Mediate Fast Inhibitory Synaptic Transmission in Drosophila Neurons  

Microsoft Academic Search

GABAergic inhibition in Drosophila, as in other insects and mammals, is important for regulation of activity in the CNS. However, the functional properties of synaptic GABA receptors in Drosophila have not been described. Here, we report that spontaneous GABAergic postsynaptic currents (sPSCs) in cultured embryonic Drosophila neurons are mediated by picrotoxin-sensitive chloride-conducting receptors. A rapid increase in spontaneous firing in

Daewoo Lee; Hailing Su; Diane K. O'Dowd



Regulation of AMPA Receptor–Mediated Synaptic Transmission by Clathrin-Dependent Receptor Internalization  

Microsoft Academic Search

Redistribution of postsynaptic AMPA- (?-amino-3-hydroxy-5-methylisoxazole-4-propionic acid–) subtype glutamate receptors may regulate synaptic strength at glutamatergic synapses, but the mediation of the redistribution is poorly understood. We show that AMPA receptors underwent clathrin-dependent endocytosis, which was accelerated by insulin in a GluR2 subunit–dependent manner. Insulin-stimulated endocytosis rapidly decreased AMPA receptor numbers in the plasma membrane, resulting in long-term depression (LTD) of

Heng-Ye Man; Jerry W. Lin; William H. Ju; Gholamreza Ahmadian; Lidong Liu; Laurence E. Becker; Morgan Sheng; Yu Tian Wang



Nicotine Selectively Enhances NMDA Receptor-Mediated Synaptic Transmission during Postnatal Development in Sensory Neocortex  

Microsoft Academic Search

The neurotransmitters acetylcholine (ACh) and glutamate have been separately implicated in synaptic plasticity during devel- opment of sensory neocortex. Here we show that these neuro- transmitters can, in fact, act synergistically via their actions at nicotinic ACh receptors (nAChRs) and NMDA receptors, re- spectively. To determine how activation of nAChRs modifies glutamatergic EPSPs, we made whole-cell recordings from visualized pyramidal

V. Bess Aramakis; Raju Metherate



Pregnenolone Sulfate Modulates Inhibitory Synaptic Transmission by Enhancing GABAA Receptor Desensitization  

Microsoft Academic Search

We examined the effects of the neurosteroid pregnenolone sulfate (PS) on GABAA receptor-mediated synaptic currents and currents elicited by rapid applications of GABA onto nu- cleated outside-out patches in cultured postnatal rat hip- pocampal neurons. At 10 mM, PS significantly depressed peak responses and accelerated the decay of evoked inhibitory syn- aptic currents. In nucleated outside-out patches, PS depressed peak

Weixing Shen; Steven Mennerick; Douglas F. Covey; Charles F. Zorumski



Neuromodulation of thoracic intraspinal visceroreceptive transmission by electrical stimulation of spinal dorsal column and somatic afferents in rats  

PubMed Central

Clinical studies have shown that neuromodulation therapies, such as spinal cord stimulation (SCS) and transcutaneous electrical nerve stimulation (TENS), reduce symptoms of chronic neuropathic and visceral pain. The neural mechanisms underlying SCS and TENS therapy are poorly understood. The present study was designed to compare the effects of SCS and TENS on spinal neuronal responses to noxious stimuli applied to the heart and esophagus. Direct stimulation of an intercostal nerve (ICNS) was used to simulate the effects of TENS. Extracellular potentials of left thoracic (T3) spinal neurons were recorded in pentobarbital anesthetized, paralyzed and ventilated male rats. SCS (50 Hz, 0.2 ms, 3–5 min) at a clinical relevant intensity (90% of motor threshold) was applied on the C1–C2 or C8-T1 ipsilateral spinal segments. Intercostal nerve stimulation (ICNS) at T3 spinal level was performed using the same parameters as SCS. Intrapericardial injection of bradykinin (IB, 10 ?g/ml, 0.2 ml, 1 min) was employed as the noxious cardiac stimulus. Noxious thoracic esophageal distension (ED, 0.4 ml, 20 s) was produced by water inflation of a latex balloon. C1–C2 SCS suppressed excitatory responses of 16/22 T3 spinal neurons to IB and 25/30 neurons to ED. C8-T1 SCS suppressed excitatory responses of 10/15 spinal neurons to IB and 17/23 neurons to ED. ICNS suppressed excitatory responses of 9/12 spinal neurons to IB and 17/22 neurons to ED. These data showed that SCS and ICNS modulated excitatory responses of T3 spinal neurons to noxious stimulation of the heart and esophagus. Perspective: Neuromodulation of noxious cardiac and esophageal inputs onto thoracic spinal neurons by spinal cord and intercostal nerves stimulation observed in the present study may help account for therapeutic effects on thoracic visceral pain by activating the spinal dorsal column or somatic afferents.

Qin, Chao; Farber, Jay P.; Linderoth, Bengt; Shahid, Abdul; Foreman, R. D.



Src, a Molecular Switch Governing Gain Control of Synaptic Transmission Mediated by N-methyl-D-Aspartate Receptors  

NASA Astrophysics Data System (ADS)

The N-methyl-D-aspartate (NMDA) receptor is a principal subtype of glutamate receptor mediating fast excitatory transmission at synapses in the dorsal horn of the spinal cord and other regions of the central nervous system. NMDA receptors are crucial for the lasting enhancement of synaptic transmission that occurs both physiologically and in pathological conditions such as chronic pain. Over the past several years, evidence has accumulated indicating that the activity of NMDA receptors is regulated by the protein tyrosine kinase, Src. Recently it has been discovered that, by means of up-regulating NMDA receptor function, activation of Src mediates the induction of the lasting enhancement of excitatory transmission known as long-term potentiation in the CA1 region of the hippocampus. Also, Src has been found to amplify the up-regulation of NMDA receptor function that is produced by raising the intracellular concentration of sodium. Sodium concentration increases in neuronal dendrites during high levels of firing activity, which is precisely when Src becomes activated. Therefore, we propose that the boost in NMDA receptor function produced by the coincidence of activating Src and raising intracellular sodium may be important in physiological and pathophysiological enhancement of excitatory transmission in the dorsal horn of the spinal cord and elsewhere in the central nervous system.

Yu, Xian-Min; Salter, Michael W.



The rubrospinal tract. II. Facilitation of interneuronal transmission in reflex paths to motoneurones  

Microsoft Academic Search

1.The effect of stimulation of the red nucleus on transmission of synaptic actions from different systems of primary afferents to alpha motoneurones has been investigated in cats, mainly with intracellular recording from motoneurones.2.The dominating effect is facilitation, presumably caused by excitatory action exerted from the rubrospinal tract on interneurones of reflex arcs. The time course of facilitation suggests that the

T. Hongo; El?bieta Jankowska; A. Lundberg



The mysterious trace amines: protean neuromodulators of synaptic transmission in mammalian brain.  


The trace amines are a structurally related group of amines and their isomers synthesized in mammalian brain and peripheral nervous tissues. They are closely associated metabolically with the dopamine, noradrenaline and serotonin neurotransmitter systems in mammalian brain. Like dopamine, noradrenaline and serotonin the trace amines have been implicated in a vast array of human disorders of affect and cognition. The trace amines are unique as they are present in trace concentrations, exhibit high rates of metabolism and are distributed heterogeneously in mammalian brain. While some are synthesized in their parent amine neurotransmitter systems, there is also evidence to suggest other trace amines may comprise their own independent neurotransmitter systems. A substantial body of evidence suggests that the trace amines may play very significant roles in the coordination of biogenic amine-based synaptic physiology. At high concentrations, they have well-characterized presynaptic "amphetamine-like" effects on catecholamine and indolamine release, reuptake and biosynthesis; at lower concentrations, they possess postsynaptic modulatory effects that potentiate the activity of other neurotransmitters, particularly dopamine and serotonin. The trace amines also possess electrophysiological effects that are in opposition to these neurotransmitters, indicating to some researchers the existence of receptors specific for the trace amines. While binding sites or receptors for a few of the trace amines have been advanced, the absence of cloned receptor protein has impeded significant development of their detailed mechanistic roles in the coordination of catecholamine and indolamine synaptic physiology. The recent discovery and characterization of a family of mammalian G protein-coupled receptors responsive to trace amines such as beta-phenylethylamine, tyramine, and octopamine, including socially ingested psychotropic drugs such as amphetamine, 3,4-methylenedioxymethamphetamine, N,N-dimethyltryptamine, and lysergic acid diethylamide, have revitalized the field of scientific studies investigating trace amine synaptic physiology, and its association with major human disorders of affect and cognition. PMID:16962229

Burchett, Scott A; Hicks, T Philip



Spike timing in CA3 pyramidal cells during behavior: implications for synaptic transmission  

PubMed Central

Spike timing is thought to be an important mechanism for transmitting information in the CNS. Recent studies have emphasized millisecond precision in spike timing, to allow temporal summation of rapid synaptic signals. However, spike timing over slower timescales could also be important, through mechanisms including activity-dependent synaptic plasticity, or temporal summation of slow PSPs such as those mediated by kainate receptors. To determine the extent to which these slower mechanisms contribute to information processing, it is first necessary to understand the properties of behaviorally relevant spike timing over this slow timescale. In this study, we examine the activity of CA3 pyramidal cells during the performance of a complex behavioral task in rats. Sustained firing rates vary over a wide range, and the firing rate of a cell is poorly correlated with the behavioral cues to which the cell responds. Non-random interactions between successive spikes can last for several seconds, but the non-random distribution of interspike intervals (ISIs) can account for the majority of nonrandom multi-spike patterns. During a stimulus, cellular responses are temporally complex, causing a shift in spike timing that favors intermediate ISIs over short and long ISIs. Response discrimination between related stimuli occurs through changes in both response time-course and response intensity. Precise synchrony between cells is limited, but loosely correlated firing between cells is common. This study indicates that spike timing is regulated over long timescales, and suggests that slow synaptic mechanisms could play a substantial role in information processing in the CNS.

Frerking, M.; Schulte, J.; Wiebe, S.P.; Staubli, U.



Critical role of promoter IV-driven BDNF transcription in GABAergic transmission and synaptic plasticity in the prefrontal cortex  

PubMed Central

Transcription of Bdnf is controlled by multiple promoters, which drive expression of multiple transcripts encoding for the same protein. Promoter IV contributes significantly to activity-dependent brain-derived neurotrophic factor (BDNF) transcription. We have generated promoter IV mutant mice (BDNF-KIV) by inserting a GFP-STOP cassette within the Bdnf exon IV locus. This genetic manipulation results in disruption of promoter IV-mediated Bdnf expression. BDNF-KIV animals exhibited significant deficits in GABAergic interneurons in the prefrontal cortex (PFC), particularly those expressing parvalbumin, a subtype implicated in executive function and schizophrenia. Moreover, disruption of promoter IV-driven Bdnf transcription impaired inhibitory but not excitatory synaptic transmission recorded from layer V pyramidal neurons in the PFC. The attenuation of GABAergic inputs resulted in an aberrant appearance of spike-timing-dependent synaptic potentiation (STDP) in PFC slices derived from BDNF-KIV, but not wild-type littermates. These results demonstrate the importance of promoter IV-dependent Bdnf transcription in GABAergic function and reveal an unexpected regulation of STDP in the PFC by BDNF.

Sakata, Kazuko; Woo, Newton H.; Martinowich, Keri; Greene, Joshua S.; Schloesser, Robert J.; Shen, Liya; Lu, Bai



Effects of the anaesthetic 2,6-diisopropylphenol on synaptic transmission in the rat olfactory cortex slice.  

PubMed Central

1. The effects of the general anaesthetic 2,6-diisopropylphenol (DIP) on synaptic transmission and the actions of amino acid transmitter candidates have been investigated in rat olfactory cortex slices. 2. On electrical stimulation of the lateral olfactory tract (LOT), DIP (20 to 200 microM) increased the area of those surface field potentials which reflect gamma-aminobutyric acid (GABA)-mediated transmission in a concentration-dependent manner in 6 out of 12 slices. In a series of conditioning experiments, DIP (50 microM) also potentiated GABA-mediated pre- and post-synaptic inhibition. 3. Perfusion of slices with DIP (50 microM) potentiated the reduction in the excitability of the terminals of the LOT produced by exogenous GABA in a picrotoxin-sensitive manner. 4. DIP (50 microM) markedly potentiated the surface depolarizations evoked by GABA, muscimol and 3-aminopropanesulphonic acid. The effect on the response to 3-aminopropanesulphonic acid was observed over a concentration range of DIP of 6.25 to 50 microM and was not blocked by the benzodiazepine receptor antagonist Ro 15-1788. 5. In slices in which GABA-mediated transmission was abolished by picrotoxin (25 microM), DIP (50 microM) had no significant effect on monosynaptically-evoked excitatory transmission but depressed the areas of those field potentials which reflect di-/polysynaptic excitations in a concentration-dependent manner (from between 1.6 and 6.25 to 50 microM). 6. In a series of conditioning experiments DIP (50 microM) abolished the increase in the excitability of the pyramidal cells evoked on stimulation of deep association fibres. 7. DIP (50 microM) had no significant effect on surface depolarizations evoked by N-methyl-D-aspartate, quisqualate and kainate or by the transmitter candidates L-glutamate and L-aspartate. 8. It is concluded that, at clinically relevant concentrations, DIP potentiates GABA-mediated transmission probably by an interaction with the GABA receptor complex and inhibits di-/polysynaptic excitations, possibly by inhibiting the release of excitatory transmitters.

Collins, G. G.



Activation of large-conductance Ca 2+-activated K + channels depresses basal synaptic transmission in the hippocampal CA1 area in APP (swe\\/ind) TgCRND8 mice  

Microsoft Academic Search

Large-conductance Ca2+-activated K+ (BK) channels regulate synaptic transmission by contributing to the repolarization phase of the action potential that invades the presynaptic terminal. BK channels are prone to activation under pathological conditions, such as brain ischemia and epilepsy. It is unclear if activation of these channels contributes to the depression of synaptic transmission observed in the early stage of Alzheimer's

Hui Ye; Shirin Jalini; Shanthini Mylvaganam; Peter Carlen



Exposure to Cocaine Regulates Inhibitory Synaptic Transmission in the Nucleus Accumbens  

PubMed Central

Medium spiny neurons (MSNs) within the nucleus accumbens shell (NAc) function to gate and prioritize emotional/motivational arousals for behavioral output. The neuronal output NAc MSNs is mainly determined by the integration of membrane excitability and excitatory/inhibitory synaptic inputs. Whereas cocaine-induced alterations at excitatory synapses and membrane excitability have been extensively examined, the overall functional output of NAc MSNs following cocaine exposure still poorly defined because little is known about whether inhibitory synaptic input to these neurons is affected by cocaine. Here, our results demonstrate multidimensional alterations at inhibitory synapses in NAc neurons following cocaine self-administration in rats. Specifically, the amplitude of miniature (m) inhibitory postsynaptic currents (IPSCs) was decreased after 21-d withdrawal from 5-d cocaine self-administration. Upon re-exposure to cocaine after 21-day withdrawal, whereas the amplitude of mIPSCs remained down-regulated, the frequency became significantly higher. Furthermore, the reversal potential of IPSCs, which was not significantly altered during withdrawal, became more hyperpolarized upon cocaine re-exposure. Moreover, the relative weight of excitatory and inhibitory inputs to NAc MSNs was significantly decreased after 1-d cocaine withdrawal, increased after 21-d withdrawal, and returned to the basal level upon cocaine re-exposure after 21-d withdrawal. These results, taken together with previous results showing cocaine-induced adaptations at excitatory synapses and intrinsic membrane excitability of NAc MSNs, may provide a relatively thorough picture of the functional state of NAc MSNs following cocaine exposure.

Otaka, Mami; Ishikawa, Masago; Lee, Brian R.; Liu, Lei; Neumann, Peter A.; Cui, Ranji; Huang, Yanhua; Schluter, Oliver M.; Dong, Yan



Exposure to cocaine regulates inhibitory synaptic transmission in the nucleus accumbens.  


Medium spiny neurons (MSNs) within the nucleus accumbens shell (NAc) function to gate and prioritize emotional/motivational arousals for behavioral output. The neuronal output of NAc MSNs is mainly determined by the integration of membrane excitability and excitatory/inhibitory synaptic inputs. Whereas cocaine-induced alterations at excitatory synapses and membrane excitability have been extensively examined, the overall functional output of NAc MSNs following cocaine exposure is still poorly defined because little is known about whether inhibitory synaptic input to these neurons is affected by cocaine. Here, our results demonstrate multidimensional alterations at inhibitory synapses in NAc neurons following cocaine self-administration in rats. Specifically, the amplitude of miniature IPSCs (mIPSCs) was decreased after 21 d withdrawal from 5 d cocaine self-administration. Upon re-exposure to cocaine after 21 d withdrawal, whereas the amplitude of mIPSCs remained downregulated, the frequency became significantly higher. Furthermore, the reversal potential of IPSCs, which was not significantly altered during withdrawal, became more hyperpolarized upon cocaine re-exposure. Moreover, the relative weight of excitatory and inhibitory inputs to NAc MSNs was significantly decreased after 1 d cocaine withdrawal, increased after 21 d withdrawal, and returned to the basal level upon cocaine re-exposure after 21 d withdrawal. These results, together with previous results showing cocaine-induced adaptations at excitatory synapses and intrinsic membrane excitability of NAc MSNs, may provide a relatively thorough picture of the functional state of NAc MSNs following cocaine exposure. PMID:23595733

Otaka, Mami; Ishikawa, Masago; Lee, Brian R; Liu, Lei; Neumann, Peter A; Cui, Ranji; Huang, Yanhua H; Schlüter, Oliver M; Dong, Yan



Postnatal Loss of P/Q-type Channels Confined to Rhombic Lip Derived Neurons Alters Synaptic Transmission at the Parallel Fiber to Purkinje Cell Synapse and Replicates Genomic Cacna1a Mutation Phenotype of Ataxia and Seizures in Mice  

PubMed Central

Ataxia, episodic dyskinesia and thalamocortical seizures are associated with an inherited loss of P/Q-type voltage-gated Ca2+ channel function. P/Q-type channels are widely expressed throughout the neuraxis, obscuring identification of the critical networks underlying these complex neurological disorders. We recently showed that the conditional postnatal loss of P/Q-type channels in cerebellar Purkinje cells (PCs) in mice (purky) leads to these aberrant phenotypes, suggesting that intrinsic alteration in PC output is a sufficient pathogenic factor for disease initiation. The question arises whether P/Q-type channel deletion confined to a single upstream cerebellar synapse might induce the pathophysiological abnormality of genomically inherited P/Q-type channel disorders. PCs integrate two excitatory inputs, climbing fibers from inferior olive and parallel fibers (PFs) from granule cells (GCs) that receive mossy fiber (MF) input derived from precerebellar nuclei. In this paper, we introduce a new mouse model with a selective knock-out of P/Q-type channels in rhombic lip derived neurons including PF- and MF-pathways (quirky). We found that in quirky mice, PF-PC synaptic transmission is reduced during low-frequency stimulation. Using focal light stimulation of GCs that express optogenetic light-sensitive channels, channelrhodopsin-2, we found that modulation of PC firing via GC input is reduced in quirky mice. Phenotypic analysis revealed that quirky mice display ataxia, dyskinesia and absence epilepsy. These results suggest that developmental alteration of patterned input confined to only one of the main afferent cerebellar excitatory synaptic pathways has a significant role in generating the neurological phenotype associated with the global genomic loss of P/Q-type channel function.

Maejima, Takashi; Wollenweber, Patric; Teusner, Lena U. C.; Noebels, Jeffrey L.; Herlitze, Stefan; Mark, Melanie D.



Sequential steps of carbohydrate signaling mediate sensory afferent differentiation.  


Differences in carbohydrate signaling control sequential steps in synaptic growth of sensory afferents in the leech. The relevant glycans are constitutive and developmentally regulated modifications of leechCAM and Tractin (family members of NCAM and L1) that are specific to the surface of sensory afferents. A mannosidic glycosylation mediates the dynamic growth of early afferents as they explore their target region through sprouting sensory arbors rich with synaptic vesicles. Later emerging galactosidic glycosylations serve as markers for subsets of the same sensory afferents that correlate with different sensory modalities. These developmentally regulated galactose markers now oppose the function of the constitutive mannose marker. Sensory afferents gain cell-cell contact with central neurons and self-similar afferents, but lose filopodia and synaptic vesicles. Extant vesicles are confined to sites of en passant synapse formation. The transformation of sensory afferent growth, progressing from mannose- to galactose-specific recognition, is consistent with a change from cell-matrix to cell-cell contact. While the constitutive mannosidic glycosylation promotes dynamic growth, developmentally regulated galactosidic glycosylations of the same cell adhesion molecules promote tissue stability. The persistence of both types of neutral glycans beyond embryonic age allows their function in synaptic plasticity during habituation and learning. PMID:14501211

Tai, Mei-Hui; Zipser, Birgit


The effects of geometrical parameters on synaptic transmission: a Monte Carlo simulation study.  

PubMed Central

Monte Carlo simulations of transmitter diffusion and its interactions with postsynaptic receptors have been used to study properties of quantal responses at central synapses. Fast synaptic responses characteristic of those recorded at glycinergic junctions on the teleost Mauthner cell (time to peak approximately 0.3-0.4 ms and decay time constant approximately 3-6 ms) served as the initial reference, and smaller contacts with fewer postsynaptic receptors were also modeled. Consistent with experimental findings, diffusion, simulated using a random walk algorithm and assuming a diffusion coefficient of 0.5-1.0 x 10(-5) cm2 s(-1), was sufficiently fast to account for transmitter removal from the synaptic cleft. Transmitter-receptor interactions were modeled as a two-step binding process, with the double-bound state having opened and closed conformations. Addition of a third binding step only slightly decreased response amplitude but significantly slowed both its rising and decay phases. The model allowed us to assess the sources of response variability and the likelihood of postsynaptic saturation as functions of multiple kinetic and spatial parameters. The method of nonstationary fluctuation analysis, typically used to estimate the number of functional channels at a synapse and single channel current, proved unreliable, presumably because the receptors in the postsynaptic matrix are not uniformly exposed to the same profile of transmitter concentration. Thus, the time course of the probability of channel opening most likely varies among receptors. Finally, possible substrates for phenomena of synaptic plasticity, such as long-term potentiation, were explored, including the diameter of the contact zone, defined by the region of pre- and postsynaptic apposition, the number and distribution of the receptors, and the degree of vesicle filling. Surprisingly, response amplitude is quite sensitive to the size of the receptor-free annulus surrounding the receptor cluster, such that expansion of the contact zone could produce an appreciable increase in quantal size, normally attributed to either the presence of more receptors or the release of more transmitter molecules. Images FIGURE 1 FIGURE 3 FIGURE 9

Kruk, P J; Korn, H; Faber, D S



Non-pain-related CRF1 activation in the amygdala facilitates synaptic transmission and pain responses  

PubMed Central

Background Corticotropin-releasing factor (CRF) plays an important role in affective states and disorders. CRF is not only a “stress hormone” but also a neuromodulator outside the hypothalamic-pituitary-adrenocortical (HPA) axis. The amygdala, a brain center for emotions, is a major site of extrahypothalamic expression of CRF and its G-protein-coupled receptors. Our previous studies showed that endogenous activation of CRF1 receptors in an arthritis pain model contributes to amygdala hyperactivity and pain-related behaviors. Here we examined the synaptic and behavioral effects of CRF in the amygdala of normal animals in the absence of tissue injury or disease. Results Whole-cell patch-clamp recordings of neurons in the latero-capsular division of the central nucleus of the amygdala (CeLC) in brain slices from normal rats showed that CRF (0.1-10 nM) increased excitatory postsynaptic currents (EPSCs) at the “nociceptive” parabrachio-amygdaloid (PB-CeLC) synapse and also increased neuronal output. Synaptic facilitation involved a postsynaptic action and was blocked by an antagonist for CRF1 (NBI27914, 1 ?M) but not CRF2 (astressin-2B, 1 ?M) and by an inhibitor of PKA (KT5720, 1 ?M) but not PKC (GF109203X, 1 ?M). CRF increased a latent NMDA receptor-mediated EPSC, and this effect also required CRF1 and PKA but not CRF2 and PKC. Stereotaxic administration of CRF (10 ?M, concentration in microdialysis probe) into the CeLC by microdialysis in awake rats increased audible and ultrasonic vocalizations and decreased hindlimb withdrawal thresholds. Behavioral effects of CRF were blocked by a NBI27914 (100 ?M) and KT5720 (100 ?M) but not GF109203x (100 ?M). CRF effects persisted when HPA axis function was suppressed by pretreatment with dexamethasone (50 ?g/kg, subcutaneously). Conclusions Non-pain-related activation of CRF1 receptors in the amygdala can trigger pain-responses in normal animals through a mechanism that involves PKA-dependent synaptic facilitation in CeLC neurons independent of HPA axis function. The results suggest that conditions of increased amygdala CRF levels can contribute to pain in the absence of tissue pathology or disease state.



Modulation of hippocampal synaptic transmission by low concentrations of cell-permeant Ca 2+ chelators: effects of Ca 2+ affinity, chelator structure and binding kinetics  

Microsoft Academic Search

Calcium chelators are commonly used for fluorescence and electrophysiological studies of neuronal Ca2+ signalling. Recently, they have also been used as neuroprotectants. Since they buffer calcium ions, these agents also modify the same signals which are being studied. These properties may be used to modulate Ca2+ signals such as those involved in synaptic transmission, and may explain their neuroprotective mechanism.

I Spigelman; M Tymianski; C. M Wallace; P. L Carlen; A. A Velumian



High dose folic acid supplementation of rats alters synaptic transmission and seizure susceptibility in offspring  

PubMed Central

Maternal folic acid supplementation is essential to reduce the risk of neural tube defects. We hypothesize that high levels of folic acid throughout gestation may produce neural networks more susceptible to seizure in offspring. We hence administered large doses of folic acid to rats before and during gestation and found their offspring had a 42% decrease in their seizure threshold. In vitro, acute application of folic acid or its metabolite 4Hfolate to neurons induced hyper-excitability and bursting. Cultured neuronal networks which develop in the presence of a low concentration (50?nM) of 4Hfolate had reduced capacity to stabilize their network dynamics after a burst of high-frequency activity, and an increase in the frequency of mEPSCs. Networks reared in the presence of the folic acid metabolite 5M4Hfolate developed a spontaneous, distinctive bursting pattern, and both metabolites produced an increase in synaptic density.

Girotto, Fernando; Scott, Lucas; Avchalumov, Yosef; Harris, Jacqueline; Iannattone, Stephanie; Drummond-Main, Chris; Tobias, Rose; Bello-Espinosa, Luis; Rho, Jong M.; Davidsen, Jorn; Teskey, G. Campbell; Colicos, Michael A.



High dose folic acid supplementation of rats alters synaptic transmission and seizure susceptibility in offspring.  


Maternal folic acid supplementation is essential to reduce the risk of neural tube defects. We hypothesize that high levels of folic acid throughout gestation may produce neural networks more susceptible to seizure in offspring. We hence administered large doses of folic acid to rats before and during gestation and found their offspring had a 42% decrease in their seizure threshold. In vitro, acute application of folic acid or its metabolite 4Hfolate to neurons induced hyper-excitability and bursting. Cultured neuronal networks which develop in the presence of a low concentration (50 nM) of 4Hfolate had reduced capacity to stabilize their network dynamics after a burst of high-frequency activity, and an increase in the frequency of mEPSCs. Networks reared in the presence of the folic acid metabolite 5M4Hfolate developed a spontaneous, distinctive bursting pattern, and both metabolites produced an increase in synaptic density. PMID:23492951

Girotto, Fernando; Scott, Lucas; Avchalumov, Yosef; Harris, Jacqueline; Iannattone, Stephanie; Drummond-Main, Chris; Tobias, Rose; Bello-Espinosa, Luis; Rho, Jong M; Davidsen, Jörn; Teskey, G Campbell; Colicos, Michael A



Synaptic vesicle endocytosis.  


Neurons can sustain high rates of synaptic transmission without exhausting their supply of synaptic vesicles. This property relies on a highly efficient local endocytic recycling of synaptic vesicle membranes, which can be reused for hundreds, possibly thousands, of exo-endocytic cycles. Morphological, physiological, molecular, and genetic studies over the last four decades have provided insight into the membrane traffic reactions that govern this recycling and its regulation. These studies have shown that synaptic vesicle endocytosis capitalizes on fundamental and general endocytic mechanisms but also involves neuron-specific adaptations of such mechanisms. Thus, investigations of these processes have advanced not only the field of synaptic transmission but also, more generally, the field of endocytosis. This article summarizes current information on synaptic vesicle endocytosis with an emphasis on the underlying molecular mechanisms and with a special focus on clathrin-mediated endocytosis, the predominant pathway of synaptic vesicle protein internalization. PMID:22763746

Saheki, Yasunori; De Camilli, Pietro



Effect of conduction block at axon bifurcations on synaptic transmission to different postsynaptic neurones in the leech.  

PubMed Central

1. The cutaneous receptive field of the medial pressure (mP) sensory neurone in the leech has been examined. The cell has one major receptive field and an anterior and a posterior minor receptive field, principally on lateral and dorsal skin. The two minor receptive fields are contiguous with the major receptive field and are innervated by fine anterior and posterior axons, but there is no overlap between major and minor receptive fields. 2. At low frequencies of stimulation of the minor receptive fields, conduction block takes place in the mP cell at the central branch point within the leech ganglion. 3. The mP cell synapses directly with many other cells in the leech ganglion, including the anterior pagoda (AP) cell, longitudinal (L) motoneurone and the annulus erector (AE) motoneurone, which were studied as a group of postsynaptic neurones. Conduction block in the mP cell affects its synaptic transmission to all three postsynaptic neurones, but the effect can be different in different postsynaptic neurones. Block at the central branch point for an impulse travelling along the anterior axon reduces transmission to the AE cell much more than to the AP or L cells, while block at the central branch for an impulse travelling along the posterior axon has the reverse effect. 4. The distribution of functional connections of the branches of the mP cell with each postsynaptic cell was studied. For this analysis, branches of the mP cell were selectively silenced either during conduction block or by laser microsurgery. Generally, nearly all of the functional connections with the L and AP cell are made by anterior branches of the mP cell while the connection with the AE cell was primarily made by posterior branches of the mP cell. 5. The possible sites of contact between the mP cell and postsynaptic cells were determined by injecting separate markers into the mP cell and a postsynaptic cell. In confirmation of physiology, the mP cell's posterior branches had few, if any, contacts with the AP cell, while anterior branches had few, if any, contacts upon the AE cell. 6. Conduction block can thus act as a switch in the central nervous system (CNS), altering the mP cell's pattern of synaptic transmission to different postsynaptic neurons depending upon the region of a single sensory neurone's receptive field that is stimulated. This effect, dependent upon inputs to a single neurone, may be expected to influence the performance of the system and its outputs. Images Fig. 2 Fig. 9 Fig. 10 Fig. 11

Gu, X N



Major impairments of glutamatergic transmission and long-term synaptic plasticity in the hippocampus of mice lacking the melanin-concentrating hormone receptor-1.  


The hypothalamic neuropeptide melanin-concentrating hormone (MCH) plays important roles in energy homeostasis, anxiety, and sleep regulation. Since the MCH receptor-1 (MCH-R1), the only functional receptor that mediates MCH functions in rodents, facilitates behavioral performance in hippocampus-dependent learning tasks, we investigated whether glutamatergic transmission in CA1 pyramidal cells could be modulated in mice lacking the MCH-R1 gene (MCH-R1(-/-)). We found that both ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartate (NMDA) receptor-mediated transmissions were diminished in the mutant mice compared with their controls. This deficit was explained, at least in part, by a postsynaptic down-regulation of these receptors since the amplitude of miniature excitatory postsynaptic currents and the NMDA/AMPA ratio were decreased. Long-term synaptic potentiation (LTP) was also impaired in MCH-R1(-/-) mice. This was due to an altered induction, rather than an impaired, expression because repeating the induction stimulus restored LTP to a normal magnitude. In addition, long-term synaptic depression was strongly diminished in MCH-R1(-/-) mice. These results suggest that MCH exerts a facilitatory effect on CA1 glutamatergic synaptic transmission and long-term synaptic plasticity. Recently, it has been shown that MCH neurons fire exclusively during sleep and mainly during rapid eye movement sleep. Thus these findings provide a mechanism by which sleep might facilitate memory consolidation. PMID:20592115

Pachoud, Bastien; Adamantidis, Antoine; Ravassard, Pascal; Luppi, Pierre-Hervé; Grisar, Thierry; Lakaye, Bernard; Salin, Paul-Antoine



Corticotrophin-releasing hormone decreases synaptic transmission in rat sensorimotor cortex in vivo.  


Corticotrophin-releasing hormone is a key regulator of the mammalian stress response. Although its actions on behavior are well documented, the actions of corticotrophin-releasing hormone in cortical neuronal systems are poorly understood. In the present experiments, adult male Sprague-Dawley rats were anesthetized and field excitatory post-synaptic potential recordings were made from sensorimotor cortex layer II/III and layer V cells. Infusions of corticotrophin-releasing hormone (100 ng/nl) directly into the sensorimotor cortex produced a significant depression of the initial excitatory component of evoked responses that could be prevented by prior administration of a corticotrophin-releasing hormone antagonist. Although requiring the activation of corticotrophin-releasing hormone receptors, the depression was also dependent upon N-methyl-D-aspartate receptor activity and could be blocked by the competitive N-methyl-D-aspartate antagonist -3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonate. These findings demonstrate that corticotrophin-releasing hormone has a novel depressant-like action in sensorimotor cortex in vivo that may play a role in modulating motor activity during periods of stress. PMID:16019154

Froc, D J; Christie, B R



A Genetic Survey of Fluoxetine Action on Synaptic Transmission in Caenorhabditis elegans  

PubMed Central

Fluoxetine is one of the most commonly prescribed medications for many behavioral and neurological disorders. Fluoxetine acts primarily as an inhibitor of the serotonin reuptake transporter (SERT) to block the removal of serotonin from the synaptic cleft, thereby enhancing serotonin signals. While the effects of fluoxetine on behavior are firmly established, debate is ongoing whether inhibition of serotonin reuptake is a sufficient explanation for its therapeutic action. Here, we provide evidence of two additional aspects of fluoxetine action through genetic analyses in Caenorhabditis elegans. We show that fluoxetine treatment and null mutation in the sole SERT gene mod-5 eliminate serotonin in specific neurons. These neurons do not synthesize serotonin but import extracellular serotonin via MOD-5/SERT. Furthermore, we show that fluoxetine acts independently of MOD-5/SERT to regulate discrete properties of acetylcholine (Ach), gamma-aminobutyric acid (GABA), and glutamate neurotransmission in the locomotory circuit. We identified that two G-protein–coupled 5-HT receptors, SER-7 and SER-5, antagonistically regulate the effects of fluoxetine and that fluoxetine binds to SER-7. Epistatic analyses suggest that SER-7 and SER-5 act upstream of AMPA receptor GLR-1 signaling. Our work provides genetic evidence that fluoxetine may influence neuronal functions and behavior by directly targeting serotonin receptors.

Kullyev, Andrey; Dempsey, Catherine M.; Miller, Sarah; Kuan, Chih-Jen; Hapiak, Vera M.; Komuniecki, Richard W.; Griffin, Christine T.; Sze, Ji Ying



Neuropeptide S-Mediated Facilitation of Synaptic Transmission Enforces Subthreshold Theta Oscillations within the Lateral Amygdala  

PubMed Central

The neuropeptide S (NPS) receptor system modulates neuronal circuit activity in the amygdala in conjunction with fear, anxiety and the expression and extinction of previously acquired fear memories. Using in vitro brain slice preparations of transgenic GAD67-GFP (?neo) mice, we investigated the effects of NPS on neural activity in the lateral amygdala as a key region for the formation and extinction of fear memories. We are able to demonstrate that NPS augments excitatory glutamatergic synaptic input onto both projection neurons and interneurons of the lateral amygdala, resulting in enhanced spike activity of both types of cells. These effects were at least in part mediated by presynaptic mechanisms. In turn, inhibition of projection neurons by local interneurons was augmented by NPS, and subthreshold oscillations were strengthened, leading to their shift into the theta frequency range. These data suggest that the multifaceted effects of NPS on amygdaloid circuitry may shape behavior-related network activity patterns in the amygdala and reflect the peptide's potent activity in various forms of affective behavior and emotional memory.

Meis, Susanne; Stork, Oliver; Munsch, Thomas



CB2 cannabinoid receptors inhibit synaptic transmission when expressed in cultured autaptic neurons  

PubMed Central

The role of CB2 in the central nervous system, particularly in neurons, has generated much controversy. Fueling the controversy are imperfect tools, which have made conclusive identification of CB2-expressing neurons problematic. Imprecise localization of CB2 has made it difficult to determine its function in neurons. Here we avoid the localization controversy and directly address the question if CB2 can modulate neurotransmission. CB2 was expressed in excitatory hippocampal autaptic neurons obtained from CB1 null mice. Whole-cell patch clamp recordings were made from these neurons to determine the effects of CB2 on short-term synaptic plasticity. CB2 expression restored depolarization induced suppression of excitation to these neurons, which was lost following genetic ablation of CB1. The endocannabinoid 2-arachidonylglycerol (2-AG) mimicked the effects of depolarization in CB2 expressing neurons. Interestingly, ongoing basal production of 2-AG resulted in constitutive activation of CB2, causing a tonic inhibition of neurotransmission that was relieved by the CB2 antagonist AM630 or the diacylglycerol lipase inhibitor RHC80267. Through immunocytochemistry and analysis of spontaneous EPSCs, paired pulse ratios and coefficients of variation we determined that CB2 exerts its function at a presynaptic site of action, likely through inhibition of voltage gated calcium channels. Therefore CB2 expressed in neurons effectively mimics the actions of CB1. Thus, neuronal CB2 is well suited to integrate into conventional neuronal endocannabinoid signaling processes, with its specific role determined by its unique and highly inducible expression profile.

Atwood, Brady K.; Straiker, Alex; Mackie, Ken



Long-term Potentiation of Inhibitory Synaptic Transmission onto Cerebellar Purkinje Neurons Contributes to Adaptation of Vestibulo-Ocular Reflex.  


Synaptic plasticity in the cerebellum is thought to contribute to motor learning. In particular, long-term depression (LTD) at parallel fiber (PF) to Purkinje neuron (PN) excitatory synapses has attracted much attention of neuroscientists as a primary cellular mechanism for motor learning. In contrast, roles of plasticity at cerebellar inhibitory synapses in vivo remain unknown. Here, we have investigated the roles of long-lasting enhancement of transmission at GABAergic synapses on a PN that is known as rebound potentiation (RP). Previous studies demonstrated that binding of GABAA receptor with GABAA receptor-associated protein (GABARAP) is required for RP, and that a peptide that blocks this binding suppresses RP induction. To address the functional roles of RP, we generated transgenic mice that express this peptide fused to a fluorescent protein selectively in PNs using the PN-specific L7 promoter. These mice failed to show RP, although they showed no changes in the basal amplitude or frequency of miniature IPSCs. The transgenic mice also showed no abnormality in gross cerebellar morphology, LTD, or other excitatory synaptic properties, or intrinsic excitability of PNs. Next, we attempted to evaluate their motor control and learning ability by examining reflex eye movements. The basal dynamic properties of the vestibulo-ocular reflex and optokinetic response, and adaptation of the latter, were normal in the transgenic mice. In contrast, the transgenic mice showed defects in the adaptation of vestibulo-ocular reflex, a model paradigm of cerebellum-dependent motor learning. These results together suggest that RP contributes to a certain type of motor learning. PMID:24155325

Tanaka, Shinsuke; Kawaguchi, Shin-Ya; Shioi, Go; Hirano, Tomoo



Isoflurane-sensitive presynaptic R-type calcium channels contribute to inhibitory synaptic transmission in the rat thalamus  

PubMed Central

Since inhibitory synaptic transmission is a major mechanism of general anesthesia, we examined the effects of isoflurane on properties of GABAergic inhibitory currents in the reticular thalamic nucleus (nRT) in brain slices. The evoked inhibitory postsynaptic currents (eIPSCs) and spontaneous miniature synaptic currents (mIPSCs) of visualized nRT cells in young and adult rats were recorded. Consistent with postsynaptic effects on GABAA receptors, isoflurane prolonged the decay-time constants of both eIPSCs and mIPCSs. Surprisingly, isoflurane completely inhibited the amplitude of eIPSCs at clinically relevant concentrations (IC50 of 240 ± 20 ?M), increased the paired-pulse ratio, and decreased the frequency of mIPSCs, indicating that presynaptic mechanisms may also contribute to the effects of isoflurane on IPSCs. The overall effect of isoflurane on eIPSCs in nRT cells was a decrease of net charge-transfer across the postsynaptic membrane. The application of 100 ?M nickel (Ni2+) and the more specific R-type Ca2+ channel blocker SNX-482 (0.5 ?M) decreased eIPSC amplitudes, increased the paired-pulse ratio, and attenuated isoflurane-induced inhibition of eIPSCs. In addition, isoflurane potently blocked currents in recombinant human CaV2.3 (?1E) channels with an IC50 of 206 ± 22 ?M. Importantly, in vivo electroencephalographic (EEG) recordings in adult CaV2.3 knockout mice demonstrated alterations in isoflurane-induced burst-suppression activity. Because the thalamus has a key function in processing sensory information, sleep, and cognition, modulation of its GABAergic tone by presynaptic R-type Ca2+ channels may contribute to the clinical effects of general anesthesia.

Joksovic, Pavle M.; Weiergraber, Marco; Lee, WooYong; Struck, Henrik; Schneider, Toni; Todorovic, Slobodan M.



How synaptic release probability shapes neuronal transmission: Information theoretic analysis in a cerebellar granule cell  

Microsoft Academic Search

A nerve cell receives multiple inputs from upstream neurons by way of its synapses. Neuron processing functions are thus influenced by changes in the biophysical properties of the synapse, such as long-term potentiation (LTP) or depression (LTD). This observation has opened new perspectives on the biophysical basis of learning and memory, but its quantitative impact on the information transmission of

Angelo Arleo; Thierry Nieus; Michele Bezzi; Anna D'Errico; Egidio D'Angelo; Olivier J.-M. D. Coenen



A phorbol diester-induced enhancement of synaptic transmission in olfactory cortex.  

PubMed Central

1. Extracellular field synaptic potentials were recorded from pial surface slices of guinea-pig olfactory cortex maintained in vitro. 2. Phorbol 12,13-dibutyrate (0.1-10 microM) enhanced the amplitude of the evoked potential (by 51.2 +/- 10.4% with 1 microM) in normal solution. When the evoked potential was partially depressed by Cd, Co, Mn or a reduced Ca concentration, phorbol 12,13-dibutyrate (1 microM) induced a much larger enhancement of the evoked potential (196.5 +/- 24.4% increase). Phorbol 12,13-diacetate and mezerein had similar effects but were less potent. 4 beta-Phorbol (10 microM) had no effect. 3. The diacylglycerol analogues, dioctanoylglycerol (100-1000 microM), 1-oleoyl-2-acetylglycerol (100-500 microM) or diolein (100 microM) had no effect on the evoked potentials, either alone or in the presence of Cd. 4. The isoquinolinylsulphonamide inhibitor (H-7) of protein kinase C slightly enhanced the e.p.s.p. and had no effect on the potentiation produced by phorbol ester. Another protein kinase C inhibitor, acridine orange (100-1000 microM), had no effect on the action of phorbol ester. 5. These results show that transmitter release, as at other synapses, is enhanced by phorbol esters but Ca did not potentiate this action. The pharmacological profile of the effect on transmitter release differed from that of protein kinase C in cell-free preparations and therefore it is unclear whether protein kinase C was involved in the present study.

Scholfield, C. N.; Smith, A. J.



A phorbol diester-induced enhancement of synaptic transmission in olfactory cortex.  


1. Extracellular field synaptic potentials were recorded from pial surface slices of guinea-pig olfactory cortex maintained in vitro. 2. Phorbol 12,13-dibutyrate (0.1-10 microM) enhanced the amplitude of the evoked potential (by 51.2 +/- 10.4% with 1 microM) in normal solution. When the evoked potential was partially depressed by Cd, Co, Mn or a reduced Ca concentration, phorbol 12,13-dibutyrate (1 microM) induced a much larger enhancement of the evoked potential (196.5 +/- 24.4% increase). Phorbol 12,13-diacetate and mezerein had similar effects but were less potent. 4 beta-Phorbol (10 microM) had no effect. 3. The diacylglycerol analogues, dioctanoylglycerol (100-1000 microM), 1-oleoyl-2-acetylglycerol (100-500 microM) or diolein (100 microM) had no effect on the evoked potentials, either alone or in the presence of Cd. 4. The isoquinolinylsulphonamide inhibitor (H-7) of protein kinase C slightly enhanced the e.p.s.p. and had no effect on the potentiation produced by phorbol ester. Another protein kinase C inhibitor, acridine orange (100-1000 microM), had no effect on the action of phorbol ester. 5. These results show that transmitter release, as at other synapses, is enhanced by phorbol esters but Ca did not potentiate this action. The pharmacological profile of the effect on transmitter release differed from that of protein kinase C in cell-free preparations and therefore it is unclear whether protein kinase C was involved in the present study. PMID:2558761

Scholfield, C N; Smith, A J



Dissociation of ?- and ?-opioid inhibition of glutamatergic synaptic transmission in superficial dorsal horn  

PubMed Central

Background There is anatomical and behavioural evidence that ?- and ?-opioid receptors modulate distinct nociceptive modalities within the superficial dorsal horn. The aim of the present study was to examine whether ?- and ?-opioid receptor activation differentially modulates TRP sensitive inputs to neurons within the superficial dorsal horn. To do this, whole cell patch clamp recordings were made from lamina I - II neurons in rat spinal cord slices in vitro to examine the effect of opioids on TRP agonist-enhanced glutamatergic spontaneous miniature excitatory postsynaptic currents (EPSCs). Results Under basal conditions the ?-opioid agonist DAMGO (3 ?M) reduced the rate of miniature EPSCs in 68% of neurons, while the ?- and ?-opioid agonists deltorphin-II (300 nM) and U69593 (300 nM) did so in 13 - 17% of neurons tested. The TRP agonists menthol (400 ?M) and icilin (100 ?M) both produced a Ca2+-dependent increase in miniature EPSC rate which was unaffected by the voltage dependent calcium channel (VDCC) blocker Cd2+. The proportion of neurons in which deltorphin-II reduced the miniature EPSC rate was enhanced in the presence of icilin (83%), but not menthol (0%). By contrast, the proportion of DAMGO and U69593 responders was unaltered in the presence of menthol (57%, 0%), or icilin (57%, 17%). Conclusions These findings demonstrate that ?-opioid receptor activation selectively inhibits inputs activated by icilin, whereas ?-opioid receptor activation has a more widespread effect on synaptic inputs to neurons in the superficial dorsal horn. These findings suggest that ?-opioids may provide a novel analgesic approach for specific, TRPA1-like mediated pain modalities.



Sparse but Selective and Potent Synaptic Transmission From the Globus Pallidus to the Subthalamic Nucleus  

PubMed Central

The reciprocally connected GABAergic globus pallidus (GP)-glutamatergic subthalamic nucleus (STN) network is critical for voluntary movement and an important site of dysfunction in movement disorders such as Parkinson's disease. Although the GP is a key determinant of STN activity, correlated GP-STN activity is rare under normal conditions. Here we define fundamental features of the GP-STN connection that contribute to poorly correlated GP-STN activity. Juxtacellular labeling of single GP neurons in vivo and stereological estimation of the total number of GABAergic GP-STN synapses suggest that the GP-STN connection is surprisingly sparse: single GP neurons maximally contact only 2% of STN neurons and single STN neurons maximally receive input from 2% of GP neurons. However, GP-STN connectivity may be considerably more selective than even these estimates imply. Light and electron microscopic analyses revealed that single GP axons give rise to sparsely distributed terminal clusters, many of which correspond to multiple synapses with individual STN neurons. Application of the minimal stimulation technique in brain slices confirmed that STN neurons receive multisynaptic unitary inputs and that these inputs largely arise from different sets of GABAergic axons. Finally, the dynamic-clamp technique was applied to quantify the impact of GP-STN inputs on STN activity. Small fractions of GP-STN input were sufficiently powerful to inhibit and synchronize the autonomous activity of STN neurons. Together these data are consistent with the conclusion that the rarity of correlated GP-STN activity in vivo is due to the sparsity and selectivity, rather than the potency, of GP-STN synaptic connections.

Baufreton, Jerome; Kirkham, Erin; Atherton, Jeremy F.; Menard, Ariane; Magill, Peter J.; Bolam, J. Paul; Bevan, Mark D.



Metabotropic glutamate receptor 2 modulates excitatory synaptic transmission in the rat globus pallidus  

Microsoft Academic Search

While group II metabotropic glutamate receptors (mGluRs) are known to be expressed in the rat globus pallidus (GP), their functions remain poorly understood. We used standard patch clamping technique in GP slices to determine the effect of group II mGluR activation on excitatory transmission in this region. Activation of group II mGluRs with the group-selective agonist DCG-IV or APDC reduced

Olga Poisik; Dinesh V. Raju; Marc Verreault; Alice Rodriguez; Oluseyi A. Abeniyi; P. Jeffrey Conn; Yoland Smith



A novel synaptic transmission mediated by a PACAP-like neuropeptide in drosophila  

Microsoft Academic Search

Neuropeptide-mediated transmission was analyzed at Drosophila larval body-wall neuromuscular junctions. Focal application of vertebrate pituitary adenylyl cyclase-activating polypeptide (PACAP38) to the neuromuscular junction region triggered two temporally distinct muscle responses: an immediate depolarization followed by a large enhancement of K+ current. This late enhancement occurred many minutes after the early depolarization. High frequency stimulation of motor nerve fibers evoked a

Yi Zhong; Louis A Peńa



Modulation of inhibitory and excitatory synaptic transmission in rat inferior colliculus after unilateral cochleectomy: an in situ and immunofluorescence study.  


We investigated whether inhibitory synaptic transmission mediated through glycinergic receptor, GABAA receptors, glutamic acid decarboxylase, the enzyme synthesizing GABA, and excitatory synaptic transmission through alpha-amino-3-hydroxi-5-methylisoxazole-4-propionic acid receptors and N-methyl-D-aspartate receptors are affected in the inferior colliculus by unilateral surgical cochleectomy. In situ hybridization and immunohistofluorescence studies were performed in normal and lesioned adult rats at various times following the lesion (1-150 days). Unilateral auditory deprivation decreased glycine receptor alpha1 and glutamic acid decarboxylase 67 expression in the contralateral central nucleus of the inferior colliculus. This decrease began one day after cochleectomy, and continued until day 8; thereafter expression was consistently low until day 150. The glycine receptor alpha1 subunit decrease did not occur if a second contralateral cochleectomy was performed either on day 8 or 150 after the first cochleectomy. Bilateral cochleectomy caused also a bilateral inferior colliculus diminution of glutamic acid decarboxylase 67 mRNA at post-lesion day 8 but there were no changes in glycine receptor alpha1 compared with controls. In contrast, the abundance of other alpha2-3, and beta glycine receptor, gephyrin, the anchoring protein of glycine receptor, the alpha1, beta2 and gamma2 subunits of GABAA receptors, GluR2, R3 subunits of alpha-amino-3-hydroxi-5-methylisoxazole-4-propionic acid receptors, and NR1 and NR2A transcripts of N-methyl-D-aspartate receptors was unaffected during the first week following the lesion. Thus, unilateral cochlear removal resulted in a selective and long-term decrease in the amount of the glycine receptor alpha1 subunit and of glutamic acid decarboxylase 67 in the contralateral central nucleus of the inferior colliculus. These changes most probably result from the induced asymmetry of excitatory auditory inputs into the central nucleus of the inferior colliculus and may be one of the mechanisms involved in the tinnitus frequently encountered in patients suffering from a sudden hearing loss. PMID:16757119

Argence, M; Saez, I; Sassu, R; Vassias, I; Vidal, P P; de Waele, C



Pre- and postnatal propylthiouracil-induced hypothyroidism impairs synaptic transmission and plasticity in area CA1 of the neonatal rat hippocampus.  


Thyroid hormones are essential for neonatal brain development. It is well established that insufficiency of thyroid hormone during critical periods of development can impair cognitive functions. The mechanisms that underlie learning deficits in hypothyroid animals, however, are not well understood. As impairments in synaptic function are likely to contribute to cognitive deficits, the current study tested whether thyroid hormone insufficiency during development would alter quantitative characteristics of synaptic function in the hippocampus. Developing rats were exposed in utero and postnatally to 0, 3, or 10 ppm propylthiouracil (PTU), a thyroid hormone synthesis inhibitor, administered in the drinking water of dams from gestation d 6 until postnatal day (PN) 30. Excitatory postsynaptic potentials and population spikes were recorded from the stratum radiatum and the pyramidal cell layer, respectively, in area CA1 of hippocampal slices from offspring between PN21 and PN30. Baseline synaptic transmission was evaluated by comparing input-output relationships between groups. Paired-pulse facilitation, paired-pulse depression, long-term potentiation, and long-term depression were recorded to examine short- and long-term synaptic plasticity. PTU reduced thyroid hormones, reduced body weight gain, and delayed eye-opening in a dose-dependent manner. Excitatory synaptic transmission was increased by developmental exposure to PTU. Thyroid hormone insufficiency was also dose-dependently associated with a reduction paired-pulse facilitation and long-term potentiation of the excitatory postsynaptic potential and elimination of paired-pulse depression of the population spike. The results indicate that thyroid hormone insufficiency compromises the functional integrity of synaptic communication in area CA1 of developing rat hippocampus and suggest that these changes may contribute to learning deficits associated with developmental hypothyroidism. PMID:12933695

Sui, Li; Gilbert, M E



Amino acid receptor mediated excitatory synaptic transmission in the cat red nucleus.  

PubMed Central

A study has been made of the effects of the selective N-methyl-D-aspartate receptor antagonist, 2-amino-5-phosphonovalerate (APV), and the broad spectrum excitatory amino acid antagonists, gamma-D-glutamylglycine (gamma-DGG), gamma-D-glutamylaminomethylsulphonate (GAMS), 4(p-chlorobenzoyl)-cis-piperazine-2, 3-dicarboxylate (pCB-PzDA) and kynurenate, have been examined on excitation evoked on neurones in the magnocellular red nucleus (m.r.n.) of the anaesthetized cat by stimulation of the interpositus nucleus (i.p.n.) and sensorimotor cortex, and by ionophoresed excitant amino acid agonists. The profile of activity of the excitatory amino acid antagonists on m.r.n. neurones was similar to that described on neurones in other areas of the central nervous system. APV selectively depressed responses to N-methyl-D-aspartate (NMDA), whereas the broader spectrum antagonists reduced responses to kainate and quisqualate as well as to NMDA. Neuronal responses to L-glutamate and L-aspartate were depressed by all the antagonists tested. I.p.n.-evoked monosynaptic responses of m.r.n. neurones were reversibly reduced by the broad spectrum antagonists, but were unaffected by APV. Cortically evoked mono- and polysynaptic excitatory responses were reversibly depressed by APV and the broad spectrum antagonist, pCB-PzDA. The action of APV corresponded with its ability to antagonize responses to NMDA. However, the cortically evoked responses appeared to be more sensitive to the actions of pCB-PzDA than to those of APV, although the former is a less effective antagonist of NMDA-induced excitation compared with APV. APV depressed excitation induced by cortical stimuli and L-glutamate and L-aspartate. However, there was no obvious correlation between the actions of the broad spectrum amino acid antagonists on synaptically evoked responses and those induced by L-glutamate or L-aspartate on the few neurones tested. These results are consistent with an amino acid being the transmitter in the interposito-rubral and cortico-rubral excitatory pathways which interacts with non-NMDA and both NMDA and non-NMDA receptors respectively. However, the identity of the transmitter acting at these receptors remains to be determined. Images Fig. 1

Davies, J; Miller, A J; Sheardown, M J



Reduction of the cholesterol sensor SCAP in the brains of mice causes impaired synaptic transmission and altered cognitive function.  


The sterol sensor SCAP is a key regulator of SREBP-2, the major transcription factor controlling cholesterol synthesis. Recently, we showed that there is a global down-regulation of cholesterol synthetic genes, as well as SREBP-2, in the brains of diabetic mice, leading to a reduction of cholesterol synthesis. We now show that in mouse models of type 1 and type 2 diabetes, this is, in part, the result of a decrease of SCAP. Homozygous disruption of the Scap gene in the brains of mice causes perinatal lethality associated with microcephaly and gliosis. Mice with haploinsufficiency of Scap in the brain show a 60% reduction of SCAP protein and ~30% reduction in brain cholesterol synthesis, similar to what is observed in diabetic mice. This results in impaired synaptic transmission, as measured by decreased paired pulse facilitation and long-term potentiation, and is associated with behavioral and cognitive changes. Thus, reduction of SCAP and the consequent suppression of cholesterol synthesis in the brain may play an important role in the increased rates of cognitive decline and Alzheimer disease observed in diabetic states. PMID:23585733

Suzuki, Ryo; Ferris, Heather A; Chee, Melissa J; Maratos-Flier, Eleftheria; Kahn, C Ronald



The chemokine BRAK/CXCL14 regulates synaptic transmission in the adult mouse dentate gyrus stem cell niche.  


The chemokine BRAK/CXCL14 is an ancient member of the chemokine family whose functions in the brain are completely unknown. We examined the distribution of CXCL14 in the nervous system during development and in the adult. Generally speaking, CXCL14 was not expressed in the nervous system prior to birth, but it was expressed in the developing whisker follicles (E14.5) and subsequently in the hair follicles and skin. Postnatally, CXCL14 was also highly expressed in many regions of the brain, including the cortex, basal ganglia, septum and hippocampus. CXCL14 was also highly expressed in the dorsal root ganglia. We observed that in the hippocampal dentate gyrus (DG) CXCL14 was expressed by GABAergic interneurons. We demonstrated that CXCL14 inhibited GABAergic transmission to nestin-EGFP-expressing neural stem/progenitor cells in the adult DG. CXCL14 inhibited both the tonic and phasic effects of synaptically released GABA. In contrast CXCL12 enhanced the effects of GABA at these same synapses. CXCL14 increased [Ca(2+)](i) in neural stem cells cultured from the postnatal brain indicating that they expressed the CXCL14 receptor. These observations are consistent with the view that CXCL12 and CXCL14 may normally act as positive and negative regulators of the effects of GABA in the adult DG stem cell niche. PMID:21955359

Banisadr, Ghazal; Bhattacharyya, Bula J; Belmadani, Abdelhak; Izen, Sarah C; Ren, Dongjun; Tran, Phuong B; Miller, Richard J



Altered Neuronal Intrinsic Properties and Reduced Synaptic Transmission of the Rat's Medial Geniculate Body in Salicylate-Induced Tinnitus  

PubMed Central

Sodium salicylate (NaSal), an aspirin metabolite, can cause tinnitus in animals and human subjects. To explore neural mechanisms underlying salicylate-induced tinnitus, we examined effects of NaSal on neural activities of the medial geniculate body (MGB), an auditory thalamic nucleus that provides the primary and immediate inputs to the auditory cortex, by using the whole-cell patch-clamp recording technique in MGB slices. Rats treated with NaSal (350 mg/kg) showed tinnitus-like behavior as revealed by the gap prepulse inhibition of acoustic startle (GPIAS) paradigm. NaSal (1.4 mM) decreased the membrane input resistance, hyperpolarized the resting membrane potential, suppressed current-evoked firing, changed the action potential, and depressed rebound depolarization in MGB neurons. NaSal also reduced the excitatory and inhibitory postsynaptic response in the MGB evoked by stimulating the brachium of the inferior colliculus. Our results demonstrate that NaSal alters neuronal intrinsic properties and reduces the synaptic transmission of the MGB, which may cause abnormal thalamic outputs to the auditory cortex and contribute to NaSal-induced tinnitus.

Jin, Yan; Wu, Shu-Hui; Lobarinas, Edward; Salvi, Richard J.; Chen, Lin



Signaling mechanism underlying ?2A -adrenergic suppression of excitatory synaptic transmission in the medial prefrontal cortex of rats.  


Stimulation of ?2A -adrenoceptors (ARs) in the prefrontal cortex (PFC) produces a beneficial effect on cognitive functions such as working memory. A previous study in our laboratory showed that ?2A -AR stimulation suppresses excitatory synaptic transmission in layer V-VI pyramidal cells of the rat medial PFC (mPFC). However, the intracellular mechanism underlying the ?2A -AR suppression remains unclear. In the present study, we recorded evoked excitatory postsynaptic current (eEPSC) in layer V-VI pyramidal cells of the mPFC, using whole-cell patch-clamp recording. We found that the ?2A -AR agonist guanfacine significantly suppresses eEPSC in mPFC pyramidal cells. The ?2A -AR inhibition is mediated by the Gi-cAMP-PKA-PP1-CaMKII-AMPAR signaling pathway, as such inhibition no longer exists when each step of this pathway is blocked with NF023, Rp-cAMP, PKI5-24 or H89, tautomycin, and KN-62 or KN-93, respectively. PMID:23701442

Yi, Feng; Liu, Shu-Su; Luo, Fei; Zhang, Xue-Han; Li, Bao-Ming



Pretreatment of Guinea Pigs with Galantamine Prevents Immediate and Delayed Effects of Soman on Inhibitory Synaptic Transmission in the Hippocampus  

PubMed Central

Galantamine has emerged as a potential antidote to prevent the acute toxicity of organophosphorus (OP) compounds. Changes in inhibitory GABAergic activity in different brain regions can contribute to both induction and maintenance of seizures in subjects exposed to the OP nerve agent soman. Here, we tested the hypothesis that galantamine can prevent immediate and delayed effects of soman on hippocampal inhibitory synaptic transmission. Spontaneous inhibitory postsynaptic currents (IPSCs) were recorded from CA1 pyramidal neurons in hippocampal slices obtained at 1 h, 24 h, or 6 to 9 days after the injection of guinea pigs with saline (0.5 ml/kg i.m.), 1×LD50 soman (26.3 ?g/kg s.c.), galantamine (8 mg/kg i.m.), or galantamine at 30 min before soman. Soman-challenged animals that were not pretreated showed mild, moderate, or severe signs of acute intoxication. At 1 h after the soman injection, the mean IPSC amplitude recorded from slices of mildly intoxicated animals and the mean IPSC frequency recorded from slices of severely intoxicated animals were larger and lower, respectively, than those recorded from slices of control animals. Regardless of the severity of the acute toxicity, at 24 h after the soman challenge the mean IPSC frequency was lower than that recorded from slices of control animals. At 6 to 9 days after the challenge, the IPSC frequency had returned to control levels, whereas the mean IPSC amplitude became larger than control. Pretreatment with galantamine prevented soman-induced changes in IPSCs. Counteracting the effects of soman on inhibitory transmission can be an important determinant of the antidotal effectiveness of galantamine.

Alexandrova, Elena A.; Aracava, Yasco; Pereira, Edna F. R.



Growth hormone and insulin-like growth factor-I alter hippocampal excitatory synaptic transmission in young and old rats.  


In rats, as in humans, normal aging is characterized by a decline in hippocampal-dependent learning and memory, as well as in glutamatergic function. Both growth hormone (GH) and insulin-like growth factor-I (IGF-I) levels have been reported to decrease with age, and treatment with either GH or IGF-I can ameliorate age-related cognitive decline. Interestingly, acute GH and IGF-I treatments enhance glutamatergic synaptic transmission in the rat hippocampus of juvenile animals. However, whether this enhancement also occurs in old rats, when cognitive impairment is ameliorated by GH and IGF-I (des-IGF-I), remains to be determined. To address this issue, we used an in vitro CA1 hippocampal slice preparation and extracellular recording techniques to study the effects of acute application of GH and IGF-I on compound field excitatory postsynaptic potentials (fEPSPs), as well as AMPA- and NMDA-dependent fEPSPs, in young adult (10 months) and old (28 months) rats. The results indicated that both GH and IGF-I increased compound-, AMPA-, and NMDA-dependent fEPSPs to a similar extent in slices from both age groups and that this augmentation was likely mediated via a postsynaptic mechanism. Initial characterization of the signaling cascades underlying these effects revealed that the GH-induced enhancement was not mediated by the JAK2 signaling element in either young adult or old rats but that the IGF-I-induced enhancement involved a PI3K-mediated mechanism in old, but not young adults. The present findings are consistent with a role for a GH- or IGF-I-induced enhancement of glutamatergic transmission in mitigating age-related cognitive impairment in old rats. PMID:22851280

Molina, Doris P; Ariwodola, Olusegun J; Weiner, Jeff L; Brunso-Bechtold, Judy K; Adams, Michelle M



Inhibitory effects of dopamine on spinal synaptic transmission via dopamine D1-like receptors in neonatal rats  

PubMed Central

BACKGROUND AND PURPOSE Dopamine released from the endings of descending dopaminergic nerve fibres in the spinal cord may be involved in modulating functions such as locomotion and nociception. Here, we examined the effects of dopamine on spinal synaptic transmissions in rats. EXPERIMENTAL APPROACH Spinal reflex potentials, monosynaptic reflex potential (MSR) and slow ventral root potential (sVRP), were measured in the isolated spinal cord of the neonatal rat. Dopamine release was measured by HPLC. KEY RESULTS Dopamine at lower concentrations (<1 µM) depressed sVRP, which is a C fibre-evoked polysynaptic response and believed to reflect nociceptive transmission. At higher concentrations (>1 µM), in addition to a potent sVRP depression, dopamine depolarized baseline potential and slightly depressed MSR. Depression of sVRP by dopamine was partially reversed by dopamine D1-like but not by D2-like receptor antagonists. SKF83959 and SKF81297, D1-like receptor agonists, and methamphetamine, an endogenous dopamine releaser, also caused the inhibition of sVRP. Methamphetamine also depressed MSR, which was inhibited by ketanserin, a 5-HT2A/2C receptor antagonist. Methamphetamine induced the release of dopamine and 5-HT from spinal cords, indicating that the release of endogenous dopamine and 5-HT depresses sVRP and MSR respectively. CONCLUSION AND IMPLICATIONS These results suggested that dopamine at lower concentrations preferentially inhibited sVRP, which is mediated via dopamine D1-like and other unidentified receptors. The dopamine-evoked depression is involved in modulating the spinal functions by the descending dopaminergic pathways.

Kawamoto, K; Otsuguro, K; Ishizuka, M; Ito, S



Pre- and post-synaptic abnormalities associated with impaired neuromuscular transmission in a group of patients with 'limb-girdle myasthenia'.  


The properties of neuromuscular junctions (NMJs) were studied in motor-point biopsy samples from eight patients with congenital myasthenic syndromes affecting primarily proximal limb muscles ['limb-girdle myasthenia' (LGM)]. All had moderate to severe weakness of the proximal muscles, without short-term clinical fatigability but with marked variation in strength over periods of weeks or months, with little or no facial weakness or ptosis and no ophthalmoplegia. Most had a characteristic gait and stance. All patients showed decrement of the compound muscle action potential (CMAP) on repetitive stimulation at 3 Hz, and increased jitter and blocking was detected by SFEMG, confirming the presence of impaired neuromuscular transmission. None of the patients had serum antibodies against acetylcholine receptors (AChRs). Two of the patients had similarly affected siblings. Intracellular recording from isolated nerve-muscle preparations revealed that the quantal content (the number of ACh quanta released per nerve impulse) was only approximately 50% of that in controls. However, the quantal size (amplitude of miniature end-plate currents) and the kinetic properties of synaptic potentials and currents were similar to control values. The area of synaptic contact and extent of post-synaptic folding were approximately 50% of control values. Thus, the quantal content per unit area of synaptic contact was normal. The number of AChRs per NMJ was also reduced to approximately 50% of normal, so the local AChR density was normal. Immunolabelling studies revealed qualitatively normal distributions and abundance of each of 14 proteins normally concentrated at the NMJ, including components of the basal lamina, post-synaptic membrane and post-synaptic cytoskeleton. DNA analysis failed to detect mutations in the genes encoding any of the following proteins: AChR subunits, rapsyn, ColQ, ChAT or muscle-specific kinase. Response of these patients to treatment was varied: few showed long-term improvement with pyridostigmine and some even deteriorated with treatments, while others had intolerable side-effects. Several patients showed improvement with 3,4-diaminopyridine, but this was generally only transient. Ephedrine was helpful in half of the patients. We conclude that impaired neuromuscular transmission in these LGM patients results from structural abnormalities of the NMJ, including reduced size and post-synaptic folding, rather from any abnormality in the immediate events of neuromuscular transmission. PMID:16870884

Slater, C R; Fawcett, P R W; Walls, T J; Lyons, P R; Bailey, S J; Beeson, D; Young, C; Gardner-Medwin, D



The effects of an Echinacea preparation on synaptic transmission and the firing properties of CA1 pyramidal cells in the hippocampus.  


Traditionally, Echinacea preparations are used as antiinflammatory agents and immune-enhancers. In addition to these effects, their anxiolytic potency has been recognized recently in laboratory tests. Our aim in this study was to uncover the potential effects of an Echinacea preparation on neuronal operations in the hippocampus, a brain region that is involved in anxiety and anxiety-related behaviors. Using in vitro electrophysiological techniques, we observed that excitatory synaptic transmission in hippocampal slices was significantly suppressed by an Echinacea extract found to be effective in anxiety tests. In contrast, no change in inhibitory synaptic transmission could be detected upon application of this extract. In addition, our experiments revealed that at low concentration the Echinacea extract reduced the spiking activity of CA1 pyramidal cells, while at high concentration increased it. This latter observation was parallel to the reduction in the magnitude of the h-current-mediated voltage responses in pyramidal cells. At any concentrations, the passive membrane properties of CA1 pyramidal cells were found to be unaltered by the Echinacea extract. In summary, the Echinacea extract can significantly regulate excitatory, but not inhibitory, synaptic transmission in the hippocampus, and this action might be involved in its anxiolytic effects observed in behaviour tests. PMID:21717515

Hájos, Norbert; Holderith, Noémi; Németh, Beáta; Papp, Orsolya I; Szabó, Gergely G; Zemankovics, Rita; Freund, Tamás F; Haller, József



Targeted expression of tetanus toxin light chain in Drosophila specifically eliminates synaptic transmission and causes behavioral defects  

Microsoft Academic Search

Tetanus toxin cleaves the synaptic vesicle protein synaptobrevin, and the ensuing loss of neurotransmitter exocytosis has implicated synaptobrevin in this process. To further the study of synaptic function in a genetically tractable organism and to generate a tool to disable neuronal communication for behavioural studies, we have expressed a gene encoding tetanus toxin light chain in Drosophila. Toxin expression in

Sean T Sweeney; Kendal Broadie; John Keane; Heiner Niemann; Cahir J O'Kane



Autism-Associated Mutations in ProSAP2/Shank3 Impair Synaptic Transmission and Neurexin-Neuroligin-Mediated Transsynaptic Signaling  

PubMed Central

Mutations in several postsynaptic proteins have recently been implicated in the molecular pathogenesis of autism and autism spectrum disorders (ASDs), including Neuroligins, Neurexins, and members of the ProSAP/Shank family, thereby suggesting that these genetic forms of autism may share common synaptic mechanisms. Initial studies of ASD-associated mutations in ProSAP2/Shank3 support a role for this protein in glutamate receptor function and spine morphology, but these synaptic phenotypes are not universally penetrant, indicating that other core facets of ProSAP2/Shank3 function must underlie synaptic deficits in patients with ASDs. In the present study, we have examined whether the ability of ProSAP2/Shank3 to interact with the cytoplasmic tail of Neuroligins functions to coordinate pre/postsynaptic signaling through the Neurexin–Neuroligin signaling complex in hippocampal neurons of Rattus norvegicus. Indeed, we find that synaptic levels of ProSAP2/Shank3 regulate AMPA and NMDA receptor-mediated synaptic transmission and induce widespread changes in the levels of presynaptic and postsynaptic proteins via Neurexin–Neuroligin transsynaptic signaling. ASD-associated mutations in ProSAP2/Shank3 disrupt not only postsynaptic AMPA and NMDA receptor signaling but also interfere with the ability of ProSAP2/Shank3 to signal across the synapse to alter presynaptic structure and function. These data indicate that ASD-associated mutations in a subset of synaptic proteins may target core cellular pathways that coordinate the functional matching and maturation of excitatory synapses in the CNS.

Arons, Magali H.; Thynne, Charlotte J.; Grabrucker, Andreas M.; Li, Dong; Schoen, Michael; Cheyne, Juliette E.; Boeckers, Tobias M.; Montgomery, Johanna M.



Endocannabinoids Suppress Excitatory Synaptic Transmission to Dorsal Raphe Serotonin Neurons through the Activation of Presynaptic CB1 Receptors  

PubMed Central

Endocannabinoid signaling in the dorsal raphe (DR) has recently been implicated in the regulation of anxiety and depression. However, the cellular mechanisms by which endocannabinoids (eCBs) regulate the excitability of DR 5-hydroxytryptamine (serotonin; 5-HT) neurons remain poorly understood. In the present study, using whole-cell recording from DR 5-HT neurons, we examined the effects of eCBs on glutamatergic synapses in the DR. We found that the eCB anandamide decreased the amplitude of evoked excitatory postsynaptic currents (eEPSCs). This effect was blocked by CB1 receptor antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM 251) and mimicked by (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate (WIN 55,212-2), a CB1 receptor agonist. The inhibition of eEPSC amplitude was associated with an increase in the paired-pulse ratio and coefficient of variance. Activation of CB1 receptors also reduced the frequency, but not the amplitude, of miniature excitatory postsynaptic currents, indicating that eCBs inhibit glutamate release in the DR. In addition, we found that depolarization of DR 5-HT neurons induced a transient inhibition of the amplitude of eEPSCs, termed depolarization-induced suppression of excitation (DSE). The induction of DSE required an increase in postsynaptic intracellular calcium and was due to a decrease in glutamate release. Furthermore, pharmacological studies showed that blockade of CB1 receptors with AM 251 abolished the DSE. In contrast, activation of CB1 receptors with WIN 55,212-2 mimicked and occluded the DSE, indicating that depolarization of DR 5-HT neurons triggers eCB release, which in turn mediates the DSE. Together, these results indicate that eCBs play a role in modulating glutamatergic synaptic transmission to DR 5-HT neurons.

Shen, Roh-Yu



Astrocytes optimize synaptic fidelity  

NASA Astrophysics Data System (ADS)

Most neuronal synapses in the central nervous system are enwrapped by an astrocytic process. This relation allows the astrocyte to listen to and feed back to the synapse and to regulate synaptic transmission. We combine a tested mathematical model for the Ca^2+ response of the synaptic astrocyte and presynaptic feedback with a detailed model for vesicle release of neurotransmitter at active zones. The predicted Ca^2+ dependence of the presynaptic synaptic vesicle release compares favorably for several types of synapses, including the Calyx of Held. We hypothesize that the feedback regulation of the astrocyte onto the presynaptic terminal optimizes the fidelity of the synapse in terms of information transmission.

Nadkarni, Suhita; Jung, Peter; Levine, Herbert



Metaplasticity: the plasticity of synaptic plasticity  

Microsoft Academic Search

In thi paper, we review experimental evidence for a novel form of persistent synaptic plasticity we call metaplasticity. Metaplasticity is induced by synaptic or cellular activity, but it is not necessarilly expressed as a change in the efficacy of normal synaptic transmission. Instead, it is manifest as a change in the ability to induce subsequent synaptic plasticity such as long-term

Wickliffe C. Abraham; Mark F. Bear



Neonatal tissue damage facilitates nociceptive synaptic input to the developing superficial dorsal horn via NGF-dependent mechanisms  

PubMed Central

Tissue injury during a critical period of early life can facilitate spontaneous glutamatergic transmission within developing pain circuits in the superficial dorsal horn (SDH) of the spinal cord. However, the extent to which neonatal tissue damage strengthens nociceptive synaptic input to specific subpopulations of SDH neurons, as well as the mechanisms underlying this distinct form of synaptic plasticity, remains unclear. Here we use in vitro whole-cell patch clamp recordings from rodent spinal cord slices to demonstrate that neonatal surgical injury selectively potentiates high-threshold primary afferent input to immature lamina II neurons. In addition, the increase in the frequency of miniature excitatory postsynaptic currents (mEPSCs) after hindpaw incision was prevented by neonatal capsaicin treatment, suggesting that early tissue injury enhances glutamate release from nociceptive synapses. This occurs in a widespread manner within the developing SDH, as incision elevated mEPSC frequency in both GABAergic and presumed glutamatergic lamina II neurons of Gad-GFP transgenic mice. The administration of exogenous nerve growth factor (NGF) into the rat hindpaw mimicked the effects of early tissue damage on excitatory synaptic function, while blocking trkA receptors in vivo abolished the changes in both spontaneous and primary afferent-evoked glutamatergic transmission following incision. These findings illustrate that neonatal tissue damage can alter the gain of developing pain pathways by activating NGF-dependent signaling cascades which modify synaptic efficacy at the first site of nociceptive processing within the CNS.

Li, Jie; Baccei, Mark L.



Reactive oxygen species enhance excitatory synaptic transmission in rat spinal dorsal horn neurons by activating TRPA1 and TRPV1 channels.  


Central neuropathic pain (CNP) in the spinal cord, such as chronic pain after spinal cord injury (SCI), is an incurable ailment. However, little is known about the spinal cord mechanisms underlying CNP. Recently, reactive oxygen species (ROS) have been recognized to play an important role in CNP of the spinal cord. However, it is unclear how ROS affect synaptic transmission in the dorsal horn of the spinal cord. To clarify how ROS impact on synaptic transmission, we investigated the effects of ROS on synaptic transmission in rat spinal cord substantia gelatinosa (SG) neurons using whole-cell patch-clamp recordings. Administration of tert-butyl hydroperoxide (t-BOOH), an ROS donor, into the spinal cord markedly increased the frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) in SG neurons. This t-BOOH-induced enhancement was not suppressed by the Na(+) channel blocker tetrodotoxin. However, in the presence of a non-N-methyl-D-aspartate glutamate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione, t-BOOH did not generate any sEPSCs. Furthermore, in the presence of a transient receptor potential ankyrin 1 (TRPA1) channel antagonist (HC-030031) or a transient receptor potential vanilloid 1 (TRPV1) channel antagonist (capsazepine or AMG9810), the t-BOOH-induced increase in the frequency of sEPSCs was inhibited. These results indicate that ROS enhance the spontaneous release of glutamate from presynaptic terminals onto SG neurons through TRPA1 and TRPV1 channel activation. Excessive activation of these ion channels by ROS may induce central sensitization in the spinal cord and result in chronic pain such as that following SCI. PMID:23707800

Nishio, N; Taniguchi, W; Sugimura, Y K; Takiguchi, N; Yamanaka, M; Kiyoyuki, Yasukuni; Yamada, H; Miyazaki, N; Yoshida, M; Nakatsuka, T



Regulation of synaptic transmission at the photoreceptor terminal: a novel role for the cation-chloride co-transporter NKCC1.  


The Na(+)-K(+)-2Cl(-) co-transporter type 1 (NKCC1) is localized primarily throughout the outer plexiform layer (OPL) of the distal retina, a synaptic lamina that is comprised of the axon terminals of photoreceptors and the dendrites of horizontal and bipolar cells. Although known to play a key role in development, signal transmission and the gating of sensory signals in other regions of the retina and in the CNS, the contribution of NKCC1 to synaptic transmission within the OPL is largely unknown. In the present study, we investigated the function of NKCC1 at the photoreceptor-horizontal cell synapse by recording the electrical responses of photoreceptors and horizontal cells before and after blocking the activity of the transporter with bumetanide (BMN). Because NKCC1 co-transports 1 Na(+), 1 K(+) and 2 Cl(-), it is electroneutral and its activation had little effect on membrane conductance. However, recordings from postsynaptic horizontal cells revealed that inhibiting NKCC1 with BMN greatly increased glutamate release from both rod and cone terminals. In addition, we found that NKCC1 directly regulates Ca(2+)-dependent exocytosis at the photoreceptor synapse, raising the possibility that NKCC1 serves to suppress bulk release of glutamate vesicles from photoreceptor terminals in the dark and at light offset. Interestingly, NKCC1 gene and protein expressions were upregulated by light, which we attribute to the light-induced release of dopamine acting on D1-like receptors. In sum, our study reveals a new role for NKCC1 in the regulation of synaptic transmission in photoreceptors. PMID:23090945

Shen, Wen; Purpura, Lauren A; Li, Baoqin; Nan, Changlong; Chang, Irene J; Ripps, Harris



Detachment of structurally intact nerve endings from chromatolytic neurones of rat superior cervical ganglion during the depression of synaptic transmission induced by post-ganglionic axotomy.  

PubMed Central

1. Electrophysiological studies showed that injury of post-ganglionic nerve fibres leads to severe and prolonged depression of synaptic transmission through the rat superior cervical ganglion, beginning within 24 h. This is in line with the results of previous studies in other species and upon other neurones. 2. electron microscopy after post-ganglionic axotomy revealed nerve endings of presynaptic type with all the specialized membrane-related features of a synaptic zone, but which were not apposed to any post-synaptic nervous element. These umusual profiles were interpreted as detached presynaptic nerve endings. In normal and control ganglia, such profiles formed at most 0-5% of all vesicle-containing profiles of presynaptic type; in ganglia with all major post-ganglionic branches cut the proportion rose to approximately 7%, between 3 and 7 d post-operatively. Over this period, the mean incidence of chromatolytic neurones was 74-6%. 3. Concomitantly, the incidence of synapses within the ganglion fell by about 75%, reaching its lowest levels between 3 and 7 d post-operatively. There was strikingly little evidence of persistence of post-synaptic membrane specializations ('membrane thickenings') following detachment of synapses. 4. At longer survival intervals the incidence of synapses gradually increased, and that of detached nerve endings gradually decreased; recovery was well advanced by 42 d. 5. The fall in the incidence of synapses was closely paralleled by a fall in the incidence of desmosome-like attachments in the ganglion; the incidence of such attachments was found to be correlated to a significant degree with that of synapses. 6. It is concluded that most or all of the synapses upon sympathetic neurones become physically dissociated during the chromatolytic reaction of these neurones to axotomy. The failure to persist of ultrastructurally specialized post-synaptic sites, and the loss of desmosomes (particularly marked for those involving purely post-ganglionic nervous elements) suggest that the post-ganglionic neurone is losing all its specializations for attachment. 7. Some evidence suggests that the satellite cells may effect the final separation between pre- and post-synaptic structures. Images Plate 2 a b c Plate 4 Plate 5 Plate 6 a b Plate 1

Matthews, M R; Nelson, V H



Different forms of glycine- and GABAA-receptor mediated inhibitory synaptic transmission in mouse superficial and deep dorsal horn neurons  

Microsoft Academic Search

BACKGROUND: Neurons in superficial (SDH) and deep (DDH) laminae of the spinal cord dorsal horn receive sensory information from skin, muscle, joints and viscera. In both regions, glycine- (GlyR) and GABAA-receptors (GABAARs) contribute to fast synaptic inhibition. For rat, several types of GABAAR coexist in the two regions and each receptor type provides different contributions to inhibitory tone. Recent work

Wayne B Anderson; Brett A Graham; Natalie J Beveridge; Paul A Tooney; Alan M Brichta; Robert J Callister



The activation of nicotinic acetylcholine receptors enhances the inhibitory synaptic transmission in the deep dorsal horn neurons of the adult rat spinal cord  

PubMed Central

Somatosensory information can be modulated by nicotinic acetylcholine receptors (nAChRs) in the superficial dorsal horn of the spinal cord. Nonetheless, the functional significance of nAChRs in the deep dorsal horn of adult animals remains unclear. Using whole-cell patch-clamp recordings from lamina V neurons in the adult rat spinal cord, we investigated whether the activation of nAChRs could modulate the inhibitory synaptic transmission in the deep dorsal horn. In the presence of CNQX and APV to block excitatory glutamatergic synaptic transmission, bath applications of nicotine (100 ?M) significantly increased the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in almost all neurons tested. The effect of nicotine was mimicked by N-methyl-4-(3-pyridinyl)-3-butene-1-amine (RJR-2403, 100 ?M), an ?4?2-nAChR agonist, and was also mimicked by choline (10 mM), an ?7-nAChR agonist. The effect of nicotine was completely blocked by the nAChR antagonist mecamylamine (5 ?M). In the presence of tetrodotoxin (0.5 ?M), nicotine (100 ?M) significantly increased the miniature IPSC frequency. On the other hand, RJR-2403 (100 ?M) or choline (10 mM) did not affect miniature IPSCs. The application of nicotine (100 ?M) also evoked a large inward current in all lamina V neurons tested when cells were held at -60 mV. Similarly, RJR-2403 (100 ?M) induced inward currents in the majority of lamina V neurons examined. On the other hand, choline (10 mM) did not elicit any detectable whole-cell currents. These results suggest that several nAChR subtypes are expressed on the presynaptic terminals, preterminals, and neuronal cell bodies within lamina V and that these nAChRs are involved in the modulation of inhibitory synaptic activity in the deep dorsal horn of the spinal cord.

Takeda, Daisuke; Nakatsuka, Terumasa; Gu, Jianguo G; Yoshida, Munehito



Enhanced G protein-dependent modulation of excitatory synaptic transmission in the cerebellum of the Ca2+ channel-mutant mouse, tottering  

PubMed Central

Tottering, a mouse model for absence epilepsy and cerebellar ataxia, carries a mutation in the gene encoding class A (P/Q-type) Ca2+ channels, the dominant exocytotic Ca2+ channel at most synapses in the mammalian central nervous system. Comparing tottering to wild-type mice, we have studied glutamatergic transmission between parallel fibres and Purkinje cells in cerebellar slices. Results from biochemical assays and electrical field recordings demonstrate that glutamate release from parallel fibre terminals of the tottering mouse is controlled largely by class B Ca2+ channels (N-type), in contrast to the P/Q-channels that dominate release from wild-type terminals. Since N-channels, in a variety of assays, are more effectively inhibited by G proteins than are P/Q-channels, we tested whether synaptic transmission between parallel fibres and Purkinje cells in tottering mice was more susceptible to inhibitory modulation by G protein-coupled receptors than in their wild-type counterparts. GABAB receptors and ?2-adrenergic receptors (activated by bath application of transmitters) produced a three- to fivefold more potent inhibition of transmission in tottering than in wild-type synapses. This increased modulation is likely to be important for cerebellar transmission in vivo, since heterosynaptic depression, produced by activating GABAergic interneurones, greatly prolonged GABAB receptor-mediated presynaptic inhibition in tottering as compared to wild-type slices. We propose that this enhanced modulation shifts the balance of synaptic input to Purkinje cells in favour of inhibition, reducing Purkinje cell output from the cerebellum, and may contribute to the aberrant motor phenotype that is characteristic of this mutant animal.

Zhou, Yu Dong; Turner, Timothy J; Dunlap, Kathleen



Synaptic activation of kainate receptors gates presynaptic CB(1) signaling at GABAergic synapses.  


Glutamate can control inhibitory synaptic transmission through activation of presynaptic kainate receptors. We found that glutamate released by train stimulation of Schaffer collaterals could lead to either short-term depression or short-term facilitation of inhibitory synaptic transmission in mouse CA1 pyramidal neurons, depending on the presence of cannabinoid type 1 (CB(1)) receptors on GABAergic afferents. The train-induced depression of inhibition (t-Di) required the mobilization of 2-arachidonoylglycerol through postsynaptic activation of metabotropic glutamate receptors and [Ca(2+)] rise. GluK1 (GluR5)-dependent depolarization of GABAergic terminals enabled t-Di by facilitating presynaptic CB(1) signaling. Thus, concerted activation of presynaptic CB(1) receptors and kainate receptors mediates short-term depression of inhibitory synaptic transmission. In contrast, in inhibitory connections expressing GluK1, but not CB(1), receptors, train stimulation of Schaffer collaterals led to short-term facilitation. Thus, activation of kainate receptors by synaptically released glutamate gates presynaptic CB(1) signaling, which in turn controls the direction of short-term heterosynaptic plasticity. PMID:20081851

Lourenço, Joana; Cannich, Astrid; Carta, Mario; Coussen, Françoise; Mulle, Christophe; Marsicano, Giovanni



Calcium/calmodulin-dependent kinase II and long-term potentiation enhance synaptic transmission by the same mechanism.  

PubMed Central

Ca(2+)-sensitive kinases are thought to play a role in long-term potentiation (LTP). To test the involvement of Ca2+/calmodulin-dependent kinase II (CaM-K II), truncated, constitutively active form of this kinase was directly injected into CA1 hippocampal pyramidal cells. Inclusion of CaM-K II in the recording pipette resulted in a gradual increase in the size of excitatory postsynaptic currents (EPSCs). No change in evoked responses occurred when the pipette contained heat-inactivated kinase. The effects of CaM-K II mimicked several features of LTP in that it caused a decreased incidence of synaptic failures, an increase in the size of spontaneous EPSCs, and an increase in the amplitude of responses to iontophoretically applied alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate. To determine whether the CaM-K II-induced enhancement and LTP share a common mechanism, occlusion experiments were carried out. The enhancing action of CaM-K II was greatly diminished by prior induction of LTP. In addition, following the increase in synaptic strength by CaM-K II, tetanic stimulation failed to evoke LTP. These findings indicate that CaM-K II alone is sufficient to augment synaptic strength and that this enhancement shares the same underlying mechanism as the enhancement observed with LTP.

Lledo, P M; Hjelmstad, G O; Mukherji, S; Soderling, T R; Malenka, R C; Nicoll, R A



Perinatal exposure to polychlorinated biphenyls alters excitatory synaptic transmission and short-term plasticity in the hippocampus of the adult rat.  


Developmental exposure to polychlorinated biphenyls (PCBs) has been associated with cognitive deficits in humans and laboratory animals. Previous work has demonstrated a reduced capacity to support long-term potentiation (LTP) in animals exposed to a PCB mixture, Aroclor 1254 (A1254) via the dam in utero and throughout the preweaning period [Brain Res. 850;1999:87-95; Toxicol. Sci. 57;2000:102-11]. Assessment of normalized input/output (I/O) functions collected prior to LTP induction failed to reveal consistent differences in baseline synaptic transmission between control and PCB-exposed groups. The present study was designed to systematically evaluate excitatory and inhibitory synaptic transmission using a more extensive I/O analysis and paired pulse functions to assess short-term plasticity. Pregnant Long-Evans rats were administered either corn oil (control) or 6 mg/kg per day of A1254 by gavage from gestational day (GD) 6 until pups were weaned on postnatal day (PND) 21. In adult male offspring (5-11 months of age), field potentials evoked by perforant path stimulation were recorded in the dentate gyrus under urethane anesthesia. Detailed I/O functions were assessed by averaging the responses evoked in the dentate gyrus to stimulus pulses delivered to the perforant path in an extensive ascending intensity series. Population spike (PS) and postsynaptic potential (PSP) amplitudes recorded in the dentate gyrus were significantly enhanced in PCB-exposed animals relative to controls at midrange intensities. No group differences were observed in EPSP slope amplitudes. Short-term plasticity was assessed by delivering pairs of stimulus pulses at interpulse intervals (IPIs) ranging from 10 to 70 ms. In the dentate gyrus this range of intervals activates both inhibitory and excitatory mechanisms leading to a pattern of depression at brief intervals (<30 ms) followed by facilitation as the interval between pulses is extended. Paired pulse depression was decreased at an intermediate IPI (30 ms) with submaximal stimulus intensities. These data augment previous work demonstrating persistent changes in hippocampal plasticity as a result of exposure to PCBs during development. Furthermore, as increases in field potential amplitudes were observed, these findings support previous conclusions that A1254-induced LTP deficits are not readily attributable to reductions in synaptic excitability. Thus, in addition to impairment in use-dependent synaptic plasticity reported previously, the present report reveals that basic components of information processing within the hippocampus are permanently altered as a result of perinatal exposure to PCBs. PMID:14637380

Gilbert, M E



Afferent diversity and the organization of central vestibular pathways  

PubMed Central

This review considers whether the vestibular system includes separate populations of sensory axons innervating individual organs and giving rise to distinct central pathways. There is a variability in the discharge properties of afferents supplying each organ. Discharge regularity provides a marker for this diversity since fibers which differ in this way also differ in many other properties. Postspike recovery of excitability determines the discharge regularity of an afferent and its sensitivity to depolarizing inputs. Sensitivity is small in regularly discharging afferents and large in irregularly discharging afferents. The enhanced sensitivity of irregular fibers explains their larger responses to sensory inputs, to efferent activation, and to externally applied galvanic currents, but not their distinctive response dynamics. Morphophysiological studies show that regular and irregular afferents innervate overlapping regions of the vestibular nuclei. Intracellular recordings of EPSPs reveal that some secondary vestibular neurons receive a restricted input from regular or irregular afferents, but that most such neurons receive a mixed input from both kinds of afferents. Anodal currents delivered to the labyrinth can result in a selective and reversible silencing of irregular afferents. Such a functional ablation can provide estimates of the relative contributions of regular and irregular inputs to a central neuron's discharge. From such estimates it is concluded that secondary neurons need not resemble their afferent inputs in discharge regularity or response dynamics. Several suggestions are made as to the potentially distinctive contributions made by regular and irregular afferents: (1) Reflecting their response dynamics, regular and irregular afferents could compensate for differences in the dynamic loads of various reflexes or of individual reflexes in different parts of their frequency range; (2) The gating of irregular inputs to secondary VOR neurons could modify the operation of reflexes under varying behavioral circumstances; (3) Two-dimensional sensitivity can arise from the convergence onto secondary neurons of otolith inputs differing in their directional properties and response dynamics; (4) Calyx afferents have relatively low gains when compared with irregular dimorphic afferents. This could serve to expand the stimulus range over which the response of calyx afferents remains linear, while at the same time preserving the other features peculiar to irregular afferents. Among those features are phasic response dynamics and large responses to efferent activation; (5) Because of the convergence of several afferents onto each secondary neuron, information transmission to the latter depends on the gain of individual afferents, but not on their discharge regularity.

Goldberg, Jay M.



VGLUT3-immunoreactive afferents of the lateral septum: ultrastructural evidence for a modulatory role of glutamate.  


Through its extensive connections with various brain regions, the lateral septum (LS) participates in the processing of cognitive, emotional and autonomic information. It is decisively involved in the generation of behavioral responses according to environmental demands. Modulatory afferents reaching the LS from the brain stem (e.g. dopaminergic, serotonergic) play a role in the adjustment of these behavioral responses. Recently, a population of vesicular glutamate transporter 3-immunoreactive (VGLUT3-ir) fibers forming prominent pericellular basket-like structures (PBLS) was described in the rat LS. These VGLUT3-ir PBLS are distributed in a layer-like pattern, which is very typical for modulatory afferents of the LS. There is meanwhile broad evidence that glutamate can act as a modulatory or co-transmitter and that those neurons, which make use of this transmission mode, primarily express VGLUT3. Thus, the VGLUT3-ir fibers within the LS could also display features typical for non-canonical glutamatergic transmission. Employing pre-embedding electron microscopy for VGLUT3 in rats, we show now that the VGLUT3-ir fibers outlining LS neurons represent axonal terminals, which primarily form symmetric synapses with somata and proximal dendrites of their target neurons. Occasionally, we also found VGLUT3-ir terminals that make canonical asymmetric synapses on distal dendrites and spines. Thus, VGLUT3-ir boutons in the LS form two different, disproportionate, populations of synaptic contacts with their target neurons. The larger one of them is indicative of employing glutamate as a modulatory transmitter. PMID:22374223

Riedel, Anett; Stöber, Franziska; Richter, Karin; Fischer, Klaus-Dieter; Miettinen, Riitta; Budinger, Eike



Neuroligin-2 deletion selectively decreases inhibitory synaptic transmission originating from fast-spiking, but not from somatostatin-positive interneurons  

PubMed Central

Neuroligins are cell-adhesion molecules involved in synapse formation and/or function. Neurons express four neuroligins (NL1–NL4), of which NL1 is specific to excitatory, and NL2 to inhibitory synapses. Excitatory and inhibitory synapses include numerous subtypes. However, it is unknown whether NL1 performs similar functions in all excitatory and NL2 in all inhibitory synapses, or whether they regulate the formation and/or function of specific subsets of synapses. To address this central question, we performed paired recordings in primary somatosensory cortex of mice lacking NL1 or NL2. Using this system, we examined neocortical microcircuits formed by reciprocal synapses between excitatory neurons and two subtypes of inhibitory interneurons, namely fast-spiking and somatostatin-positive interneurons. We find that the NL1 deletion had little effect on inhibitory synapses, whereas the NL2 deletion decreased (40–50%) the unitary (cell-to-cell) IPSC amplitude evoked from single fast-spiking interneurons. Strikingly, the NL2 deletion had no effect on IPSC amplitude evoked from single somatostatin-positive inhibitory interneurons. Moreover, the frequency of unitary synaptic connections between individual fast-spiking and somatostatin-positive interneurons and excitatory neurons was unchanged. The decrease in unitary IPSC amplitude originating from fast-spiking interneurons in NL2-deficient mice was due to a multiplicative and uniform down-scaling of the amplitude distribution, which in turn was mediated by a decrease in both synaptic quantal amplitude and quantal content – the latter inferred from an increase in the coefficient of variation. Thus, NL2 is not necessary for establishing unitary inhibitory synaptic connections, but is selectively required for “scaling up” unitary connections originating from a subset of interneurons.

Gibson, Jay R.; Huber, Kimberly M.; Sudhof, Thomas C.



Ceftriaxone normalizes nucleus accumbens synaptic transmission, glutamate transport, and export following cocaine self-administration and extinction training.  


Decreased basal glutamate levels are observed in the rat nucleus accumbens (NA) core following cocaine self-administration. This disruption of glutamate homeostasis arises from a reduction in the export of glutamate via system x(C)(-) and is accompanied by a decrease in expression of xCT, the catalytic subunit of system x(C)(-). A second hallmark of disrupted homeostasis is a decrease in expression and function of the major glutamate transporter, GLT-1. We have previously shown that chronic treatment with the antibiotic ceftriaxone restores xCT and GLT-1 expression following cocaine self-administration and attenuates both cue- and cocaine-primed reinstatement. Here we used a (3)H-glutamate uptake assay and microdialysis to test the hypothesis that ceftriaxone restores the function of both GLT-1 and xCT (glutamate reuptake and export, respectively) in the NA core following cocaine self-administration. We also used electrophysiology to investigate the ability of ceftriaxone to normalize measures of synaptic plasticity following cocaine. We found that 5 d of ceftriaxone treatment following cocaine self-administration restores basal glutamate levels in the accumbens core, likely through an upregulation of system x(C)(-) function. We also found that ceftriaxone restores glutamate reuptake and attenuates the increase in synaptically released glutamate that accompanies cocaine-primed reinstatement. Ceftriaxone also reversed the cocaine-induced synaptic potentiation in the accumbens core, evidenced by normalized spontaneous EPSC amplitude and frequency and evoked EPSC amplitude. These data indicate that ceftriaxone normalizes multiple aspects of glutamate homeostasis following cocaine self-administration and thus holds the potential to reduce relapse in human cocaine addicts. PMID:22956831

Trantham-Davidson, Heather; LaLumiere, Ryan T; Reissner, Kathryn J; Kalivas, Peter W; Knackstedt, Lori A



DCG-IV inhibits synaptic transmission by activation of NMDA receptors in area CA1 of rat hippocampus  

Microsoft Academic Search

We investigated the synaptic depressant action of the metabotropic glutamate receptor group II agonist, (2S,1?R,2?R,3?R)-2-(2?,3?-dicarboxycyclopropyl)-glycine (DCG-IV), in area CA1 of rat hippocampus. A brief bath application of DCG-IV (10 ?M) caused a rapidly reversible depression to 0.57±0.22 (i.e., 43%) of baseline excitatory postsynaptic potential (epsp) slope. This depression could not be attenuated by the metabotropic glutamate receptor antagonists ?-methyl-l-CCGI\\/(2S,3S,4S)-2-methyl-2-(carboxycyclopropyl)glycine (MCCG),

Nicholas A Breakwell; LingQian Huang; Michael J Rowan; Roger Anwyl



In pursuit of P2X3 antagonists: novel therapeutics for chronic pain and afferent sensitization.  


Treating pain by inhibiting ATP activation of P2X3-containing receptors heralds an exciting new approach to pain management, and Afferent's program marks the vanguard in a new class of drugs poised to explore this approach to meet the significant unmet needs in pain management. P2X3 receptor subunits are expressed predominately and selectively in so-called C- and A?-fiber primary afferent neurons in most tissues and organ systems, including skin, joints, and hollow organs, suggesting a high degree of specificity to the pain sensing system in the human body. P2X3 antagonists block the activation of these fibers by ATP and stand to offer an alternative approach to the management of pain and discomfort. In addition, P2X3 is expressed pre-synaptically at central terminals of C-fiber afferent neurons, where ATP further sensitizes transmission of painful signals. As a result of the selectivity of the expression of P2X3, there is a lower likelihood of adverse effects in the brain, gastrointestinal, or cardiovascular tissues, effects which remain limiting factors for many existing pain therapeutics. In the periphery, ATP (the factor that triggers P2X3 receptor activation) can be released from various cells as a result of tissue inflammation, injury or stress, as well as visceral organ distension, and stimulate these local nociceptors. The P2X3 receptor rationale has aroused a formidable level of investigation producing many reports that clarify the potential role of ATP as a pain mediator, in chronic sensitized states in particular, and has piqued the interest of pharmaceutical companies. P2X receptor-mediated afferent activation has been implicated in inflammatory, visceral, and neuropathic pain states, as well as in airways hyperreactivity, migraine, itch, and cancer pain. It is well appreciated that oftentimes new mechanisms translate poorly from models into clinical efficacy and effectiveness; however, the breadth of activity seen from P2X3 inhibition in models offers a realistic chance that this novel mechanism to inhibit afferent nerve sensitization may find its place in the sun and bring some merciful relief to the torment of persistent discomfort and pain. The development philosophy at Afferent is to conduct proof of concept patient studies and best identify target patient groups that may benefit from this new intervention. PMID:22095157

Ford, Anthony P



Synaptic Vesicle Phosphoproteins and Regulation of Synaptic Function  

Microsoft Academic Search

Complex brain functions, such as learning and memory, are believed to involve changes in the efficiency of communication between nerve cells. Therefore, the elucidation of the molecular mechanisms that regulate synaptic transmission, the process of intercellular communication, is an essential step toward understanding nervous system function. Several proteins associated with synaptic vesicles, the organelles that store neurotransmitters, are targets for

Paul Greengard; Flavia Valtorta; Andrew J. Czernik; Fabio Benfenati



Transgene-mediated GDNF expression enhances synaptic connectivity and GABA transmission to improve functional outcome after spinal cord contusion  

PubMed Central

Glial cell line-derived trophic factor (GDNF) is a peptide with pleiotropic survival and growth promoting effects on neurons. We found that intraspinal injection of a non-replicating herpes simplex virus (HSV)-based vector coding for GDNF 2 hours after blunt trauma to the thoraco-lumbar spinal cord produced sustained improvement in motor behavioral outcomes up to 5 weeks following injury. The improvement in behavior correlated with an increase in synaptophysin and glutamic acid decarboxylase (GAD) in the spinal cord at the level of injury. Addition of recombinant GDNF protein to primary spinal cord neurons in-vitro resulted in enhanced neurite growth and a marked increase in protein levels of GAD65 and GAD67, synapsin I and synaptophysin. GDNF-mediated increases in GAD and the synaptic markers were blocked by the MEK inhibitor UO126, but not by the PI3K inhibitor LY294002. These results suggest that GDNF, acting through the MEK-ERK pathway enhances axonal sprouting, synaptic connectivity, and GABAergic neurotransmission in the spinal cord, that result in improved behavioral outcomes after spinal cord contusion injury.

Koelsch, Angela; Feng, YongJia; Fink, David J.; Mata, Marina



Relative contribution of pre- and post-synaptic effects to the neostigmine-induced recovery of neuromuscular transmission blocked by vecuronium.  


The relative contribution of the pre- and post-synaptic effects to the neostigmine-induced recovery of neuromuscular transmission blocked by vecuronium was studied. A conjunction of myographical and electrophysiological techniques was employed. The preparation was the sciatic nerve-extensor digitorum longus muscle of the rat, in vitro. The physiological variables recorded were nerve-evoked twitches (generated at 0.1 Hz), tetanic contractions (generated at 50 Hz) and end-plate potentials (epps), generated in trains of 50 Hz. The epps were analyzed in: amplitude of first epp in the train; mean amplitude of the 30th to the 59th epp in the train (epps-plateau); half-decay time of the epp; early tetanic rundown of epps in the train; plateau tetanic rundown of epps in the train; quantal content of the epps and quantal size. In myographical experiments, a concentration of vecuronium was found (0.8 ?m) that affected both twitches and tetanic contractions and a concentration of neostigmine was found (0.048 ?m) that completely restored the twitch affected by vecuronium. The cellular effects of vecuronium and neostigmine, studied alone or in association, in the above-mentioned concentrations, were scrutinized by means of electrophysiological techniques. These showed that vecuronium alone decreased the peak amplitude, the quantal content of epps and the quantal size and reinforced the tetanic rundown of epps. Neostigmine alone increased the peak amplitude, the quantal content and the half-decay time of the epps. When employed in the presence of vecuronium, neostigmine increased both the quantal content of the epps (via a presynaptic effect) and the half-decay time of the epps (via a postsynaptic effect). Seeing the pre- and the post-synaptic effects of neostigmine were of similar magnitude, they permit to conclude that both these effects contributed significantly to the restoration by neostigmine of the neuromuscular transmission blocked by vecuronium. PMID:20408882

Baso, Ana Cristina Z; Serra, Carmen Sílvia M; Oliveira, Antonio Carlos



Prenatal Ethanol Exposure Alters Synaptic Plasticity in the Dorsolateral Striatum of Rat Offspring via Changing the Reactivity of Dopamine Receptor  

PubMed Central

Prenatal exposure to high-level ethanol (EtOH) has been reported to produce hyperlocomotion in offspring. Previous studies have demonstrated synaptic plasticity in cortical afferent to the dorsolateral (DL) striatum is involved in the pathogensis of hyperlocomotion. Here, prenatal EtOH-exposed rat offspring were used to investigate whether maternal EtOH exposure affected synaptic plasticity in the DL striatum. We found high-frequency stimulation (HFS) induced a weaker long-term potentiation (LTP) in EtOH rats than that in control rats at postnatal day (PD) 15. The same protocol of HFS induced long-term depression (LTD) in control group but still LTP in EtOH group at PD 30 or PD 40. Furthermore, enhancement of basal synaptic transmission accompanied by the decrease of pair-pulse facilitation (PPF) was observed in PD 30 EtOH offspring. The perfusion with D1-type receptors (D1R) antagonist SCH23390 recovered synaptic transmission and blocked the induction of abnormal LTP in PD 30 EtOH offspring. The perfusion with D2-type receptors (D2R) agonist quinpirole reversed EtOH-induced LTP into D1R- and metabotropic glutamate receptor-dependent LTD. The data provide the functional evidence that prenatal ethanol exposure led to the persistent abnormal synaptic plasticity in the DL striatum via disturbing the balance between D1R and D2R.

Zhou, Rong; Wang, Shenjun; Zhu, Xuejiang



Efferent fibers innervate gustatory and mechanosensitive afferent fibers in frog fungiform papillae.  


A possibility of efferent innervation of gustatory and mechanosensitive afferent fiber endings was studied in frog fungiform papillae with a suction electrode. The amplitude of antidromic impulses in a papillary afferent fiber induced by antidromically stimulating an afferent fiber of glossopharyngeal nerve (GPN) with low voltage pulses was inhibited for 40 s after the parasympathetic efferent fibers of GPN were stimulated orthodromically with high voltage pulses at 30 Hz for 10 s. This implies that electrical positivity of the outer surface of papillary afferent membrane was reduced by the efferent fiber-induced excitatory postsynaptic potential. The inhibition of afferent responses in the papillae was blocked by substance P receptor blocker, L-703,606, indicating that substance P is probably released from the efferent fiber terminals. Slow negative synaptic potential, which corresponded to a slow depolarizing synaptic potential, was extracellularly induced in papillary afferent terminals for 45 s by stimulating the parasympathetic efferent fibers of GPN with high voltage pulses at 30 Hz for 10 s. This synaptic potential was also blocked by L-703,606. These data indicate that papillary afferent fiber endings are innervated by parasympathetic efferent fibers. PMID:21994412

Sato, Toshihide; Nishishita, Kazuhisa; Okada, Yukio; Toda, Kazuo



Protein kinase A-dependent enhanced NMDA receptor function in pain-related synaptic plasticity in rat amygdala neurones  

PubMed Central

Mechanisms of pain-related plasticity in the amygdala, a key player in emotionality, were studied at the cellular and molecular levels in a model of arthritic pain. The influence of the arthritis pain state induced in vivo on synaptic transmission and N-methyl-d-aspartate (NMDA) receptor function was examined in vitro using whole-cell voltage-clamp recordings of neurones in the latero-capsular part of the central nucleus of the amygdala (CeA), which is now defined as the ‘nociceptive amygdala’. Synaptic transmission was evoked by electrical stimulation of afferents from the pontine parabrachial area (part of the spino-parabrachio-amygdaloid pain pathway) in brain slices from control rats and from arthritic rats. This study shows that pain-related synaptic plasticity is accompanied by protein kinase A (PKA)-mediated enhanced NMDA-receptor function and increased phosphorylation of NMDA-receptor 1 (NR1) subunits. Synaptic plasticity in the arthritis pain model, but not normal synaptic transmission in control neurones, was inhibited by a selective NMDA receptor antagonist. Accordingly, an NMDA receptor-mediated synaptic component was recorded in neurones from arthritic animals, but not in control neurones, and was blocked by inhibition of PKA but not protein kinase C (PKC). Exogenous NMDA evoked a larger inward current in neurones from arthritic animals than in control neurones, indicating a postsynaptic effect. Paired-pulse facilitation, a measure of presynaptic mechanisms, was not affected by an NMDA-receptor antagonist. Increased levels of phosphorylated NR1 protein, but not of total NR1, were measured in the CeA of arthritic rats compared to controls. Our results suggest that pain-related synaptic plasticity in the amygdala involves a critical switch of postsynaptic NMDA receptor function through PKA-dependent NR1 phosphorylation.

Bird, Gary C; Lash, L Leanne; Han, Jeong S; Zou, Xiaoju; Willis, William D; Neugebauer, Volker



A-type potassium channels differentially tune afferent pathways from rat solitary tract nucleus to caudal ventrolateral medulla or paraventricular hypothalamus  

PubMed Central

The solitary tract nucleus (NTS) conveys visceral information to diverse central networks involved in homeostatic regulation. Although afferent information content arriving at various CNS sites varies substantially, little is known about the contribution of processing within the NTS to these differences. Using retrograde dyes to identify specific NTS projection neurons, we recently reported that solitary tract (ST) afferents directly contact NTS neurons projecting to caudal ventrolateral medulla (CVLM) but largely only indirectly contact neurons projecting to the hypothalamic paraventricular nucleus (PVN). Since intrinsic properties impact information transmission, here we evaluated potassium channel expression and somatodendritic morphology of projection neurons and their relation to afferent information output directed to PVN or CVLM pathways. In slices, tracer-identified projection neurons were classified as directly or indirectly (polysynaptically) coupled to ST afferents by EPSC latency characteristics (directly coupled, jitter < 200 ?s). In each neuron, voltage-dependent potassium currents (IK) were evaluated and, in representative neurons, biocytin-filled structures were quantified. Both CVLM- and PVN-projecting neurons had similar, tetraethylammonium-sensitive IK. However, only PVN-projecting NTS neurons displayed large transient, 4aminopyridine-sensitive, A-type currents (IKA). PVN-projecting neurons had larger cell bodies with more elaborate dendritic morphology than CVLM-projecting neurons. ST shocks faithfully (> 75%) triggered action potentials in CVLM-projecting neurons but spike output was uniformly low (< 20%) in PVN-projecting neurons. Pre-conditioning hyperpolarization removed IKA inactivation and attenuated ST-evoked spike generation along PVN but not CVLM pathways. Thus, multiple differences in structure, organization, synaptic transmission and ion channel expression tune the overall fidelity of afferent signals that reach these destinations.

Bailey, T W; Hermes, S M; Whittier, K L; Aicher, S A; Andresen, M C



Ethanol Disruption of Synaptic Neurotransmission.  

National Technical Information Service (NTIS)

The goal of this research program was to understand how acute and chronic ethanol administration disrupts synaptic transmission in the central nervous system. The overall hypothesis was that ethanol depresses neurotransmission at neurotransmitter receptor...

R. S. Aronstam



Ethanol Disruption of Synaptic Neurotransmission.  

National Technical Information Service (NTIS)

The goal of this research is to understand how acute and chronic ethanol administration disrupts synaptic transmission in the central nervous system. The underlying hypothesis is that ethanol depresses neurotransmission at neurotransmitter receptors by al...

R. S. Aronstam



Haploinsufficiency in peptidylglycine alpha-amidating monooxygenase leads to altered synaptic transmission in the amygdala and impaired emotional responses.  


The mammalian amygdala expresses various neuropeptides whose signaling has been implicated in emotionality. Many neuropeptides require amidation for full activation by peptidylglycine ?-amidating monooxygenase (PAM), a transmembrane vesicular cuproenzyme and regulator of the secretory pathway. Mice heterozygous for the Pam gene (PAM(+/-)) exhibit physiological and behavioral abnormalities related to specific peptidergic pathways. In the present study, we evaluated emotionality and examined molecular and cellular responses that characterize neurophysiological differences in the PAM(+/-) amygdala. PAM(+/-) mice presented with anxiety-like behaviors in the zero maze that were alleviated by diazepam. PAM(+/-) animals were deficient in short- and long-term contextual and cued fear conditioning and required higher shock intensities to establish fear-potentiated startle than their wild-type littermates. Immunohistochemical analysis of the amygdala revealed PAM expression in pyramidal neurons and local interneurons that synthesize GABA. We performed whole-cell recordings of pyramidal neurons in the PAM(+/-) amygdala to elucidate neurophysiological correlates of the fear behavioral phenotypes. Consistent with these observations, thalamic afferent synapses in the PAM(+/-) lateral nucleus were deficient in long-term potentiation. This deficit was apparent in the absence and presence of the GABA(A) receptor antagonist picrotoxin and was abolished when both GABA(A) and GABA(B) receptors were blocked. Both evoked and spontaneous excitatory signals were enhanced in the PAM(+/-) lateral nucleus. Phasic GABAergic signaling was also augmented in the PAM(+/-) amygdala, and this difference comprised activity-independent and -dependent components. These physiological findings represent perturbations in the PAM(+/-) amygdala that may underlie the aberrant emotional responses in the intact animal. PMID:20943906

Gaier, Eric D; Rodriguiz, Ramona M; Ma, Xin-Ming M; Sivaramakrishnan, Shobhana; Bousquet-Moore, Danielle; Wetsel, William C; Eipper, Betty A; Mains, Richard E



Pre- and postsynaptic effects of norepinephrine on ?-aminobutyric acid-mediated synaptic transmission in layer 2/3 of the rat auditory cortex.  


Noradrenergic terminals from the locus coeruleus release norepinephrine (NE) throughout most brain areas, including the auditory cortex, where they affect neural processing by modulating numerous cellular properties including the inhibitory ?-aminobutyric acid (GABA)ergic transmission. We recently demonstrated that NE affects GABAergic signaling onto cortical pyramidal cells in a complex manner. In this study, we used a combination of patch-clamp recording and immunohistochemical techniques to identify the synaptic site and the location of the adrenergic receptors involved in the modulation of GABAergic signaling in cortical layer 2/3 of the rat. Our results showed that NE increases the frequency of spike-independent miniature inhibitory postsynaptic currents (mIPSCs), as well as the probability of release of unitary inhibitory postsynaptic currents (IPSCs) obtained with patch-clamp pair-recordings. The pharmacology of mIPSCs and the identification of adrenergic receptors in neurons containing the GABAergic marker parvalbumin (PV) suggest that NE increases the presynaptic probability of GABA release by activating ?(2) - and ?-receptors on PV-positive neurons. On the contrary, bath-applied NE or phenylephrine, decreased the current mediated by pressure application of the GABA(A) -receptor agonist muscimol, as well as the amplitude-but not the frequency-of mIPSCs, indicating that activation of postsynaptic ?(1) adrenoceptors reversibly depressed GABAergic currents. We speculate that while a generalized postsynaptic decrease of GABAergic inhibition might decrease the synaptic activation threshold for pyramidal neurons corresponding to an alert state, NE might promote perception and sensory binding by facilitating lateral inhibition as well as the production of ?-oscillations by a selective enhancement of perisomatic inhibition. PMID:21905124

Salgado, Humberto; Garcia-Oscos, Francisco; Martinolich, Laura; Hall, Shawn; Restom, Robert; Tseng, Kuei Y; Atzori, Marco



Implications of All-or-None Synaptic Transmission and Short-Term Depression beyond Vesicle Depletion: A Computational Study  

Microsoft Academic Search

The all-or-none character of transmission at central synapses is commonly viewed as evidence that only one vesicle can be released per action potential at a single release site. This inter- pretation is still a matter of debate; its resolution is important for our understanding of the nature of quantal response. In this work we explore observable consequences of the univesicular

Victor Matveev; Xiao-Jing Wang



Cooperation of NMDA and tachykinin NK 1 and NK 2 receptors in the medullary transmission of vagal afferent input from the acid-threatened rat stomach  

Microsoft Academic Search

Noxious challenge of the rat gastric mucosa by hydrochloric acid (HCl) is signaled to the nucleus tractus solitarii (NTS) and area postrema (AP). This study examined the participation of glutamate and tachykinins in the medullary transmission process. Activation of neurons was visualized by in situ hybridization autoradiography of c-fos messenger RNA (mRNA) 45 min after intragastric (IG) administration of 0.5

Milana Joci?; Rufina Schuligoi; Elisabeth Schöninkle; Maria A. Pabst; Peter Holzer



Mice lacking brain/kidney phosphate-activated glutaminase (GLS1) have impaired glutamatergic synaptic transmission, altered breathing, disorganized goal-directed behavior and die shortly after birth  

PubMed Central

Neurotransmitter glutamate has been thought to derive mainly from glutamine via the action of glutaminase type 1 (GLS1). To address the importance of this pathway in glutamatergic transmission, we knocked out GLS1 in mice. The insertion of a STOP cassette by homologous recombination produced a null allele that blocked transcription, encoded no immunoreactive protein and abolished GLS1 enzymatic activity. Null mutants were slightly smaller, were deficient in goal-directed behavior, hypoventilated and died in the first post-natal day. No gross or microscopic defects were detected in peripheral organs or in the central nervous system. In cultured neurons from the null mutants, miniature EPSC amplitude and duration were normal; however, the amplitude of evoked EPSCs decayed more rapidly with sustained 10 Hz stimulation, consistent with an observed reduction in depolarization-evoked glutamate release. Because of this activity-dependent impairment in glutamatergic transmission, we surmised that respiratory networks, which require temporal summation of synaptic input, would be particularly affected. We found that the amplitude of inspirations was decreased in vivo, chemosensitivity to CO2 was severely altered, and the frequency of pacemaker activity recorded in the respiratory generator in the Pre-Bötzinger complex, a glutamatergic brainstem network that can be isolated in vitro, was increased. Our results show that while alternate pathways to GLS1 glutamate synthesis support baseline glutamatergic transmission, the GLS1 pathway is essential for maintaining the function of active synapses, and so the mutation is associated with impaired respiratory function, abnormal goal-directed behavior and neonatal demise.

Masson, Justine; Darmon, Michele; Conjard, Agnes; Chuhma, Nao; Ropert, Nicole; Thoby-Brisson, Muriel; Foutz, Arthur S.; Parrot, Sandrine; Miller, Gretchen M.; Jorisch, Renee; Polan, Jonathan; Hamon, Michel; Hen, Rene; Rayport, Stephen



Activation of Presynaptic GABAB(1a,2) Receptors Inhibits Synaptic Transmission at Mammalian Inhibitory Cholinergic Olivocochlear-Hair Cell Synapses.  


The synapse between olivocochlear (OC) neurons and cochlear mechanosensory hair cells is cholinergic, fast, and inhibitory. The inhibitory sign of this cholinergic synapse is accounted for by the activation of Ca(2+)-permeable postsynaptic ?9?10 nicotinic receptors coupled to the opening of hyperpolarizing Ca(2+)-activated small-conductance type 2 (SK2)K(+) channels. Acetylcholine (ACh) release at this synapse is supported by both P/Q- and N-type voltage-gated calcium channels (VGCCs). Although the OC synapse is cholinergic, an abundant OC GABA innervation is present along the mammalian cochlea. The role of this neurotransmitter at the OC efferent innervation, however, is for the most part unknown. We show that GABA fails to evoke fast postsynaptic inhibitory currents in apical developing inner and outer hair cells. However, electrical stimulation of OC efferent fibers activates presynaptic GABAB(1a,2) receptors [GABAB(1a,2)Rs] that downregulate the amount of ACh released at the OC-hair cell synapse, by inhibiting P/Q-type VGCCs. We confirmed the expression of GABABRs at OC terminals contacting the hair cells by coimmunostaining for GFP and synaptophysin in transgenic mice expressing GABAB1-GFP fusion proteins. Moreover, coimmunostaining with antibodies against the GABA synthetic enzyme glutamic acid decarboxylase and synaptophysin support the idea that GABA is directly synthesized at OC terminals contacting the hair cells during development. Thus, we demonstrate for the first time a physiological role for GABA in cochlear synaptic function. In addition, our data suggest that the GABAB1a isoform selectively inhibits release at efferent cholinergic synapses. PMID:24068816

Wedemeyer, Carolina; Zorrilla de San Martín, Javier; Ballestero, Jimena; Gómez-Casati, María Eugenia; Torbidoni, Ana Vanesa; Fuchs, Paul A; Bettler, Bernhard; Elgoyhen, Ana Belén; Katz, Eleonora



Mutation of the calcium channel gene Cacna1f disrupts calcium signaling, synaptic transmission and cellular organization in mouse retina  

Microsoft Academic Search

Retinal neural transmission represents a key function of the eye. Identifying the molecular components of this vital process is helped by studies of selected human genetic eye disorders. For example, mutations in the calcium channel subunit gene CACNA1F cause incomplete X-linked congenital stationary night blindness (CSNB2 or iCSNB), a human retinal disorder with abnormal electrophysiological response and visual impair- ments

Fiona Mansergh; Noelle C. Orton; John P. Vessey; Melanie R. Lalonde; William K. Stell; Francois Tremblay; Steven Barnes; Derrick E. Rancourt; N. Torben



Patterns of connectivity of spinal interneurons with single muscle afferents.  


A technique was developed to measure, in the anesthetized and paralyzed cat under artificial ventilation, changes of excitability to intraspinal stimulation simultaneously in two different afferent fibers or in two collaterals of the same afferent fiber. Intraspinal stimulation reduced the threshold of single muscle afferent fibers ending in the intermediate nucleus. This effect was seen with strengths below those required to activate the afferent fiber tested (1.5-12 microA), occurred at a short latency (1.5-2.0 ms), reached a maximum between 15 and 30 ms, and lasted up to 100 ms. The effects produced by graded stimulation applied at the shortest conditioning-testing stimulus time intervals increased by fixed steps, suggesting recruitment of discrete elements, most likely of last-order interneurons mediating primary afferent depolarization (PAD). The short-latency increases in excitability produced by the weakest effective intraspinal stimuli were usually detected only in the collateral closest to the stimulating micropipette, indicating that the stimulated interneurons mediating PAD have spatially restricted actions. The short-latency PAD produced by intraspinal stimuli, as well as the PAD produced by stimulation of the posterior biceps and semitendinosus (PBSt) nerve or by stimulation of the bulbar reticular formation (RF), was depressed 19-30 min after the i.v. injection of 0.5 mg/kg of picrotoxin, suggesting that all these effects were mediated by GABAergic mechanisms. The PAD elicited by stimulation of muscle and/or cutaneous nerves was depressed following the i.v. injection of (-)-baclofen, whereas the PAD elicited in the same collateral by stimulation of the RF was baclofen-resistant. The short-latency PAD produced by intraspinal stimulation was not always depressed by i.v. injections of (-)-baclofen. Baclofen-sensitive and baclofen-resistant monosynaptic PADs could be produced in different collaterals of the same afferent fiber. The results suggest that the intraspinal terminals of single muscle afferents receive synapses from more than one PAD-mediating GABAergic interneuron and that a single last-order interneuron has synaptic connections with a restricted number of intraspinal terminals and/or collaterals of the same afferent fiber. In addition, they support the existence of separate subsets of last-order baclofen-sensitive and baclofen-resistant interneurons that respond predominantly to segmental and to descending inputs. It is suggested that the restricted nature of the PAD plays an important role in the central control of the synaptic effectiveness of group I muscle afferents. PMID:9262194

Quevedo, J; Eguibar, J R; Lomeli, J; Rudomin, P



Convergence of excitatory and inhibitory hair cell transmitters shapes vestibular afferent responses  

PubMed Central

The vestibular semicircular canals respond to angular acceleration that is integrated to angular velocity by the biofluid mechanics of the canals and is the primary origin of afferent responses encoding velocity. Surprisingly, some afferents actually report angular acceleration. Our data indicate that hair-cell/afferent synapses introduce a mathematical derivative in these afferents that partially cancels the biomechanical integration and results in discharge rates encoding angular acceleration. We examined the role of convergent synaptic inputs from hair cells to this mathematical differentiation. A significant reduction in the order of the differentiation was observed for low-frequency stimuli after ?-aminobutyric acid type B receptor antagonist administration. Results demonstrate that ?-aminobutyric acid participates in shaping the temporal dynamics of afferent responses.

Holstein, Gay R.; Rabbitt, Richard D.; Martinelli, Giorgio P.; Friedrich, Victor L.; Boyle, Richard D.; Highstein, Stephen M.



Synaptic organization of damaged infraorbital nerve axons in perinatal rats: demonstration by galanin immunocytochemistry  

Microsoft Academic Search

Neonatal transection of the infraorbital nerve (ION; the trigeminal, V, branch that supplies the mystacial vibrissae follicles) results in an upregulation of galanin in the central arbors of primary afferent axons. The present study was undertaken to evaluate the synaptic organization of these galanin-positive primary afferents and compare it with that of normal neurobiotin\\/biocytin-labeled primary afferent axons from animals of

Robert S. Crissman; Li Zheng; Nicolas L. Chiaia; Robert W. Rhoades



Glutamate transport blockade has a differential effect on AMPA and NMDA receptor-mediated synaptic transmission in the developing barrel cortex.  


High affinity glutamate transport plays an important role in maintaining a low extracellular glutamate concentration in the CNS. Excitotoxicity due to a loss of glutamate transporter function has been implicated in disease processes such as stroke and amyotrophic lateral sclerosis (ALS). We studied the effects of glutamate transport inhibitors on thalamocortical synapses at developing (postnatal day 3-8) layer IV neurons in the barrel cortex using the thalamocortical slice preparation and whole-cell recordings. Inhibition of glutamate transport by D,L-threo-beta-hydroxyaspartate (THA), a combination of THA and dihydrokainate (DHK), or by L-trans-pyrrolidine-2,4-dicarboxylate (tPDC), caused a reversible blockade of AMPA and kainate receptor-mediated dual component excitatory postsynaptic currents (AMPA/KA EPSCs). This effect was not blocked by cyclothiazide (CTZ) indicating that is was not due to desensitisation of AMPARs. Under conditions in which NMDA receptors were unblocked the transport inhibitors caused the massive activation of NMDA receptors leading to the rapid loss of recordings. Previous studies using these transport inhibitors on brain slices from older animals reported no or only modest effects on synaptic transmission. Therefore the data in the present study suggest that neurons in the developing neocortex are particularly sensitive to glutamate transporter function. Furthermore the effects of transport inhibition are dependent upon whether neurons are sufficiently depolarised to relieve the voltage-dependent block of NMDA receptors. PMID:10699439

Kidd, F L; Isaac, J T



Monoallelic deletion of the microRNA biogenesis gene Dgcr8 produces deficits in the development of excitatory synaptic transmission in the prefrontal cortex  

PubMed Central

Background Neuronal phenotypes associated with hemizygosity of individual genes within the 22q11.2 deletion syndrome locus hold potential towards understanding the pathogenesis of schizophrenia and autism. Included among these genes is Dgcr8, which encodes an RNA-binding protein required for microRNA biogenesis. Dgcr8 haploinsufficient mice (Dgcr8+/-) have reduced expression of microRNAs in brain and display cognitive deficits, but how microRNA deficiency affects the development and function of neurons in the cerebral cortex is not fully understood. Results In this study, we show that Dgcr8+/- mice display reduced expression of a subset of microRNAs in the prefrontal cortex, a deficit that emerges over postnatal development. Layer V pyramidal neurons in the medial prefrontal cortex of Dgcr8+/- mice have altered electrical properties, decreased complexity of basal dendrites, and reduced excitatory synaptic transmission. Conclusions These findings demonstrate that precise microRNA expression is critical for the postnatal development of prefrontal cortical circuitry. Similar defects in neuronal maturation resulting from microRNA deficiency could represent endophenotypes of certain neuropsychiatric diseases of developmental onset.



Early afferent signaling in the outer plexiform layer regulates development of horizontal cell morphology.  


The dendritic patterning of retinal horizontal cells has been shown to be specified by the cone photoreceptor afferents. The present investigation has addressed whether this specification is due to visually dependent synaptic transmission in the outer plexiform layer or to some other early, pre-visual, neural activity. Individually labeled horizontal cells from dark-reared mice, as well as from mice carrying a mutation in the Cacna1f gene, which encodes the pore-forming calcium channel subunit Ca(v)1.4, were assessed for various morphological features. The dark-reared mice showed no alteration in any of these features, despite showing a compromised maximal voltage response in the electroretinograms. The retinas of Cacna1f mutant mice, by contrast, showed conspicuous morphological changes that mimicked the effects observed previously in coneless transgenic mice. These changes were present as early as postnatal day 10, when the shape and density of the cone pedicles appeared normal. Ultrastructurally, however, the pedicles at this early stage, as well as in maturity, lacked synaptic ribbons and the invaginations associated with postsynaptic processes. These results suggest a role for this calcium channel subunit in ribbon assembly in addition to its role in modulating calcium influx and glutamate release. Together, they suggest a complex cascade of interactions between developing cone pedicles and horizontal cell dendrites involving early spontaneous activity, dendritic attraction, ribbon assembly, and pedicle invagination. PMID:18076080

Raven, Mary A; Orton, Noelle C; Nassar, Hadi; Williams, Gary A; Stell, William K; Jacobs, Gerald H; Bech-Hansen, N Torben; Reese, Benjamin E



Hydrogen sulfide augments synaptic neurotransmission in the nucleus of the solitary tract.  


Within the brain stem, the nucleus tractus solitarii (NTS) serves as a principal central site for sensory afferent integration from the cardiovascular and respiratory reflexes. Neuronal activity and synaptic transmission in the NTS are highly pliable and subject to neuromodulation. In the central nervous system, hydrogen sulfide (H?S) is a gasotransmitter generated primarily by the enzyme cystathionine-?-synthase (CBS). We sought to determine the role of H?S, and its generation by CBS, in NTS excitability. Real-time RT-PCR, immunoblot, and immunohistochemistry analysis identified the presence of CBS in the NTS. Patch-clamp electrophysiology in brain stem slices examined excitatory postsynaptic currents (EPSCs) and membrane properties in monosynaptically driven NTS neurons. Confocal imaging of labeled afferent synaptic terminals in NTS slices monitored intracellular calcium. Exogenous H?S significantly increased the amplitude of evoked solitary tract (TS)-EPSCs, frequency of miniature (m)EPSCs, and presynaptic terminal calcium fluorescence in the NTS. H?S did not alter action potential discharge or postsynaptic properties. On the other hand, the CBS inhibitor aminooxyacetate (AOA) significantly reduced the amplitude of TS-EPSCs and presynaptic terminal calcium fluorescence in the NTS without altering postsynaptic properties. Taken together, these data support a presynaptic role for endogenous H?S in modulation of excitatory neurotransmission in the NTS. PMID:21734104

Austgen, James R; Hermann, Gerlinda E; Dantzler, Heather A; Rogers, Richard C; Kline, David D



Effects of the P 2-purinoceptor antagonists suramin and pyridoxal-phosphate-6-azophenyl-2?,4?-disulfonic acid on glutamatergic synaptic transmission in rat dorsal horn neurons of the spinal cord  

Microsoft Academic Search

The effects of suramin and pyridoxal-phosphate-6-azophenyl-2?,4?-disulfonic acid (PPADS) on glutamatergic synaptic transmission were studied on dorsal horn lamina II neurons of rat spinal cord slice preparation and cultured dorsal horn neurons. Suramin at 100 ?M significantly suppressed the amplitude of the evoked excitatory postsynaptic currents (EPSCs) by 33%, miniature EPSC (mEPSC) amplitude was decreased by 46% and the mEPSC frequency

Jianguo G Gu; Rita Bardoni; Pier Cosimo Magherini; Amy B MacDermott



Physiological effects of sustained blockade of excitatory synaptic transmission on spontaneously active developing neuronal networks—an inquiry into the reciprocal linkage between intrinsic biorhythms and neuroplasticity in early ontogeny  

Microsoft Academic Search

Spontaneous bioelectric activity (SBA) taking the form of extracellularly recorded spike trains (SBA) has been quantitatively analyzed in organotypic neonatal rat visual cortex explants at different ages in vitro, and the effects investigated of both short- and long-term pharmacological suppression of glutamatergic synaptic transmission. In the presence of APV, a selective NMDA receptor blocker, 1–2- (but not 3-)week-old cultures recovered

M. A Corner; J van Pelt; P. S Wolters; R. E Baker; R. H Nuytinck



Role of P2 purinergic receptors in synaptic transmission under normoxic and ischaemic conditions in the CA1 region of rat hippocampal slices.  


The role of ATP and its stable analogue ATPgammaS [adenosine-5'-o-(3-thio)triphosphate] was studied in rat hippocampal neurotransmission under normoxic conditions and during oxygen and glucose deprivation (OGD). Field excitatory postsynaptic potentials (fEPSPs) from the dendritic layer or population spikes (PSs) from the soma were extracellularly recorded in the CA1 area of the rat hippocampus. Exogenous application of ATP or ATPgammaS reduced fEPSP and PS amplitudes. In both cases the inhibitory effect was blocked by the selective A(1) adenosine receptor antagonist DPCPX (8-cyclopentyl-1,3-dipropylxanthine) and was potentiated by different ecto-ATPase inhibitors: ARL 67156 (6-N,N-diethyl-D: -beta,gamma-dibromomethylene), BGO 136 (1-hydroxynaphthalene-3,6-disulfonate) and PV4 [hexapotassium dihydrogen monotitanoundecatungstocobaltate(II) tridecahydrate, K(6)H(2)[TiW(11)CoO(40)].13H(2)O]. ATPgammaS-mediated inhibition was reduced by the P2 antagonist suramin [8-(3-benzamido-4-methylbenzamido)naphthalene-1,3,5-trisulfonate] at the somatic level and by other P2 blockers, PPADS (pyridoxalphosphate-6-azophenyl-2',4'-disulfonate) and MRS 2179 (2'-deoxy-N (6)-methyladenosine 3',5'-bisphosphate), at the dendritic level. After removal of both P2 agonists, a persistent increase in evoked synaptic responses was recorded both at the dendritic and somatic levels. This effect was prevented in the presence of different P2 antagonists. A 7-min OGD induced tissue anoxic depolarization and was invariably followed by irreversible loss of fEPSP. PPADS, suramin, MRS2179 or BBG (brilliant blue G) significantly prevented the irreversible failure of neurotransmission induced by 7-min OGD. Furthermore, in the presence of these P2 antagonists, the development of anoxic depolarization was blocked or significantly delayed. Our results indicate that P2 receptors modulate CA1 synaptic transmission under normoxic conditions by eliciting both inhibitory and excitatory effects. In the same brain region, P2 receptor stimulation plays a deleterious role during a severe OGD insult. PMID:18404434

Coppi, Elisabetta; Pugliese, Anna Maria; Stephan, Holger; Müller, Christa E; Pedata, Felicita



TRPA1-expressing primary afferents synapse with a morphologically identified subclass of substantia gelatinosa neurons in the adult rat spinal cord.  


The TRPA1 channel has been proposed to be a molecular transducer of cold and inflammatory nociceptive signals. It is expressed on a subset of small primary afferent neurons both in the peripheral terminals, where it serves as a sensor, and on the central nerve endings in the dorsal horn. The substantia gelatinosa (SG) of the spinal cord is a key site for integration of noxious inputs. The SG neurons are morphologically and functionally heterogeneous and the precise synaptic circuits of the SG are poorly understood. We examined how activation of TRPA1 channels affects synaptic transmission onto SG neurons using whole-cell patch-clamp recordings and morphological analyses in adult rat spinal cord slices. Cinnamaldehyde (TRPA1 agonist) elicited a barrage of excitatory postsynaptic currents (EPSCs) in a subset of the SG neurons that responded to allyl isothiocyanate (less specific TRPA1 agonist) and capsaicin (TRPV1 agonist). Cinnamaldehyde evoked EPSCs in vertical and radial but not islet or central SG cells. Notably, cinnamaldehyde produced no change in inhibitory postsynaptic currents and nor did it produce direct postsynaptic effects. In the presence of tetrodotoxin, cinnamaldehyde increased the frequency but not amplitude of miniature EPSCs. Intriguingly, cinnamaldehyde had a selective inhibitory action on monosynaptic C- (but not Adelta-) fiber-evoked EPSCs. These results indicate that activation of spinal TRPA1 presynaptically facilitates miniature excitatory synaptic transmission from primary afferents onto vertical and radial cells to initiate action potentials. The presence of TRPA1 channels on the central terminals raises the possibility of bidirectional modulatory action in morphologically identified subclasses of SG neurons. PMID:20497466

Uta, Daisuke; Furue, Hidemasa; Pickering, Anthony E; Rashid, Md Harunor; Mizuguchi-Takase, Hiroko; Katafuchi, Toshihiko; Imoto, Keiji; Yoshimura, Megumu



The Abused Inhalant Toluene Differentially Modulates Excitatory and Inhibitory Synaptic Transmission in Deep-Layer Neurons of the Medial Prefrontal Cortex  

PubMed Central

Volatile organic solvents such as toluene are voluntarily inhaled for their intoxicating effects. Solvent use is especially prevalent among adolescents, and is associated with deficits in a wide range of cognitive tasks including attention, behavioral control, and risk assessment. Despite these findings, little is known about the effects of toluene on brain areas mediating these behaviors. In this study, whole-cell patch-clamp recordings were used to determine the effect toluene on neurons within the medial PFC, a region critically involved in cognitive function. Toluene had no effect on measures of intrinsic excitability, but enhanced stimulus-evoked ?-amino butyric acid A-mediated inhibitory postsynaptic currents (IPSCs). In the presence of tetrodotoxin (TTX) to block action potentials, toluene increased the frequency and amplitude of miniature IPSCs. In contrast, toluene induced a delayed but persistent decrease in evoked or spontaneous AMPA-mediated excitatory postsynaptic currents (EPSCs). This effect was prevented by an intracellular calcium chelator or by the ryanodine receptor and SERCA inhibitors, dantrolene or thapsigargin, respectively, suggesting that toluene may mobilize intracellular calcium pools. The toluene-induced reduction in AMPA EPSCs was also prevented by a cannabinoid receptor (CB1R) antagonist, and was occluded by the CB1 agonist WIN 55,212-2 that itself induced a profound decrease in AMPA-mediated EPSCs. Toluene had no effect on the frequency or amplitude of miniature EPSCs recorded in the presence of TTX. Finally, toluene dose-dependently inhibited N-methyl--aspartate (NMDA)-mediated EPSCs and the magnitude and reversibility of this effect was CB1R sensitive indicating both direct and indirect actions of toluene on NMDA-mediated responses. Together, these results suggest that the effect of toluene on cognitive behaviors may result from its action on inhibitory and excitatory synaptic transmission of PFC neurons.

Beckley, Jacob T; Woodward, John J



5-Hydroxytryptamine 2C receptors tonically augment synaptic currents in the nucleus tractus solitarii  

PubMed Central

The nucleus tractus solitarii (nTS) is the primary termination and integration point for visceral afferents in the brain stem. Afferent glutamate release and its efficacy on postsynaptic activity within this nucleus are modulated by additional neuromodulators and transmitters, including serotonin (5-HT) acting through its receptors. The 5-HT2 receptors in the medulla modulate the cardiorespiratory system and autonomic reflexes, but the distribution of the 5-HT2C receptor and the role of these receptors during synaptic transmission in the nTS remain largely unknown. In the present study, we examined the distribution of 5-HT2C receptors in the nTS and their role in modulating excitatory postsynaptic currents (EPSCs) in monosynaptic nTS neurons in the horizontal brain stem slice. Real-time RT-PCR and immunohistochemistry identified 5-HT2C receptor message and protein in the nTS and suggested postsynaptic localization. In nTS neurons innervated by general visceral afferents, 5-HT2C receptor activation increased solitary tract (TS)-EPSC amplitude and input resistance and depolarized membrane potential. Conversely, 5-HT2C receptor blockade reduced TS-EPSC and miniature EPSC amplitude, as well as input resistance, and hyperpolarized membrane potential. Synaptic parameters in nTS neurons that receive sensory input from carotid body chemoafferents were also attenuated by 5-HT2C receptor blockade. Taken together, these data suggest that 5-HT2C receptors in the nTS are located postsynaptically and augment excitatory neurotransmission.

Austgen, James R.; Dantzler, Heather A.; Barger, Brenna K.



Cyclooxygenase2 inhibitor inhibits the hippocampal synaptic reorganization by inhibiting MAPK\\/ERK activity and modulating GABAergic transmission in pilocarpine-induced status epilepticus rats  

Microsoft Academic Search

Recurring and spontaneous seizures in epilepsy result from cell signaling aberrations thought to include synaptic reorganization\\u000a and various neurotransmitter abnormalities, especially gamma-amino butyric acid (GABA) and glutamate. Cyclooxygenase-2 (COX-2)\\u000a activity produces oxidative stress and results in the production of prostaglandins that have many injurious effects. COX-2\\u000a transcription is induced by synaptic activity; therefore COX-2 may play a significant role in

Zhang Haiju; Sun Ruopeng; Lei Gefei; Yang Lu; Liu Chunxi



Lipid signaling: Sleep, synaptic plasticity, and neuroprotection  

Microsoft Academic Search

Increasing evidence indicates that bioactive lipids participate in the regulation of synaptic function and dysfunction. We have demonstrated that signaling mediated by platelet-activating factor (PAF) and cyclooxygenase (COX)-2-synthesized PGE2 is involved in synaptic plasticity, memory, and neuronal protection [Clark GD, Happel LT, Zorumski CF, Bazan NG. Enhancement of hippocampal excitatory synaptic transmission by platelet-activating factor. Neuron 1992; 9:1211; Kato K,

Chu Chen; Nicolas G. Bazan



Short-term synaptic plasticity in the nociceptive thalamic-anterior cingulate pathway  

PubMed Central

Background Although the mechanisms of short- and long-term potentiation of nociceptive-evoked responses are well known in the spinal cord, including central sensitization, there has been a growing body of information on such events in the cerebral cortex. In view of the importance of anterior cingulate cortex (ACC) in chronic pain conditions, this review considers neuronal plasticities in the thalamocingulate pathway that may be the earliest changes associated with such syndromes. Results A single nociceptive electrical stimulus to the sciatic nerve induced a prominent sink current in the layer II/III of the ACC in vivo, while high frequency stimulation potentiated the response of this current. Paired-pulse facilitation by electrical stimulation of midline, mediodorsal and intralaminar thalamic nuclei (MITN) suggesting that the MITN projection to ACC mediates the nociceptive short-term plasticity. The short-term synaptic plasticities were evaluated for different inputs in vitro where the medial thalamic and contralateral corpus callosum afferents were compared. Stimulation of the mediodorsal afferent evoked a stronger short-term synaptic plasticity and effectively transferred the bursting thalamic activity to cingulate cortex that was not true for contralateral stimulation. This short-term enhancement of synaptic transmission was mediated by polysynaptic pathways and NMDA receptors. Layer II/III neurons of the ACC express a short-term plasticity that involves glutamate and presynaptic calcium influx and is an important mechanism of the short-term plasticity. Conclusion The potentiation of ACC neuronal activity induced by thalamic bursting suggest that short-term synaptic plasticities enable the processing of nociceptive information from the medial thalamus and this temporal response variability is particularly important in pain because temporal maintenance of the response supports cortical integration and memory formation related to noxious events. Moreover, these modifications of cingulate synapses appear to regulate afferent signals that may be important to the transition from acute to chronic pain conditions associated with persistent peripheral noxious stimulation. Enhanced and maintained nociceptive activities in cingulate cortex, therefore, can become adverse and it will be important to learn how to regulate such changes in thalamic firing patterns that transmit nociceptive information to ACC in early stages of chronic pain.

Shyu, Bai-Chuang; Vogt, Brent A



Growth factors in synaptic function  

PubMed Central

Synapses are increasingly recognized as key structures that malfunction in disorders like schizophrenia, mental retardation, and neurodegenerative diseases. The importance and complexity of the synapse has fuelled research into the molecular mechanisms underlying synaptogenesis, synaptic transmission, and plasticity. In this regard, neurotrophic factors such as netrin, Wnt, transforming growth factor-? (TGF-?), tumor necrosis factor-? (TNF-?), and others have gained prominence for their ability to regulate synaptic function. Several of these factors were first implicated in neuroprotection, neuronal growth, and axon guidance. However, their roles in synaptic development and function have become increasingly clear, and the downstream signaling pathways employed by these factors have begun to be elucidated. In this review, we will address the role of these factors and their downstream effectors in synaptic function in vivo and in cultured neurons.

Poon, Vivian Y.; Choi, Sojoong; Park, Mikyoung



GABAB receptor modulation of synaptic function  

PubMed Central

Neuromodulators have complex effects on both the presynaptic release and postsynaptic detection of neurotransmitters. Here we describe recent advances in our understanding of synaptic modulation by metabotropic GABAB receptors. By inhibiting multivesicular release from the presynaptic terminal, these receptors decrease the synaptic glutamate signal. GABAB receptors also inhibit the Ca2+ permeability of NMDA receptors to decrease Ca2+ signals in postsynaptic spines. These new findings highlight the importance of GABAB receptors in regulating many aspects of synaptic transmission. They also point to novel questions about the spatiotemporal dynamics and sources of synaptic modulation in the brain.

Chalifoux, Jason R.; Carter, Adam G.



Synaptic Transmission between Dorsal Root Ganglion and Dorsal Horn Neurons in Culture: Antagonism of Monosynaptic Excitatory Postsynaptic Potentials and Glutamate Excitation by Kynurenate  

Microsoft Academic Search

intracellular recording techniques have been used to pro- vide information on the identity of excitatory sensory trans- mitters released at synapses formed between dorsal root ganglion (DRG) and dorsal horn neurons maintained in cell culture. Explants of embryonic rat DRG were added to dis- sociated cultures of embryonic dorsal horn neurons and synaptic potentials were recorded intracellularly from dorsal horn



Pre and Postnatal Propylthiouracil-Induced Hypothyroidism Impairs Synaptic Transmission and Plasticity in Area CA1 of the Neonatal Rat Hippocampus  

Microsoft Academic Search

Thyroid hormones are essential for neonatal brain develop- ment. It is well established that insufficiency of thyroid hor- mone during critical periods of development can impair cog- nitive functions. The mechanisms that underlie learning deficits in hypothyroid animals, however, are not well under- stood. As impairments in synaptic function are likely to con- tribute to cognitive deficits, the current study




Subthreshold sodium current underlies essential functional specializations at primary auditory afferents.  


Primary auditory afferents are generally perceived as passive, timing-preserving lines of communication. Contrasting this view, identifiable auditory afferents to the goldfish Mauthner cell undergo potentiation of their mixed--electrical and chemical--synapses in response to high-frequency bursts of activity. This property likely represents a mechanism of input sensitization because they provide the Mauthner cell with essential information for the initiation of an escape response. Consistent with this synaptic specialization, we show here that these afferents exhibit an intrinsic ability to respond with bursts of 200-600 Hz and this property critically relies on the activation of a persistent sodium current, which is counterbalanced by the delayed activation of an A-type potassium current. Furthermore, the interaction between these conductances with the membrane passive properties supports the presence of electrical resonance, whose frequency preference is consistent with both the effective range of hearing in goldfish and the firing frequencies required for synaptic facilitation, an obligatory requisite for the induction of activity-dependent changes. Thus our data show that the presence of a persistent sodium current is functionally essential and allows these afferents to translate behaviorally relevant auditory signals into patterns of activity that match the requirements of their fast and highly modifiable synapses. The functional specializations of these neurons suggest that auditory afferents might be capable of more sophisticated contributions to auditory processing than has been generally recognized. PMID:18234982

Curti, Sebastián; Gómez, Leonel; Budelli, Ruben; Pereda, Alberto E



Synaptic electronics.  


Conventional computers excel in logic and accurate scientific calculations but make hard work of open ended problems that human brains handle easily. Even von Neumann-the mathematician and polymath who first developed the programming architecture that forms the basis of today's computers-was already looking to the brain for future developments before his death in 1957 [1]. Neuromorphic computing uses approaches that better mimic the working of the human brain. Recent developments in nanotechnology are now providing structures with very accommodating properties for neuromorphic approaches. This special issue, with guest editors James K Gimzewski and Dominique Vuillaume, is devoted to research at the serendipitous interface between the two disciplines. 'Synaptic electronics', looks at artificial devices with connections that demonstrate behaviour similar to synapses in the nervous system allowing a new and more powerful approach to computing. Synapses and connecting neurons respond differently to incident signals depending on the history of signals previously experienced, ultimately leading to short term and long term memory behaviour. The basic characteristics of a synapse can be replicated with around ten simple transistors. However with the human brain having around 10(11) neurons and 10(15) synapses, artificial neurons and synapses from basic transistors are unlikely to accommodate the scalability required. The discovery of nanoscale elements that function as 'memristors' has provided a key tool for the implementation of synaptic connections [2]. Leon Chua first developed the concept of the 'The memristor-the missing circuit element' in 1971 [3]. In this special issue he presents a tutorial describing how memristor research has fed into our understanding of synaptic behaviour and how they can be applied in information processing [4]. He also describes, 'The new principle of local activity, which uncovers a minuscule life-enabling "Goldilocks zone", dubbed the edge of chaos, where complex phenomena, including creativity and intelligence, may emerge'. Also in this issue R Stanley Williams and colleagues report results from simulations that demonstrate the potential for using Mott transistors as building blocks for scalable neuristor-based integrated circuits without transistors [5]. The scalability of neural chip designs is also tackled in the design reported by Narayan Srinivasa and colleagues in the US [6]. Meanwhile Carsten Timm and Massimiliano Di Ventra describe simulations of a molecular transistor in which electrons strongly coupled to a vibrational mode lead to a Franck-Condon (FC) blockade that mimics the spiking action potentials in synaptic memory behaviour [7]. The 'atomic switches' used to demonstrate synaptic behaviour by a collaboration of researchers in California and Japan also come under further scrutiny in this issue. James K Gimzewski and colleagues consider the difference between the behaviour of an atomic switch in isolation and in a network [8]. As the authors point out, 'The work presented represents steps in a unified approach of experimentation and theory of complex systems to make atomic switch networks a uniquely scalable platform for neuromorphic computing'. Researchers in Germany [9] and Sweden [10] also report on theoretical approaches to modelling networks of memristive elements and complementary resistive switches for synaptic devices. As Vincent Derycke and colleagues in France point out, 'Actual experimental demonstrations of neural network type circuits based on non-conventional/non-CMOS memory devices and displaying function learning capabilities remain very scarce'. They describe how their work using carbon nanotubes provides a rare demonstration of actual function learning with synapses based on nanoscale building blocks [11]. However, this is far from the only experimental work reported in this issue, others include: short-term memory of TiO2-based electrochemical capacitors [12]; a neuromorphic circuit composed of a nanoscale 1-kbit resistive random-access memory (RRAM)

Demming, Anna; Gimzewski, James K; Vuillaume, Dominique



The afferent volleys responsible for spinal proprioceptive reflexes in man  

PubMed Central

1. To define the neural volleys responsible for the Achilles tendon jerk and the H reflex, muscle afferent activity was recorded using micro-electrodes inserted percutaneously into appropriate fascicles of the tibial nerve in the popliteal fossa. 2. The response of soleus muscle afferents to tendon percussion consisted of a dispersed volley, starting 3·5-7·0 ms after percussion, increasing to a peak over 6·5-11·0 ms, and lasting 25-30 ms, depending on the strength of percussion. Electrical stimuli to the sciatic nerve at a level adequate to evoke an H reflex but subthreshold for the M wave produced a more synchronized volley, the fastest fibres of which had conduction velocities of 62-67 m/s, and the slowest 36-45 m/s. 3. The wave of acceleration produced by percussion subthreshold for the ankle jerk spread along the skin at over 150 m/s. Midway between the bellies of the gastrocnemii it consisted of a damped oscillation with four to five separate phases and maximum amplitude approximately one-twentieth of that recorded on the Achilles tendon. 4. With ten primary spindle endings, tendon percussion subthreshold for the ankle jerk elicited two to five spike discharges per tap, the shortest interspike intervals being 4-7 ms. Tendon percussion elicited single discharges from two Golgi tendon organs, and altered the discharge pattern of a single secondary spindle ending. The degree of dispersion of the multi-unit muscle afferent volley can be explained by the pattern of discharge of primary spindle endings. 5. Percussion on the Achilles tendon evoked crisp afferent volleys in recordings from nerve fascicles innervating flexor hallucis longus, tibialis posterior, the intrinsic muscles of the foot and the skin of the foot. Electrical stimuli delivered to the tibial nerve in the popliteal fossa at a level sufficient for the H reflex of soleus produced either a volley in muscle afferents from the intrinsic muscles of the foot or a volley in cutaneous afferents from the foot. 6. For comparable stimuli in the two positions, the H reflex was inhibited but the Achilles tendon jerk enhanced when the ankle was dorsiflexed from 105° to 90°. 7. The duration of the rise times of the excitatory post-synaptic potentials (e.p.s.p.s) produced in soleus motoneurones by electrical stimulation, and by tendon percussion subthreshold for the H reflex and the ankle jerk respectively, was estimated from post-stimulus time histograms of the discharge of voluntarily activated single motor units in soleus. The mean e.p.s.p. rise times were 1·9 ms for electrical stimulation and 6·6 ms for tendon percussion. There was evidence that the duration of the electrically evoked e.p.s.p. was curtailed by an inhibitory post-synaptic potential (i.p.s.p.) of only slightly longer latency than the e.p.s.p. 8. The mechanically induced and electrically induced afferent volleys are not homogeneous volleys in group I a afferents from triceps surae. The afferent volleys differ in so many respects that it is probably invalid to compare the H reflex and tendon jerk as a measure of fusimotor activity. It is suggested that neither reflex can be considered a purely monosynaptic reflex.

Burke, David; Gandevia, Simon C.; McKeon, Brian



Non-linear summation of unit synaptic potentials in spinal motoneurones of the cat  

PubMed Central

1. Monosynaptic excitatory post-synaptic potentials (EPSPs) produced in spinal motoneurones of the cat by stimulation of a single afferent fibre were recorded with intracellular electrodes. 2. In total, seventy-three triceps surae motoneurones were studied with stimulation of thirty-six different afferent fibres. 3. The mean amplitude of the EPSPs evoked by single afferent impulses ranged from 0·06 to 2·0 mV with an average of 0·27 mV. 4. The mean number of unit EPSPs responding to a single afferent impulse (m) was calculated from the number of failures. The values ranged from 0·7 to more than 5. About 10% of the sample showed no failure of synaptic response in about 200 consecutive trials. The m values for these synaptic responses were estimated to range from 5 to 15. 5. In the majority of tests, the observed amplitude fluctuations of monosynaptic EPSPs evoked by stimulation of a single fibre were less than those expected from Poisson's law. This discrepancy may be accounted for by non-linear summation of the unit EPSPs at dendritic synaptic sites. 6. It is suggested that the synaptic responses initiated at different sites of a motoneurone may summate linearly at the soma, although summation of unit EPSPs is non-linear at individual synaptic sites.

Kuno, M.; Miyahara, J. T.



A Model of Bidirectional Synaptic Plasticity: From Signaling Network to Channel Conductance  

ERIC Educational Resources Information Center

|In many regions of the brain, including the mammalian cortex, the strength of synaptic transmission can be bidirectionally regulated by cortical activity (synaptic plasticity). One line of evidence indicates that long-term synaptic potentiation (LTP) and long-term synaptic depression (LTD), correlate with the phosphorylation/dephosphorylation of…

Castellani, Gastone C.; Quinlan, Elizabeth M.; Bersani, Ferdinando; Cooper, Leon N.; Shouval, Harel Z.



A Model of Bidirectional Synaptic Plasticity: From Signaling Network to Channel Conductance  

ERIC Educational Resources Information Center

In many regions of the brain, including the mammalian cortex, the strength of synaptic transmission can be bidirectionally regulated by cortical activity (synaptic plasticity). One line of evidence indicates that long-term synaptic potentiation (LTP) and long-term synaptic depression (LTD), correlate with the phosphorylation/dephosphorylation of…

Castellani, Gastone C.; Quinlan, Elizabeth M.; Bersani, Ferdinando; Cooper, Leon N.; Shouval, Harel Z.



Role of Afferents in the Differentiation of Bipolar Cells in the Mouse Retina  

PubMed Central

To establish dendritic arbors that integrate properly into a neural circuit, neurons must rely on cues from the local environment. The neurons presynaptic to these arbors, the afferents, are one potential source of these cues, but the particular dendritic features they regulate remain unclear. Retinal bipolar cells can be classified by the type of photoreceptor, cone or rod, forming synaptic contacts with their dendrites, suggesting a potential role of these afferents in shaping the bipolar cell dendritic arbor. In the present investigation, the role of photoreceptors in directing the differentiation of bipolar cells has been studied using two genetically modified “coneless” and “conefull” mice. Single cone (Type 7) and rod bipolar cells were labeled with DiI to reveal the entire dendritic arbor, and subsequently analyzed for several morphological features. For both cone and rod bipolar cells, the dendritic field area, number of dendritic terminals, and stratification of terminals in the outer plexiform layer (OPL) were comparable among coneless, conefull, and wildtype retinas, and the overall morphological appearance of each type of cell was largely conserved, indicating an independence from afferent specification. The presence of normal afferents was, however, found to be critical for the proper spatial distribution of dendritic terminals, exhibiting a clustered distribution for the cone bipolar cells and a dispersed distribution for the rod bipolar cells. These results demonstrate a selectivity in the afferent dependency of bipolar cell differentiation, their basic morphogenetic plan commanded cell-intrinsically, and their fine terminal connectivity directed by the afferents themselves.

Keeley, Patrick W.; Reese, Benjamin E.



FMRFamide-related peptide expression in the vestibular-afferent neurons.  


Vestibular-afferent neurons innervate hair cells from the sensory epithelia of vestibular end-organs and their action-potential discharge dynamics are driven by linear and angular accelerations of the head. The electrical activity of the vestibular-afferent neurons depends on their intrinsic properties and on the synaptic input from hair cells and from the terminals of the efferent system. Here we report that vestibular-afferent neurons of the rat are immunoreactive to RFamide-related peptides, and that the stronger signal comes from calyx-shaped neuron dendrites, with no signal detected in hair cells or supporting cells. The whole-cell voltage clamp recording of isolated afferent neurons showed that they express robust acid-sensing ionic currents (ASICs). Extracellular multiunit recordings of the vestibular nerve in a preparation in vitro of the rat inner ear showed that the perfusion of FMRFamide (a snail ortholog of this family of neuropeptides) exerts an excitatory effect on the afferent-neurons spike-discharge rate. Because the FMRFamide cannot activate the ASIC but reduces its desensitization generating a more robust current, its effect indicates that the ASIC are tonically active in the vestibular-afferent neurons and modulated by RFamide-like peptides. PMID:22342307

Mercado, Francisco; López, Iván; Ortega, Aida; Almanza, Angélica; Soto, Enrique; Vega, Rosario



Synaptic vesicle pools and dynamics.  


Synaptic vesicles release neurotransmitter at chemical synapses, thus initiating the flow of information in neural networks. To achieve this, vesicles undergo a dynamic cycle of fusion and retrieval to maintain the structural and functional integrity of the presynaptic terminals in which they reside. Moreover, compelling evidence indicates these vesicles differ in their availability for release and mobilization in response to stimuli, prompting classification into at least three different functional pools. Ongoing studies of the molecular and cellular bases for this heterogeneity attempt to link structure to physiology and clarify how regulation of vesicle pools influences synaptic strength and presynaptic plasticity. We discuss prevailing perspectives on vesicle pools, the role they play in shaping synaptic transmission, and the open questions that challenge current understanding. PMID:22745285

Alabi, AbdulRasheed A; Tsien, Richard W



Intrinsic primary afferent neuronsof the intestine  

Microsoft Academic Search

After a long period of inconclusive observations, the intrinsic primary afferent neurons of the intestine have been identified. The intestine is thus equipped with two groups of afferent neurons, those with cell bodies in cranial and dorsal root ganglia, and these recently identified afferent neurons with cell bodies in the wall of the intestine.The first, tentative, identification of intrinsic primary




Multi-locus genome-wide association analysis supports the role of glutamatergic synaptic transmission in the etiology of major depressive disorder  

PubMed Central

Major depressive disorder (MDD) is a common psychiatric illness characterized by low mood and loss of interest in pleasurable activities. Despite years of effort, recent genome-wide association studies (GWAS) have identified few susceptibility variants or genes that are robustly associated with MDD. Standard single-SNP (single nucleotide polymorphism)-based GWAS analysis typically has limited power to deal with the extensive heterogeneity and substantial polygenic contribution of individually weak genetic effects underlying the pathogenesis of MDD. Here, we report an alternative, gene-set-based association analysis of MDD in an effort to identify groups of biologically related genetic variants that are involved in the same molecular function or cellular processes and exhibit a significant level of aggregated association with MDD. In particular, we used a text-mining-based data analysis to prioritize candidate gene sets implicated in MDD and conducted a multi-locus association analysis to look for enriched signals of nominally associated MDD susceptibility loci within each of the gene sets. Our primary analysis is based on the meta-analysis of three large MDD GWAS data sets (total N=4346 cases and 4430 controls). After correction for multiple testing, we found that genes involved in glutamatergic synaptic neurotransmission were significantly associated with MDD (set-based association P=6.9 × 10?4). This result is consistent with previous studies that support a role of the glutamatergic system in synaptic plasticity and MDD and support the potential utility of targeting glutamatergic neurotransmission in the treatment of MDD.

Lee, P H; Perlis, R H; Jung, J-Y; Byrne, E M; Rueckert, E; Siburian, R; Haddad, S; Mayerfeld, C E; Heath, A C; Pergadia, M L; Madden, P A F; Boomsma, D I; Penninx, B W; Sklar, P; Martin, N G; Wray, N R; Purcell, S M; Smoller, J W



Neuroligins and Neurexins Link Synaptic Function to Cognitive Disease  

PubMed Central

Preface The brain processes information by transmitting signals at synapses, which connect neurons into vast networks of communicating cells. In these networks, synapses not only transmit, but also process and refine information. Neurexins and neuroligins are synaptic cell-adhesion molecules that connect pre- and postsynaptic neurons at synapses, mediate trans-synaptic signaling, and shape neural network properties by specifying synaptic functions. In humans, alterations in neurexin or neuroligin genes are implicated in autism and other cognitive diseases, connecting synaptic cell adhesion to cognition and its disorders. Thus, neurexins and neuroligins are core components of the molecular machinery that controls synaptic transmission and enables neural networks to process complex signals.

Sudhof, Thomas C.



Impact of Synaptic Neurotransmitter Concentration Time Course on the Kinetics and Pharmacological Modulation of Inhibitory Synaptic Currents  

PubMed Central

The time course of synaptic currents is a crucial determinant of rapid signaling between neurons. Traditionally, the mechanisms underlying the shape of synaptic signals are classified as pre- and post-synaptic. Over the last two decades, an extensive body of evidence indicated that synaptic signals are critically shaped by the neurotransmitter time course which encompasses several phenomena including pre- and post-synaptic ones. The agonist transient depends on neurotransmitter release mechanisms, diffusion within the synaptic cleft, spill-over to the extra-synaptic space, uptake, and binding to post-synaptic receptors. Most estimates indicate that the neurotransmitter transient is very brief, lasting between one hundred up to several hundreds of microseconds, implying that post-synaptic activation is characterized by a high degree of non-equilibrium. Moreover, pharmacological studies provide evidence that the kinetics of agonist transient plays a crucial role in setting the susceptibility of synaptic currents to modulation by a variety of compounds of physiological or clinical relevance. More recently, the role of the neurotransmitter time course has been emphasized by studies carried out on brain slice models that revealed a striking, cell-dependent variability of synaptic agonist waveforms ranging from rapid pulses to slow volume transmission. In the present paper we review the advances on studies addressing the impact of synaptic neurotransmitter transient on kinetics and pharmacological modulation of synaptic currents at inhibitory synapses.

Barberis, Andrea; Petrini, Enrica Maria; Mozrzymas, Jerzy W.



Identity of Endogenous NMDAR Glycine Site Agonist in Amygdala Is Determined by Synaptic Activity Level  

PubMed Central

Mechanisms of NMDA receptor-dependent synaptic plasticity contribute to the acquisition and retention of conditioned fear memory. However, synaptic rules which may determine the extent of NMDA receptor activation in the amygdala, a key structure implicated in fear learning, remain unknown. Here we show that the identity of the NMDAR glycine site agonist at synapses in the lateral nucleus of the amygdala may depend on the level of synaptic activation. Tonic activation of NMDARs at synapses in the amygdala under low-activity conditions is supported by ambient D-serine, whereas glycine may be released from astrocytes in response to afferent impulses. The release of glycine may decode the increases in afferent activity levels into enhanced NMDAR-mediated synaptic events, serving an essential function in the induction of NMDAR-dependent long-term potentiation in fear conditioning pathways.

Li, Yan; Sacchi, Silvia; Pollegioni, Loredano; Basu, Alo C.; Coyle, Joseph T.; Bolshakov, Vadim Y.



Formation and Stability of Synaptic Receptor Domains  

NASA Astrophysics Data System (ADS)

Neurotransmitter receptor molecules, concentrated in postsynaptic domains along with scaffold and a number of other molecules, are key regulators of signal transmission across synapses. Combining experiment and theory, we develop a quantitative description of synaptic receptor domains in terms of a reaction-diffusion model. We show that interactions between only receptors and scaffolds, together with the rapid diffusion of receptors on the cell membrane, are sufficient for the formation and stable characteristic size of synaptic receptor domains. Our work reconciles long-term stability of synaptic receptor domains with rapid turnover and diffusion of individual receptors, and suggests novel mechanisms for a form of short-term, postsynaptic plasticity.

Haselwandter, Christoph A.; Calamai, Martino; Kardar, Mehran; Triller, Antoine; Azeredo da Silveira, Rava



Striatal Grafts and Synaptic Plasticity  

Microsoft Academic Search

Whilst it has been demonstrated previously that embryonic striatal grafts restore the ability of the lesioned striatum to\\u000a learn new tasks, it has only been recently speculated that this is due to restoration of cellular correlates of learning and\\u000a memory. We demonstrate that embryonic striatal grafts not only restore baseline transmission, but also display synaptic plasticity,\\u000a appropriate to that observed

David Mazzocchi-Jones; Máté Döbrössy; Stephen Dunnett


Afferent Deprivation Elicits a Transcriptional Response Associated with Neuronal Survival After a Critical Period in the Mouse Cochlear Nucleus  

PubMed Central

The mechanisms underlying enhanced plasticity of synaptic connections and susceptibilities to manipulations of afferent activity in developing sensory systems are not well understood. One example is the rapid and dramatic neuron death that occurs after removal of afferent input to the cochlear nucleus (CN) of young mammals and birds. The molecular basis of this critical period of neuronal vulnerability and the transition to survival independent of afferent input remains to be defined. Here we used microarray analyses, real time RT PCR, and immunohistochemistry of the mouse CN to show that deafferentation results in strikingly different sets of regulated genes in vulnerable (postnatal day (P) 7) and invulnerable (P21) CN. An unexpectedly large set of immune-related genes was induced by afferent deprivation after the critical period, which corresponded with glial proliferation over the same time frame. Apoptotic gene expression was not highly regulated in the vulnerable CN after afferent deprivation but, surprisingly, did increase after deafferentation at P21, when all neurons ultimately survive. Pharmacological activity blockade in the 8th nerve mimicked afferent deprivation for only a subset of the afferent deprivation regulated genes, indicating the presence of an additional factor not dependent on action potential-mediated signaling that is also responsible for transcriptional changes. Overall, our results suggest that the cell death machinery during this critical period is mainly constitutive, whereas after the critical period neuronal survival could be actively promoted by both constitutive and induced gene expression.

Harris, Julie A.; Iguchi, Fukuichiro; Seidl, Armin H.; Lurie, Diana I.; Rubel, Edwin W



Theta Frequency Background Tunes Transmission but Not Summation of Spiking Responses  

PubMed Central

Hippocampal neurons are known to fire as a function of frequency and phase of spontaneous network rhythms, associated with the animal's behaviour. This dependence is believed to give rise to precise rate and temporal codes. However, it is not well understood how these periodic membrane potential fluctuations affect the integration of synaptic inputs. Here we used sinusoidal current injection to the soma of CA1 pyramidal neurons in the rat brain slice to simulate background oscillations in the physiologically relevant theta and gamma frequency range. We used a detailed compartmental model to show that somatic current injection gave comparable results to more physiological synaptically driven theta rhythms incorporating excitatory input in the dendrites, and inhibitory input near the soma. We systematically varied the phase of synaptic inputs with respect to this background, and recorded changes in response and summation properties of CA1 neurons using whole-cell patch recordings. The response of the cell was dependent on both the phase of synaptic inputs and frequency of the background input. The probability of the cell spiking for a given synaptic input was up to 40% greater during the depolarized phases between 30–135 degrees of theta frequency current injection. Summation gain on the other hand, was not affected either by the background frequency or the phasic afferent inputs. This flat summation gain, coupled with the enhanced spiking probability during depolarized phases of the theta cycle, resulted in enhanced transmission of summed inputs during the same phase window of 30–135 degrees. Overall, our study suggests that although oscillations provide windows of opportunity to selectively boost transmission and EPSP size, summation of synaptic inputs remains unaffected during membrane oscillations.

Parameshwaran, Dhanya; Bhalla, Upinder S.



Metabotropic glutamate receptors and striatal synaptic plasticity: implications for neurological diseases  

Microsoft Academic Search

Long- and short-term changes in the efficacy of synaptic transmission are known as synaptic plasticity. Phenomena such as long-term depression (LTD) and long-term potentiation (LTP) are two classical forms of synaptic plasticity that are expressed in several brain areas, including the striatum. Bi-directional changes in corticostriatal synaptic transmission, i.e. LTD and LTP, have been proposed to represent the cellular mechanisms

Paolo Gubellini; Antonio Pisani; Diego Centonze; Giorgio Bernardi; Paolo Calabresi



Presynaptic inhibition of primary afferents by depolarization: observations supporting nontraditional mechanisms.  


Primary afferent neurotransmission is the fundamental first step in the central processing of sensory stimuli and is controlled by pre- and postsynaptic inhibitory mechanisms. Presynaptic inhibition (PSI) is probably the more powerful form of inhibitory control in all primary afferent fibers. A major mechanism producing afferent PSI is via a channel-mediated depolarization of their intraspinal terminals, which can be recorded extracellularly as a dorsal root potential (DRP). Based on measures of DRP latency it has been inferred that this primary afferent depolarization (PAD) of low-threshold afferents is mediated by minimally trisynaptic pathways with pharmacologically identified GABAergic interneurons forming last-order axo-axonic synapses onto afferent terminals. There is still no "squeaky clean" evidence of this organization. This paper describes recent and historical work that supports the existence of PAD occurring by more direct pathways and with a complex pharmacology that questions the proprietary role of GABA and GABA(A) receptors in this process. Cholinergic transmission in particular may contribute significantly to PAD, including via direct release from primary afferents. PMID:20536928

Hochman, Shawn; Shreckengost, Jacob; Kimura, Hiroshi; Quevedo, Jorge



Connections between thoraco-coxal proprioceptive afferents and motor neurons in the locust.  


The position of the coxal segment of the locust hind leg relative to the thorax is monitored by a variety of proprioceptors, including three chordotonal organs and a myochordotonal organ. The sensory neurons of two of these proprioceptors, the posterior joint chordotonal organ (pjCO) and the myochordotonal organ (MCO), have axons in the purely sensory metathoracic nerve 2C (N2C). The connections made by these afferents with metathoracic motor neurons innervating thoraco-coxal and wing muscles were investigated by electrical stimulation of N2C and by matching postsynaptic potentials in motor neurons with afferent spikes in N2C. Stretch applied to the anterior rotator muscle of the coxa (M121), with which the MCO is associated, evoked sensory spikes in N2C. Some of the MCO afferent neurons make direct excitatory chemical synaptic connections with motor neurons innervating the thoraco-coxal muscles M121, M126 and M125. Parallel polysynaptic pathways via unidentified interneurons also exist between MCO afferents and these motor neurons. Connections with the common inhibitor 1 neuron and motor neurons innervating the thoraco-coxal muscles M123/4 and wing muscles M113 and M127 are polysynaptic. Afferents of the pjCO also make polysynaptic connections with motor neurons innervating thoraco-coxal and wing muscles, but no evidence for monosynaptic pathways was found. PMID:10637173

Wildman, M



Fluoxetine (Prozac) and Serotonin Act on Excitatory Synaptic Transmission to Suppress Single Layer 2/3 Pyramidal Neuron-Triggered Cell Assemblies in the Human Prefrontal Cortex  

PubMed Central

Selective serotonin reuptake inhibitors are the most widely prescribed drugs targeting the CNS with acute and chronic effects in cognitive, emotional and behavioral processes. This suggests that microcircuits of the human cerebral cortex are powerfully modulated by selective serotonin reuptake inhibitors, however, direct measurements of serotonergic regulation on human synaptic interactions are missing. Using multiple whole-cell patch-clamp recordings from neurons in acute cortical slices derived from nonpathological human samples of the prefrontal cortex, we show that neuronal assemblies triggered by single action potentials of individual neurons in the human cortex are suppressed by therapeutic doses of fluoxetine (Prozac). This effect is boosted and can be mimicked by physiological concentrations of serotonin through 5HT-2A and 5HT-1A receptors. Monosynaptic excitatory connections from pyramidal cells to interneurons were suppressed by application of serotonin leaving the monosynaptic output of GABAergic cells unaffected. Changes in failure rate, in paired-pulse ratio, and in the coefficient of variation of the amplitude of EPSPs suggest a presynaptic action of serotonin. In conclusion, activation of neuronal assemblies, which were suggested as building blocks of high order cognitive processes, are effectively downregulated by the acute action of selective serotonin reuptake inhibitors or serotonin at the site of pyramidal output in human microcircuits.

Komlosi, Gergely; Molnar, Gabor; Rozsa, Marton; Olah, Szabolcs; Barzo, Pal



The fraction of activated N-methyl-d-Aspartate receptors during synaptic transmission remains constant in the presence of the glutamate release inhibitor riluzole  

PubMed Central

Excessive N-methyl-d-aspartate (NMDA) receptor activation is widely accepted to mediate calcium-dependent glutamate excitotoxicity. The uncompetitive, voltage-dependent NMDA receptor antagonist memantine has been successfully used clinically in the treatment of neurodegenerative dementia and is internationally registered for the treatment of moderate to severe Alzheimer?s disease. Glutamate release inhibitors (GRIs) may also be promising for the therapy of some neurodegenerative diseases. During the clinical use of GRIs, it could be questioned whether there would still be a sufficient number of active NMDA receptors to allow any additional effects of memantine or similar NMDA receptor antagonists. To address this question, we determined the fraction of NMDA receptors contributing to postsynaptic events in the presence of therapeutically relevant concentrations of the GRI riluzole (1 ?M) using an in vitro hippocampal slice preparation. We measured the charge transfer of pharmacologically isolated excitatory synaptic responses before and after the application of the selective, competitive NMDA receptor antagonist D-AP5 (100 ?M). The fraction of activated NMDA receptors under control conditions did not differ from those in the presence of riluzole. It is therefore likely that NMDA receptor antagonists would be able to exert additional therapeutic effects in combination therapy with GRIs.

Zieglgansberger, W.; Parsons, C. G.



Fluoxetine (prozac) and serotonin act on excitatory synaptic transmission to suppress single layer 2/3 pyramidal neuron-triggered cell assemblies in the human prefrontal cortex.  


Selective serotonin reuptake inhibitors are the most widely prescribed drugs targeting the CNS with acute and chronic effects in cognitive, emotional and behavioral processes. This suggests that microcircuits of the human cerebral cortex are powerfully modulated by selective serotonin reuptake inhibitors, however, direct measurements of serotonergic regulation on human synaptic interactions are missing. Using multiple whole-cell patch-clamp recordings from neurons in acute cortical slices derived from nonpathological human samples of the prefrontal cortex, we show that neuronal assemblies triggered by single action potentials of individual neurons in the human cortex are suppressed by therapeutic doses of fluoxetine (Prozac). This effect is boosted and can be mimicked by physiological concentrations of serotonin through 5HT-2A and 5HT-1A receptors. Monosynaptic excitatory connections from pyramidal cells to interneurons were suppressed by application of serotonin leaving the monosynaptic output of GABAergic cells unaffected. Changes in failure rate, in paired-pulse ratio, and in the coefficient of variation of the amplitude of EPSPs suggest a presynaptic action of serotonin. In conclusion, activation of neuronal assemblies, which were suggested as building blocks of high order cognitive processes, are effectively downregulated by the acute action of selective serotonin reuptake inhibitors or serotonin at the site of pyramidal output in human microcircuits. PMID:23152619

Komlósi, Gergely; Molnár, Gábor; Rózsa, Márton; Oláh, Szabolcs; Barzó, Pál; Tamás, Gábor



Postnatal deamidation of 4E-BP2 in brain enhances its association with raptor and alters kinetics of excitatory synaptic transmission  

PubMed Central

Summary The eIF4E-binding proteins (4E-BPs) repress translation initiation by preventing eIF4F complex formation. Of the three mammalian 4E-BPs, only 4E-BP2 is enriched in the mammalian brain and plays an important role in synaptic plasticity and learning and memory formation. Here we describe asparagine deamidation as brain-specific posttranslational modification of 4E-BP2. Deamidation is the spontaneous conversion of asparagines to aspartates. Two deamidation sites were mapped to an asparagine-rich sequence unique to 4E-BP2. Deamidated 4E-BP2 exhibits increased binding to the mammalian Target of Rapamycin (mTOR)-binding protein raptor, which effects its reduced association with eIF4E. 4E-BP2 deamidation occurs during postnatal development, concomitant with the attenuation of the activity of the PI3K-Akt-mTOR signalling pathway. Expression of deamidated 4E-BP2 in 4E-BP2?/? neurons yielded mEPSCs exhibiting increased charge transfer with slower rise and decay kinetics, relative to the wild type form. 4E-BP2 deamidation may represent a compensatory mechanism for the developmental reduction of PI3K-Akt-mTOR signalling.

Bidinosti, Michael; Ran, Israeli; Sanchez-Carbente, Maria R.; Martineau, Yvan; Gingras, Anne-Claude; Gkogkas, Christos; Raught, Brian; Bramham, Clive; Sossin, Wayne S.; Costa-Mattioli, Mauro; DesGroseillers, Luc; Lacaille, Jean-Claude; Sonenberg, Nahum



Short-term plasticity at primary afferent synapse in rat spinal dorsal horn and its biological function.  


Short-term plasticity (STP) is an important element of information processing in neuronal networks. As the first synaptic relay between primary afferent fibers (PAFs) and central neurons, primary afferent synapses in spinal dorsal horn (DH) are essential to the initial processing of somatosensory information. In this research, we examined the STP between Adelta-PAFs and spinal DH neurons by patch-clamp recording. Our results showed that depression dominated the STP at primary afferent synapses. The curves of STP had no significant changes in the presence of bicuculline, CTZ or AP-5. Lowering extracellular Ca(2+) concentration ([Ca(2+)](o)) from 2.4 to 0.8 mM reduced the depression of synaptic responses at all stimulus rates, while raising [Ca(2+)](o) from 2.4 to 4.0 mM increased the synaptic depression. Increasing the bath temperature from 24 to 32 degrees C clearly reduced the depression of all responses. These results indicate that the observed STP is of presynaptic origin and depends on transmitter release. By fitting the experimental data recorded under different conditions, a model of STP was used to quantitatively characterize the observed STP and to analyze the possible mechanisms underlying the effects of [Ca(2+)](o) and temperature. Furthermore, using a model neuron receiving synaptic inputs, we found that with this form of STP, postsynaptic DH neurons could detect rate changes in both rapidly- and slowly-firing afferents with equal sensitivity. The present study links the intrinsic STP properties of primary afferent synapses with their role in processing neural information, and provides a basis for further research on the STP in spinal DH and its biological function under in vivo conditions. PMID:16864969

Wan, Ye-hong; Jian, Zhong; Wang, Wen-ting; Xu, Hui; Hu, San-jue; Ju, Gong



How many kinds of visceral afferents?  

PubMed Central

Most afferent signals from the viscera do not give rise to conscious experience and yet they participate in the complex neural control of visceral functions. Surprisingly little information is available on the origin, morphology, and receptor functional characteristics of the nerve endings of most primary afferent neurones to the digestive tract. This review deals with the morphological nature of the afferent neurones that supply the gastrointestinal tract specifically.

Costa, M; Brookes, S; Zagorodnyuk, V



Specificity of afferent synapses onto plane-polarized hair cells in the posterior lateral line of the zebrafish  

PubMed Central

The proper wiring of the vertebrate brain represents an extraordinary developmental challenge, requiring billions of neurons to select their appropriate synaptic targets. In view of this complexity, simple vertebrate systems provide necessary models for understanding how synaptic specificity arises. The posterior lateral-line organ of larval zebrafish consists of polarized hair cells organized in discrete clusters known as neuromasts. Here we show that each afferent neuron of the posterior lateral line establishes specific contacts with hair cells of the same hair-bundle polarity. We quantify this specificity by modeling the neuron as a biased selector of hair-cell polarity and find evidence for bias from as early as 2.5 days post-fertilization. More than half of the neurons form contacts on multiple neuromasts, but the innervated organs are spatially consecutive and the polarity preference is consistent. Using a novel reagent for correlative electron microscopy, HRP-mCherry, we show that these contacts are indeed afferent synapses bearing vesicle-loaded synaptic ribbons. Moreover, afferent neurons reassume their biased innervation pattern after hair-cell ablation and regeneration. By documenting specificity in the pattern of neuronal connectivity during development and in the context of organ regeneration, these results establish the posterior lateral-line organ as a vertebrate system for the in vivo study of synaptic target selection.

Nagiel, Aaron; Andor-Ardo, Daniel



Neuron morphology and synaptic architecture in the medial superior olivary nucleus  

Microsoft Academic Search

Dendritic arborization pattern, spatial and synaptic relations of various neuron types and the terminal distribution of afferent axons of various origin were studied in the medial superior olivary nucleus of the cat using Golgi, degeneration, electron microscope and horseradish peroxidase techniques. Three types of neurons clearly different in morphological features, distribution, neighbourhood relations, input and output characteristics were distinguished: (1)

A. Kiss; K. Majorossy



Nicotine and Synaptic Plasticity in Prefrontal Cortex  

NSDL National Science Digital Library

Nicotinic receptor activation enhances working memory and attention. The prefrontal cortex is a key brain area involved in working memory, and plasticity of excitatory synaptic transmission within the cortex is likely an important cellular mechanism of memory. A recent study has explored the cellular and synaptic basis of nicotine’s effects on excitability within the prefrontal cortex. The findings suggest that nicotine enhances inhibitory synaptic inputs to layer V pyramidal cells, which suppresses induction of long-term potentiation (LTP). This inhibitory effect can be overcome by stimulating the pyramidal cells in bursts, which suggests a modification in the signal-to-noise ratio for synaptic input. Thus, the impact of strong stimuli on working memory would be enhanced when combined with nicotinic receptor activity. These findings may lead to novel and more effective treatments for memory disorders.

Daniel S. McGehee (University of Chicago;Department of Anesthesia and Critical Care REV)



Permanent central synaptic disconnection of proprioceptors after nerve injury and regeneration. I. Loss of VGLUT1/IA synapses on motoneurons  

PubMed Central

Motor and sensory proprioceptive axons reinnervate muscles after peripheral nerve transections followed by microsurgical reattachment; nevertheless, motor coordination remains abnormal and stretch reflexes absent. We analyzed the possibility that permanent losses of central IA afferent synapses, as a consequence of peripheral nerve injury, are responsible for this deficit. VGLUT1 was used as a marker of proprioceptive synapses on rat motoneurons. After nerve injuries synapses are stripped from motoneurons, but while other excitatory and inhibitory inputs eventually recover, VGLUT1 synapses are permanently lost on the cell body (75–95% synaptic losses) and on the proximal 100 ?m of dendrite (50% loss). Lost VGLUT1 synapses did not recover, even many months after muscle reinnervation. Interestingly, VGLUT1 density in more distal dendrites did not change. To investigate whether losses are due to VGLUT1 downregulation in injured IA afferents or to complete synaptic disassembly and regression of IA ventral projections, we studied the central trajectories and synaptic varicosities of axon collaterals from control and regenerated afferents with IA-like responses to stretch that were intracellularly filled with neurobiotin. VGLUT1 was present in all synaptic varicosities, identified with the synaptic marker SV2, of control and regenerated afferents. However, regenerated afferents lacked axon collaterals and synapses in lamina IX. In conjunction with the companion electrophysiological study [Bullinger KL, Nardelli P, Pinter MJ, Alvarez FJ, Cope TC. J Neurophysiol (August 10, 2011). doi:10.1152/jn.01097.2010], we conclude that peripheral nerve injuries cause a permanent retraction of IA afferent synaptic varicosities from lamina IX and disconnection with motoneurons that is not recovered after peripheral regeneration and reinnervation of muscle by sensory and motor axons.

Titus-Mitchell, Haley E.; Bullinger, Katie L.; Kraszpulski, Michal; Nardelli, Paul; Cope, Timothy C.



Finite Post Synaptic Potentials Cause a Fast Neuronal Response  

PubMed Central

A generic property of the communication between neurons is the exchange of pulses at discrete time points, the action potentials. However, the prevalent theory of spiking neuronal networks of integrate-and-fire model neurons relies on two assumptions: the superposition of many afferent synaptic impulses is approximated by Gaussian white noise, equivalent to a vanishing magnitude of the synaptic impulses, and the transfer of time varying signals by neurons is assessable by linearization. Going beyond both approximations, we find that in the presence of synaptic impulses the response to transient inputs differs qualitatively from previous predictions. It is instantaneous rather than exhibiting low-pass characteristics, depends non-linearly on the amplitude of the impulse, is asymmetric for excitation and inhibition and is promoted by a characteristic level of synaptic background noise. These findings resolve contradictions between the earlier theory and experimental observations. Here we review the recent theoretical progress that enabled these insights. We explain why the membrane potential near threshold is sensitive to properties of the afferent noise and show how this shapes the neural response. A further extension of the theory to time evolution in discrete steps quantifies simulation artifacts and yields improved methods to cross check results.

Helias, Moritz; Deger, Moritz; Rotter, Stefan; Diesmann, Markus



Synaptic Vesicle Transporter Expression Regulates Vesicle Phenotype and Quantal Size  

Microsoft Academic Search

While the transporters that accumulate classical neurotransmit- ters in synaptic vesicles have been identified, little is known about how their expression regulates synaptic transmission. We have used adenoviral-mediated transfection to increase expres- sion of the brain vesicular monoamine transporter VMAT2 and presynaptic amperometric recordings to characterize the effects on quantal release. In presynaptic axonal varicosities of ventral midbrain neurons in

Emmanuel N. Pothos; Kristin E. Larsen; David E. Krantz; Yong-jian Liu; John W. Haycock; Wanda Setlik; Michael D. Gershon; Robert H. Edwards; David Sulzer



Afferent Fibers with Multiple Encoding Sites.  

National Technical Information Service (NTIS)

A primary afferent fiber with the capability for initiating impulses at more than one sensory terminal belongs to one of two classes. The first, termed simulanteous reset, appears to be more common in nature, including most, if not all myelinated afferent...

J. P. Eagles R. L. Purple



Vagal afferent fibres determine the oxytocin-induced modulation of gastric tone.  


Oxytocin (OXT) inputs to the dorsal vagal complex (DVC; nucleus of the tractus solitarius (NTS) dorsal motor nucleus of the vagus (DMV) and area postrema) decrease gastric tone and motility. Our first aim was to investigate the mechanism(s) of OXT-induced gastric relaxation. We demonstrated recently that vagal afferent inputs modulate NTS-DMV synapses involved in gastric and pancreatic reflexes via group II metabotropic glutamate receptors (mGluRs). Our second aim was to investigate whether group II mGluRs similarly influence the response of vagal motoneurons to OXT. Microinjection of OXT in the DVC decreased gastric tone in a dose-dependent manner. The OXT-induced gastric relaxation was enhanced following bethanechol and reduced by l-NAME administration, suggesting a nitrergic mechanism of gastroinhibition. DVC application of the group II mGluR antagonist EGLU induced a gastroinhibition that was not dose dependent and shifted the gastric effects of OXT to a cholinergic-mediated mechanism. Evoked and miniature GABAergic synaptic currents between NTS and identified gastric-projecting DMV neurones were not affected by OXT in any neurones tested, unless the brainstem slice was (a) pretreated with EGLU or (b) derived from rats that had earlier received a surgical vagal deafferentation. Conversely, OXT inhibited glutamatergic currents even in naive slices, but their responses were unaffected by EGLU pretreatment. These results suggest that the OXT-induced gastroinhibition is mediated by activation of the NANC pathway. Inhibition of brainstem group II mGluRs, however, uncovers the ability of OXT to modulate GABAergic transmission between the NTS and DMV, resulting in the engagement of an otherwise silent cholinergic vagal neurocircuit. PMID:23587885

Holmes, Gregory M; Browning, Kirsteen N; Babic, Tanja; Fortna, Samuel R; Coleman, F Holly; Travagli, R Alberto



Transcriptional coupling of synaptic transmission and energy metabolism: Role of nuclear respiratory factor 1 in co-regulating neuronal nitric oxide synthase and cytochrome c oxidase genes in neurons  

PubMed Central

SUMMARY Neuronal activity is highly dependent on energy metabolism; yet, the two processes have traditionally been regarded as independently regulated at the transcriptional level. Recently, we found that the same transcription factor, nuclear respiratory factor 1 (NRF-1) co-regulates an important energy-generating enzyme, cytochrome c oxidase, as well as critical subunits of glutamatergic receptors. The present study tests our hypothesis that the co-regulation extends to the next level of glutamatergic synapses, namely, neuronal nitric oxide synthase, which generates nitric oxide as a downstream signaling molecule. Using in silico analysis, electrophoretic mobility shift assay, chromatin immunoprecipitation, promoter mutations, and NRF-1 silencing, we documented that NRF-1 functionally bound to Nos1, but not Nos2 (inducible) and Nos3 (endothelial) gene promoters. Both COX and Nos1 transcripts were up-regulated by depolarizing KCl treatment and down-regulated by TTX-mediated impulse blockade in neurons. However, NRF-1 silencing blocked the up-regulation of both Nos1 and COX induced by KCl depolarization, and over-expression of NRF-1 rescued both Nos1 and COX transcripts downregulated by TTX. These findings are consistent with our hypothesis that synaptic neuronal transmission and energy metabolism are tightly coupled at the molecular level.

Dhar, Shilpa S.; Liang, Huan Ling; Wong-Riley, Margaret T. T.



Differences in Synaptic GABA A Receptor Number Underlie Variation in GABA Mini Amplitude  

Microsoft Academic Search

In many neurons, responses to individual quanta of transmitter exhibit large variations in amplitude. The origin of this variability, although central to our understanding of synaptic transmission and plasticity, remains controversial. To examine the relationship between quantal amplitude and postsynaptic receptor number, we adopted a novel approach, combining patch-clamp recording of synaptic currents with quantitative immunogold localization of synaptic receptors.

Zoltan Nusser; Stuart Cull-Candy; Mark Farrant



Mechanism of the 5-hydroxytryptamine 2A receptor-mediated facilitation of synaptic activity in prefrontal cortex.  


Classic hallucinogens such as lysergic acid diethylamide are thought to elicit their psychotropic actions via serotonin receptors of the 5-hydroxytryptamine 2A subtype (5-HT(2A)R). One likely site for these effects is the prefrontal cortex (PFC). Previous studies have shown that activation of 5-HT(2A)Rs in this region results in a robust increase in spontaneous glutamatergic synaptic activity, and these results have led to the widely held idea that hallucinogens elicit their effect by modulating synaptic transmission within the PFC. Here, we combine cellular and molecular biological approaches, including single-cell 5-HT(2A)Rs inactivation and 5-HT(2A)R rescue over a 5-HT(2A)R knockout genetic background, to distinguish between competing hypotheses accounting for these effects. The results from these experiments do not support the idea that 5-HT(2A)Rs elicit the release of an excitatory retrograde messenger nor that they activate thalamocortical afferents, the two dominant hypotheses. Rather, they suggest that 5-HT(2A)Rs facilitate intrinsic networks within the PFC. Consistent with this idea, we locate a discrete subpopulation of pyramidal cells that is strongly excited by 5-HT(2A)R activation. PMID:17535909

Béďque, Jean-Claude; Imad, Mays; Mladenovic, Ljiljana; Gingrich, Jay A; Andrade, Rodrigo



Resting Discharge Patterns of Macular Primary Afferents in Otoconia-Deficient Mice  

PubMed Central

Vestibular primary afferents in the normal mammal are spontaneously active. The consensus hypothesis states that such discharge patterns are independent of stimulation and depend instead on excitation by vestibular hair cells due to background release of synaptic neurotransmitter. In the case of otoconial sensory receptors, it is difficult to test the independence of resting discharge from natural tonic stimulation by gravity. We examined this question by studying discharge patterns of single vestibular primary afferent neurons in the absence of gravity stimulation using two mutant strains of mice that lack otoconia (OTO?; head tilt, het-Nox3, and tilted, tlt-Otop1). Our findings demonstrated that macular primary afferent neurons exhibit robust resting discharge activity in OTO? mice. Spike interval coefficient of variation (CV?=?SD/mean spike interval) values reflected both regular and irregular discharge patterns in OTO? mice, and the range of values for rate-normalized CV was similar to mice and other mammals with intact otoconia although there were proportionately fewer irregular fibers. Mean discharge rates were slightly higher in otoconia-deficient strains even after accounting for proportionately fewer irregular fibers [OTO??=?75.4?±?31.1(113) vs OTO+?=?68.1?±?28.5(143) in sp/s]. These results confirm the hypothesis that resting activity in macular primary afferents occurs in the absence of ambient stimulation. The robust discharge rates are interesting in that they may reflect the presence of a functionally ‘up-regulated’ tonic excitatory process in the absence of natural sensory stimulation.

Jones, S. M.; Hoffman, L. F.



Direct Evidence for Cortical Suppression of Somatosensory Afferents during Visuomotor Adaptation  

Microsoft Academic Search

Upon exposure to novel visuomotor relationships, the information carried by visual and proprioceptive signals becomes discrepant, often disrupting motor execution. It has been shown that degradation of the proprioceptive sense (arising either from disease or experimental manipulation) enhances performance when drawing with mirror-reversed vision. Given that the central nervous system can exert a dynamic control over the transmission of afferent

Pierre-Michel Bernier; Boris Burle; Franck Vidal; Thierry Hasbroucq; Jean Blouin



Transmission in a locomotor-related group Ib pathway from hindlimb extensor muscles in the cat  

Microsoft Academic Search

It has been previously shown that phasic stimulation of group I afferents from ankle and knee extensor muscles may entrain and\\/or reset the intrinsic locomotor rhythm; these afferents are thus acting on motoneurones through the spinal rhythm generators. It was also concluded that the major part of these effects originates from Golgi tendon organ Ib afferents. Transmission in this pathway

J.-P. Gossard; R. M. Brownstone; I. Barajon; H. Hultborn



Endogenous Brain Derived Neurotrophic Factor in the Nucleus Tractus Solitarius Tonically Regulates Synaptic and Autonomic Function  

PubMed Central

Brain derived neurotrophic factor (BDNF) and its receptor, TrkB, are highly expressed in the nucleus tractus solitarius (nTS), the principal target of cardiovascular primary afferent input to the brainstem. However, little is known about the role of BDNF signaling in nTS in cardiovascular homeostasis. We examined whether BDNF in nTS modulates cardiovascular function in vivo and regulates synaptic and/or neuronal activity in isolated brainstem slices. Microinjection of BDNF into the rat medial nTS (mnTS), a region critical for baroreflex control of sympathetic outflow, produced dose-dependent increases in mean arterial pressure (MAP), heart rate (HR) and lumbar sympathetic nerve activity (LSNA) that were blocked by the tyrosine kinase inhibitor K252a. In contrast, immunoneutralization of endogenous BDNF (antiBDNF), or microinjection of K252a alone, decreased MAP, HR and LSNA. The effects of antiBDNF were abolished by blockade of ionotropic glutamate receptors, indicating a role for glutamate signaling in the response to BDNF. In vitro, BDNF reduced the amplitude of miniature excitatory postsynaptic currents (mEPSCs) as well as solitary tract (TS)-evoked EPSC amplitude and action potential discharge (APD) in second-order nTS neurons. BDNF effects on EPSCs were independent of GABAergic signaling and ablated by AMPA receptor blockade. In contrast, K252a increased spontaneous EPSC frequency and TS-evoked EPSC amplitude. BDNF also attenuated APD evoked by injection of depolarizing current into second-order neurons, indicating reduced intrinsic neuronal excitability. Our data demonstrate that BDNF signaling in mnTS plays a tonic role in regulating cardiovascular function, likely via modulation of primary afferent glutamatergic excitatory transmission and neural activity.

Clark, Catharine G.; Hasser, Eileen M.; Kunze, Diana L.; Katz, David M.; Kline, David D.



MAGUKs, Synaptic Development, and Synaptic Plasticity  

PubMed Central

MAGUKs are proteins that act as key scaffolds in surface complexes containing receptors, adhesion proteins, and various signaling molecules. These complexes evolved prior to the appearance of multicellular animals and play key roles in cell-cell intercommunication. A major example of this is the neuronal synapse, which contains several presynaptic and postsynaptic MAGUKs including PSD-95, SAP102, SAP97, PSD-93, CASK, and MAGIs. Here, they play roles in both synaptic development and in later synaptic plasticity events. During development, MAGUKs help to organize the postsynaptic density via associations with other scaffolding proteins, such as Shank, and the actin cytoskeleton. They affect the clustering of glutamate receptors and other receptors, and these associations change with development. MAGUKs are involved in long-term potentiation and depression (e.g., via their phosphorylation by kinases and phosphorylation of other proteins associated with MAGUKs). Importantly, synapse development and function are dependent on the kind of MAGUK present. For example, SAP102 shows high mobility and is present in early synaptic development. Later, much of SAP102 is replaced by PSD-95, a more stable synaptic MAGUK; this is associated with changes in glutamate receptor types that are characteristic of synaptic maturation.

Zheng, Chan-Ying; Seabold, Gail K.; Horak, Martin; Petralia, Ronald S.



Coupling of energy metabolism and synaptic transmission at the transcriptional level: Role of nuclear respiratory factor 1 in regulating both cytochrome c oxidase and NMDA glutamate receptor subunit genes  

PubMed Central

Neuronal activity and energy metabolism are tightly coupled processes. Regions high in neuronal activity, especially of the glutamatergic type, have high levels of cytochrome c oxidase (COX). Perturbations in neuronal activity affect the expressions of COX and glutamatergic N-methyl-D-aspartate receptor subunit 1 (NR1). The present study sought to test our hypothesis that the coupling extends to the transcriptional level, whereby NR1 and possibly other NR subunits and COX are co-regulated by the same transcription factor, nuclear respiratory factor 1 (NRF-1), which regulates all COX subunit genes. By means of multiple approaches, including in silico analysis, electrophoretic mobility shift and supershift assays, in vivo chromatin immunoprecipitation, promoter mutations, and real-time quantitative PCR, NRF-1 was found to functionally bind to the promoters of Grin 1 (NR1), Grin 2b (NR2b) and COX subunit genes, but not of Grin2a and Grin3a genes. These transcripts were up-regulated by KCl and down-regulated by TTX in cultured primary neurons. However, silencing of NRF-1 with small interference RNA blocked the up-regulation of Grin1, Grin2b, and COX induced by KCl, and over-expression of NRF-1 rescued these transcripts that were suppressed by TTX. NRF-1 binding sites on Grin1 and Grin2b genes are also highly conserved among mice, rats, and humans. Thus, NRF-1 is an essential transcription factor critical in the co-regulation of NR1, NR2b, and COX, and coupling exists at the transcriptional level to ensure coordinated expressions of proteins important for synaptic transmission and energy metabolism.

Dhar, Shilpa S.; Wong-Riley, Margaret T. T.



Ca2+/calmodulin-dependent kinase II mediates simultaneous enhancement of gap-junctional conductance and glutamatergic transmission  

PubMed Central

While chemical synapses are very plastic and modifiable by defined activity patterns, gap junctions, which mediate electrical transmission, have been classically perceived as passive intercellular channels. Excitatory transmission between auditory afferents and the goldfish Mauthner cell is mediated by coexisting gap junctions and glutamatergic synapses. Although an increased intracellular Ca2+ concentration is expected to reduce gap junctional conductance, both components of the synaptic response were instead enhanced by postsynaptic increases in Ca2+ concentration, produced by patterned synaptic activity or intradendritic Ca2+ injections. The synaptically induced potentiations were blocked by intradendritic injection of KN-93, a Ca2+/calmodulin-dependent kinase (CaM-K) inhibitor, or CaM-KIINtide, a potent and specific peptide inhibitor of CaM-KII, whereas the responses were potentiated by injection of an activated form of CaM-KII. The striking similarities of the mechanisms reported here with those proposed for long-term potentiation of mammalian glutamatergic synapses suggest that gap junctions are also similarly regulated and indicate a primary role for CaM-KII in shaping and regulating interneuronal communication, regardless of its modality.

Pereda, Alberto E.; Bell, Theodore D.; Chang, Bill H.; Czernik, Andrew J.; Nairn, Angus C.; Soderling, Thomas R.; Faber, Donald S.



Movement and afferent representations in human motor areas: a simultaneous neuroimaging and transcranial magnetic/peripheral nerve-stimulation study  

PubMed Central

Neuroimaging combined with transcranial magnetic stimulation (TMS) to primary motor cortex (M1) is an emerging technique that can examine motor-system functionality through evoked activity. However, because sensory afferents from twitching muscles are widely represented in motor areas the amount of evoked activity directly resulting from TMS remains unclear. We delivered suprathreshold TMS to left M1 or gave electrical right median nerve stimulation (MNS) in 18 healthy volunteers while simultaneously conducting functional magnetic resonance imaging and monitoring with electromyography (EMG). We examined in detail the localization of TMS-, muscle afferent- and superficial afferent-induced activity in M1 subdivisions. Muscle afferent- and TMS-evoked activity occurred mainly in rostral M1, while superficial afferents generated a slightly different activation distribution. In 12 participants who yielded quantifiable EMG, differences in brain activity ascribed to differences in movement-size were adjusted using integrated information from the EMGs. Sensory components only explained 10–20% of the suprathreshold TMS-induced activity, indicating that locally and remotely evoked activity in motor areas mostly resulted from the recruitment of neural and synaptic activity. The present study appears to justify the use of fMRI combined with suprathreshold TMS to M1 for evoked motor network imaging.

Shitara, H.; Shinozaki, T.; Takagishi, K.; Honda, M.; Hanakawa, T.



Movement and afferent representations in human motor areas: a simultaneous neuroimaging and transcranial magnetic/peripheral nerve-stimulation study.  


Neuroimaging combined with transcranial magnetic stimulation (TMS) to primary motor cortex (M1) is an emerging technique that can examine motor-system functionality through evoked activity. However, because sensory afferents from twitching muscles are widely represented in motor areas the amount of evoked activity directly resulting from TMS remains unclear. We delivered suprathreshold TMS to left M1 or gave electrical right median nerve stimulation (MNS) in 18 healthy volunteers while simultaneously conducting functional magnetic resonance imaging and monitoring with electromyography (EMG). We examined in detail the localization of TMS-, muscle afferent- and superficial afferent-induced activity in M1 subdivisions. Muscle afferent- and TMS-evoked activity occurred mainly in rostral M1, while superficial afferents generated a slightly different activation distribution. In 12 participants who yielded quantifiable EMG, differences in brain activity ascribed to differences in movement-size were adjusted using integrated information from the EMGs. Sensory components only explained 10-20% of the suprathreshold TMS-induced activity, indicating that locally and remotely evoked activity in motor areas mostly resulted from the recruitment of neural and synaptic activity. The present study appears to justify the use of fMRI combined with suprathreshold TMS to M1 for evoked motor network imaging. PMID:24062660

Shitara, H; Shinozaki, T; Takagishi, K; Honda, M; Hanakawa, T



The temporoammonic input to the hippocampal CA1 region displays distinctly different synaptic plasticity compared to the Schaffer collateral input in vivo: significance for synaptic information processing  

PubMed Central

In terms of its sub-regional differentiation, the hippocampal CA1 region receives cortical information directly via the perforant (temporoammonic) path (pp-CA1 synapse) and indirectly via the tri-synaptic pathway where the last relay station is the Schaffer collateral-CA1 synapse (Sc-CA1 synapse). Research to date on pp-CA1 synapses has been conducted predominantly in vitro and never in awake animals, but these studies hint that information processing at this synapse might be distinct to processing at the Sc-CA1 synapse. Here, we characterized synaptic properties and synaptic plasticity at the pp-CA1 synapse of freely behaving adult rats. We observed that field excitatory postsynaptic potentials at the pp-CA1 synapse have longer onset latencies and a shorter time-to-peak compared to the Sc-CA1 synapse. LTP (>24 h) was successfully evoked by tetanic afferent stimulation of pp-CA1 synapses. Low frequency stimulation evoked synaptic depression at Sc-CA1 synapses, but did not elicit LTD at pp-CA1 synapses unless the Schaffer collateral afferents to the CA1 region had been severed. Paired-pulse responses also showed significant differences. Our data suggest that synaptic plasticity at the pp-CA1 synapse is distinct from the Sc-CA1 synapse and that this may reflect its specific role in hippocampal information processing.

Aksoy-Aksel, Ayla; Manahan-Vaughan, Denise



The temporoammonic input to the hippocampal CA1 region displays distinctly different synaptic plasticity compared to the Schaffer collateral input in vivo: significance for synaptic information processing.  


In terms of its sub-regional differentiation, the hippocampal CA1 region receives cortical information directly via the perforant (temporoammonic) path (pp-CA1 synapse) and indirectly via the tri-synaptic pathway where the last relay station is the Schaffer collateral-CA1 synapse (Sc-CA1 synapse). Research to date on pp-CA1 synapses has been conducted predominantly in vitro and never in awake animals, but these studies hint that information processing at this synapse might be distinct to processing at the Sc-CA1 synapse. Here, we characterized synaptic properties and synaptic plasticity at the pp-CA1 synapse of freely behaving adult rats. We observed that field excitatory postsynaptic potentials at the pp-CA1 synapse have longer onset latencies and a shorter time-to-peak compared to the Sc-CA1 synapse. LTP (>24 h) was successfully evoked by tetanic afferent stimulation of pp-CA1 synapses. Low frequency stimulation evoked synaptic depression at Sc-CA1 synapses, but did not elicit LTD at pp-CA1 synapses unless the Schaffer collateral afferents to the CA1 region had been severed. Paired-pulse responses also showed significant differences. Our data suggest that synaptic plasticity at the pp-CA1 synapse is distinct from the Sc-CA1 synapse and that this may reflect its specific role in hippocampal information processing. PMID:23986697

Aksoy-Aksel, Ayla; Manahan-Vaughan, Denise



Quantification of morphological differences in boutons from different afferent populations to the nucleus accumbens.  


The nucleus accumbens (Acb) receives convergent glutamatergic inputs from the prefrontal cortex (PFC), central thalamus, basolateral amygdala and the ventral subiculum of the hippocampus. The principal neurons of the nucleus accumbens are modulated by specific sets of convergent afferent inputs, the local circuit neurons also receive a substantial number of glutamatergic inputs, but the full complement of these has yet to be established. The aim of these studies was to define characteristics of the different glutamatergic afferent inputs to the nucleus accumbens that would aid their identification. To enable the characterisation of the glutamatergic inputs to nucleus accumbens neurons we first labelled the four main glutamatergic sources of afferent input to the accumbens with the anterograde tracer biotinylated dextran amine (BDA). Using an unbiased systematic sampling method, the morphological characteristics of their synaptic boutons were measured and assessed at the electron microscopic level. From the criteria assessed, a comparison of the four afferent sources was made, characteristics such as bouton size and vesicle density had significantly different population means, however, the only characteristic that allowed discrimination between the four major glutamatergic afferent to the nucleus accumbens was that of vesicle size. The vesicles in boutons from amygdala were larger than the subiculum which, in turn, were larger than the prefrontal cortex, the thalamus were the smallest in size. The methods used also allow a comparison of the relative frequency of different sized postsynaptic structures targeted, the prefrontal cortex almost exclusively targeted spines whereas the thalamus and the subiculum, in addition to spines, targeted proximal and distal dendrites. PMID:15064148

French, Sarah Jane; Totterdell, Susan



Ceramidase Regulates Synaptic Vesicle Exocytosis and Trafficking  

PubMed Central

A screen for Drosophila synaptic dysfunction mutants identified slug-a-bed (slab). The slab gene encodes ceramidase, a central enzyme in sphingolipid metabolism and regulation. Sphingolipids are major constituents of lipid rafts, membrane domains with roles in vesicle trafficking, and signaling pathways. Null slab mutants arrest as fully developed embryos with severely reduced movement. The SLAB protein is widely expressed in different tissues but enriched in neurons at all stages of development. Targeted neuronal expression of slab rescues mutant lethality, demonstrating the essential neuronal function of the protein. C5-ceramide applied to living preparations is rapidly accumulated at neuromuscular junction (NMJ) synapses dependent on the SLAB expression level, indicating that synaptic sphingolipid trafficking and distribution is regulated by SLAB function. Evoked synaptic currents at slab mutant NMJs are reduced by 50–70%, whereas postsynaptic glutamate-gated currents are normal, demonstrating a specific presynaptic impairment. Hypertonic saline-evoked synaptic vesicle fusion is similarly impaired by 50–70%, demonstrating a loss of readily releasable vesicles. In addition, FM1-43 dye uptake is reduced in slab mutant presynaptic terminals, indicating a smaller cycling vesicle pool. Ultrastructural analyses of mutants reveal a normal vesicle distribution clustered and docked at active zones, but fewer vesicles in reserve regions, and a twofold to threefold increased incidence of vesicles linked together and tethered at the plasma membrane. These results indicate that SLAB ceramidase function controls presynaptic terminal sphingolipid composition to regulate vesicle fusion and trafficking, and thus the strength and reliability of synaptic transmission.

Rohrbough, Jeffrey; Rushton, Emma; Palanker, Laura; Woodruff, Elvin; Matthies, Heinrich J. G.; Acharya, Usha; Acharya, Jairaj K.; Broadie, Kendal



Deep Tissue Afferents, but not Cutaneous Afferents, Mediate Transcutaneous Electrical Nerve Stimulation–Induced Antihyperalgesia  

Microsoft Academic Search

In this study we investigated the involvement of cutaneous versus knee joint afferents in the antihyperalgesia produced by transcutaneous electrical nerve stimulation (TENS) by differentially blocking primary afferents with local anesthetics. Hyperalgesia was induced in rats by inflaming one knee joint with 3% kaolin-carrageenan and assessed by measuring paw withdrawal latency to heat before and 4 hours after injection. Skin

Rajan Radhakrishnan; Kathleen A. Sluka



Input-output relation of transmission through cuneate nucleus.  

PubMed Central

1. In decerebrate cats, micro-electrodes were inserted into the cuneate nucleus to stimulate afferent terminals with single shocks of varying intensities. Estimates of the input and output of the nucleus were obtained by integrating antidromic responses in forelimb cutaneous nerves and orthodromic responses in the medial lemniscus. 2. Input-output curves were normally very non-linear, reflecting the high synaptic potency of small inputs. They were fitted readily by power functions, with exponents averaging 0-50. 3. The normal input-output relation rapidly disappeared after interruption of the blood supply. A loss of synaptic efficiency of small inputs was indicated by curves with exponents of greater than or equal to 1; this was associated with a sharp increase in terminal excitability. 4. Within the range of surface temperature 30-40 degrees C, warming made the input-output curves steeper but reduced terminal excitability, whereas cooling had the opposite effect. The efficiency of transmission was thus inversely correlated with terminal excitability. 5. The non-linear shape of cuneate input-output curves is probably not determined by inhibitory control, since picrotoxin depressed rather than enhanced outputs. 6. On the other hand, pentobarbitone made the input-output curves markedly steeper and tended to lower terminal excitability.

Krnjevic, K; Morris, M E



Prenatal Exposure to Elevated NT3 Disrupts Synaptic Selectivity in the Spinal Cord  

PubMed Central

Monosynaptic connections between muscle spindle (Ia) afferents and motoneurons (MNs), the central portion of the stretch reflex circuit, are highly specific, but the mechanisms underlying this specificity are largely unknown. In this study, we report that embryonic over-expression of NT3 in muscles disrupts the development of these specific Ia-MN connections, utilizing transgenic (mlc/NT3) mice that express elevated levels of NT3 in muscles during development. In mlc/NT3 mice, there is a substantial increase in the amplitudes of monosynaptic excitatory postsynaptic potentials evoked by Ia afferents in MNs as measured with extracellular recordings from ventral roots. Despite this increased functional projection of Ia afferents, there is no obvious change in the anatomical density of Ia projections into the ventral horn of the spinal cord. Intracellular recordings from MNs revealed a major disruption in the pattern of Ia-MN connections. In addition to the normal connections between Ia afferents and MNs supplying the same muscle, there were also strong monosynaptic inputs from Ia afferents supplying unrelated muscles, which explains the increase seen in extracellular recordings. There was also a large variability in the strength of Ia input to individual MNs, both from correct and incorrect Ia afferents. Postnatal muscular administration of NT3 did not cause these changes in connectivity. These results indicate that prenatal exposure to elevated levels of NT3 disrupts the normal mechanisms responsible for synaptic selectivity in the stretch reflex circuit.

Wang, Z.; Li, L-Y.; Taylor, M. T.; Wright, D. E.; Frank, E.