Presynaptic Action Potentials Research Articles

Synaptic decision making: flipping switch-like synapses with cubic autocatalysis.

Event Abstract Back to Event Synaptic decision making: flipping switch-like synapses with cubic autocatalysis. In the brain, the process of learning is a noisy decision making process. At the level of a single synapse, when two connected neurons are active, each generating a different noisy, but perhaps correlated, sequence of action potentials, the synapse connecting them faces a decision ? how or whether to modify the strength of that connection. Recent work suggests that this change in synapse strength might come in the form of one of two binary decisions (O'Connor et al., PNAS102:9679-9684, 2005). For a synapse in a low-state, the decision is whether to increase in strength (long-term potentiation; LTP), or remain the same. For a synapse in a high-state, the decision is whether to decrease in strength (long-term depression; LTD) or remain the same. When plasticity is measured in a population of synapses, graded learning rules can be measured which reflect the statistics of the single synapse decisions. One form of learning rule which has generated a great deal of interest over the last decade is spike-timing dependent plasticity (STDP), in which the amount and direction of plasticity is a function of the timing difference between presynaptic and postsynaptic action potentials. In hippocampal synapses however, the story is more complicated: both the magnitude and direction of plasticity are influenced by other activity parameters such as spiking frequency, the number of pairings delivered (Wittenberg and Wang, J Neurosci 26:6610-6617, 2006). The biophysical mechanism by which neural activity changes the strength and state of a synapse is well-studied. Both increases in synapse strength and decreases in synapse strength are initiated by increases in postsynaptic [Ca2+] at the synapse above baseline [Ca2+] levels. Large calcium transients drive synapses to potentiate, whereas moderate and prolonged calcium transient drive synapses to depress. The goal of this work is to synthesize and summarize these experimental findings with a simple biophysical model for a switch-like synapse. We construct a simple model based on the bistability arising from cubic autocatalysis, which is reminiscent of the Activator/Inhibitor models for spatial pattern formation in animal coats. With this approach we are able to naturally capture the features of the learning rule determined at the CA3-CA1 synapse described above. Conference: Computational and systems neuroscience 2009, Salt Lake City, UT, United States, 26 Feb - 3 Mar, 2009. Presentation Type: Poster Presentation Topic: Poster Presentations Citation: (2009). Synaptic decision making: flipping switch-like synapses with cubic autocatalysis.. Front. Syst. Neurosci. Conference Abstract: Computational and systems neuroscience 2009. doi: 10.3389/conf.neuro.06.2009.03.273 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 04 Feb 2009; Published Online: 04 Feb 2009. Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract Supplemental Data The Authors in Frontiers Google Google Scholar PubMed Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Firing-rate response properties of spiking neurons: beyond the diffusion limit

Event Abstract Back to Event Firing-rate response properties of spiking neurons: beyond the diffusion limit Eilen Nordlie1*, Tom Tetzlaff1 and Gaute T. Einevoll1 1 Norwegian University of Life Sciences, Department of Mathematical Sciences and Technology, Norway Instantaneous firing rates are often used to describe either the compound spiking activity of neuron ensembles (population rate) or the trial-averaged response of individual neurons to multiple repetitions of the same stimulus. For the case of weak synapses and high input firing rates (diffusion limit), the (linear) rate response of an ensemble of independent neurons has been derived in previous studies for several integrate-and-fire (IaF) neuron models [1-5]. The assumption of weak synapses can however not always be justified: in the early visual pathway, for example, single action potentials emitted by retinal ganglion cells initiate response spikes in postsynaptic thalamic cells with a high probability [6]. Also within the cortex, a considerable fraction of synapses has moderately strong weights [7,8]. It is unclear to what extent the results obtained under the diffusion approximation can be generalised to these cases.Here, we numerically investigate the response properties of leaky IaFneurons receiving input spikes through arbitrarily strong excitatory (current-based alpha-) synapses. The input spike trains are modelled as Poisson point-processes with sinusoidal intensity. Modulation amplitudes and phases of the trial-averaged spike responses are measured for a broad range of stimulus modulation frequencies and synaptic weights.We show that the input-output rate transmission can be well modelled by a simple first-order low-pass filter (Fig.A). The dependence of the cutoff frequency fcon the synaptic weight w (Fig.B) is dominated by a sharp increase of fc at a critical weight wc (the minimal weight for which a single presynaptic action potential leads to a threshold crossing in the postsynaptic cell; dashed vertical line in Fig.B). In general, the cutoff frequencies are determined by the time constants τm and τs of both the membrane and the postsynaptic currents. The dependence on τm disappears if the synaptic weights are normalised by wc. The remaining dependence on τs is most prominent in the supercritical regime (w>wc). Acknowledgements:We acknowledge partial support by the Research Council of Norway (eNEURO, NOTUR) and the Honda Research Institute Europe. All simulations were carried out with the NEST simulation tool (see http://www.nest-initiative.org).

Synaptic Vesicles in Mature Calyx of Held Synapses Sense Higher Nanodomain Calcium Concentrations during Action Potential-Evoked Glutamate Release

During development of the calyx of Held synapse, presynaptic action potentials (APs) become substantially faster and briefer. Nevertheless, this synapse is able to upregulate quantal output triggered by arriving APs. Briefer APs lead to less effective gating of voltage-gated Ca(2+) channels (VGCCs). Therefore, mechanisms downstream of Ca(2+) entry must effectively compensate for the attenuated Ca(2+) influx associated with shorter APs in more mature calyces. This compensation could be achieved by tighter spatial coupling between VGCCs and synaptic vesicles, so that the latter are exposed to higher intracellular Ca(2+) concentration ([Ca(2+)](i)). Alternatively or additionally, the Ca(2+) sensitivity of the release apparatus may increase during synapse development. To differentiate between these possibilities, we combined paired patch-clamp recordings with Ca(2+) imaging and flash photolysis of caged Ca(2+) and estimated the [Ca(2+)](i) requirements for vesicle release in the developing mouse calyx of Held synapse. Surprisingly, the dose-response relationship between [Ca(2+)](i) and release rate was shifted slightly to the right in more mature calyces, rendering their vesicles slightly less sensitive to incoming Ca(2+). Taking into account the time course and peak rates of AP-evoked release transients for the corresponding developmental stages, we estimate the local [Ca(2+)](i)"seen" by the Ca(2+) sensors on synaptic vesicles to increase from 35 to 56 mum [from postnatal day 9 (P9)-P11 to P16-P19]. Our results reinforce the idea that developmental tightening of the spatial coupling between VGCCs and synaptic vesicles plays a predominant role in enhancing quantal output at this synapse and possibly other central synapses.

Functional tetrodotoxin-resistant Na + channels are expressed presynaptically in rat dorsal root ganglia neurons

The tetrodotoxin-resistant (TTX-R) voltage-gated Na + channels Na v1.8 and Na v1.9 are expressed by a subset of primary sensory neurons and have been implicated in various pain states. Although recent studies suggest involvement of TTX-R Na + channels in sensory synaptic transmission and spinal pain processing, it remains unknown whether TTX-R Na + channels are expressed and function presynaptically. We examined expression of TTX-R channels at sensory synapses formed between rat dorsal root ganglion (DRG) and spinal cord (SC) neurons in a DRG/SC co-culture system. Immunostaining showed extensive labeling of presynaptic axonal boutons with Na v1.8- and Na v1.9-specific antibodies. Measurements using the fluorescent Na + indicator SBFI demonstrated action potential–induced presynaptic Na + entry that was resistant to tetrodotoxin (TTX) but was blocked by lidocaine. Furthermore, presynaptic [Ca 2+] i elevation in response to a single action potential was not affected by TTX in TTX-resistant DRG neurons. Finally, glutamatergic synaptic transmission was not inhibited by TTX in more than 50% of synaptic pairs examined; subsequent treatment with lidocaine completely blocked these TTX-resistant excitatory postsynaptic currents. Taken together, these results provide evidence for presynaptic expression of functional TTX-R Na + channels that may be important for shaping presynaptic action potentials and regulating transmitter release at the first sensory synapse.

Control of Presynaptic Function by a Persistent Na + Current

Little is known about ion channels that regulate the graded, subthreshold properties of nerve terminals. Using the calyx of Held, we demonstrate here a large presynaptic persistent Na(+) current with unusually hyperpolarized activation voltage. This feature allowed the current to determine both the resting potential and resting conductance of the nerve terminal. Calyces express presynaptic glycine receptors whose activation depolarizes the synapse. We found that activation of the persistent Na(+) current was an essential component in the response to glycine. This Na(+) current originated at or very close to the terminal and was sustained even after trains of large spike-like depolarizations. Because Na(+) channels also underlie the presynaptic action potential, we conclude that their action both triggers and modulates exocytosis through control of presynaptic membrane voltage.

An action potential‐induced and ryanodine sensitive calcium transient dynamically regulates transmitter release at synapses between Lymnaea neurons

The notion that calcium released through ryanodine receptors effects presynaptic neurotransmitter release is gaining acceptance with the observation that this calcium does indeed contribute to both action potential-evoked and spontaneous transmitter release in a variety of preparations. However, the dynamics of this calcium release and its impact on transmitter release has not yet been fully elucidated. Moreover, in contrast to vertebrate synapses, much less is known about the involvement of ryanodine receptors in the regulation of transmitter release at invertebrate synapses. In this study, we reconstructed specific synapses between individually identifiable preand postsynaptic neurons from Lymnaea to demonstrate that although ryanodine reduces the amplitude of the action potential-induced calcium transient, it does not however, alter the resting calcium level. These data suggest that action potential-induced calcium release through ryanodine receptors is fast and highly dynamic and in turn regulates transmitter release at reconstructed synapses between Lymnaea neurons. This study thus provides direct evidence that a dynamic ryanodine receptor-mediated calcium transient occurs with the presynaptic action potential.

Role of Rab27 in synaptic transmission at the squid giant synapse

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 Ca(2+) current. This result was confirmed in in vitro synaptosomes by using total internal reflection fluorescence microscopy. Thus, synaptosomal Ca(2+)-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.

Hydrozoan nematocytes send and receive synaptic signals induced by mechano-chemical stimuli

Nematocytes, the stinging cells of Hydrozoa, can be considered as prototypic mechanosensory hair cells bearing a concentric hair bundle, the cnidocil apparatus. These cells produce typical mechanoreceptor potentials in response to deflection of their cnidocil. Here we show that mechanosensory signals are relayed to neighbouring nematocytes via chemical neurotransmission and that nematocytes receive synaptic input from surrounding nematocytes, hair cells and probably from epithelial cells. Intracellular voltage recordings from stenotele nematocytes of capitate hydroid polyps showed two distinct types of responses when other nematocytes within the same tentacle were mechanically stimulated: (i) graded depolarizations of variable duration ('L-potentials'), and (ii) uniform impulse-like, often repetitive depolarizations ('T-potentials') that occurred in correlation with contractions of epitheliomuscular cells. Voltage clamp experiments showed that despite the stereotyped time course of T-potentials, their generation did not involve electrically excitable conductances. Instead, time course, post-stimulus delay, susceptibility to blockers of neurotransmission and gap junctions, and induction by electrical stimulation of other nematocytes indicate that L- and T-potentials are postsynaptic, most likely glutamatergic potentials. Both result from different presynaptic pathways: L-potentials are induced monosynaptically by presynaptic receptor potentials, T-potentials are most likely triggered by presynaptic action potentials propagating through the ectodermal epithelium via gap junctions. Moreover, contact-chemosensory (phospholipid) stimulation of the presynaptic nematocyte is a positive modulator of the nematocyte's afferent synaptic efficacy and of cnidocyst discharge, both triggered by mechanoreceptor potentials. The results reveal that hydrozoan nematocytes act as bimodal sensory cells, signalling coincident chemical and mechanical stimuli indicative of prey, and receive signals from other nematocytes and sensory cells.

Diazepam attenuates the post-traumatic hyperactivity of excitatory synapses in rat hippocampal CA1 neurons

The effect of diazepam, a benzodiazepine derivative, on the post-traumatic hyperactivity of excitatory synaptic transmission was examined in rat hippocampal CA1 area. Optical recordings showed that the activity of hippocampal neurons was enhanced in rats treated with fluid percussion injury (FPI) as compared with that of sham-operated rats. The optical response was characterized by fast and slow components. FPI did not affect the fast component that reflects presynaptic action potentials, but enhanced the slow component that reflects excitatory synaptic responses. Intracellular recordings showed that the amplitude and duration of the excitatory postsynaptic potential (EPSP) were increased after FPI. However, FPI did not affect the resting membrane potential and action potentials of hippocampal neurons. Intraperitoneal (i.p.) administration of diazepam (30 and 90 min after FPI) attenuated the post-traumatic hyperactivity of the slow optical response. The slope of input-to-output relation of excitatory synapses was decreased by acute administration of diazepam to FPI rats, but not by delayed administration of diazepam (4 and 5 h after FPI). The fast optical responses were not affected by either FPI or i.p. administration of diazepam. These results suggest that administration of diazepam at early post-traumatic period prevents the FPI-induced delayed enhancement of excitatory synaptic transmission in rat hippocampal CA1 neurons.

Frequency-Dependent Glycinergic Inhibition Modulates Plasticity in Hippocampus

Previous studies have demonstrated the presence of functional glycine receptors (GlyRs) in hippocampus. In this work, we examine the baseline activity and activity-dependent modulation of GlyRs in region CA1. We find that strychnine-sensitive GlyRs are open in the resting CA1 pyramidal cell, creating a state of tonic inhibition that "shunts" the magnitude of EPSPs evoked by electrical stimulation of the Schaffer collateral inputs. This GlyR-mediated shunting conductance is independent of the presynaptic stimulation rate; however, pairs of presynaptic and postsynaptic action potentials, repeated at frequencies above 5 Hz, reduce the GlyR-mediated conductance and increase peak EPSP magnitudes to levels at least 20% larger than those seen with presynaptic stimulation alone. We refer to this phenomenon as rate-dependent efficacy (RDE). Exogenous GlyR agonists (glycine, taurine) block RDE by preventing the closure of postsynaptic GlyRs. The GlyR antagonist strychnine blocks postsynaptic GlyRs under all conditions, occluding RDE. During RDE, GlyRs are less responsive to local glycine application, suggesting that a reduction in the number or sensitivity of membrane-inserted GlyRs underlies RDE. By extending the RDE induction protocol to include 500 paired presynaptic and postsynaptic spikes, we can induce long-term synaptic depression (LTD). Manipulations that lead to reduced functionality of GlyRs, either pharmacologically or through RDE, also lead to increased LTD. This result suggests that RDE contributes to long-term synaptic plasticity in the hippocampus.

GABAB Receptor Modulation of Feedforward Inhibition through Hippocampal Neurogliaform Cells

Feedforward inhibition of neurons is a fundamental component of information flow control in the brain. We studied the roles played by neurogliaform cells (NGFCs) of stratum lacunosum moleculare of the hippocampus in providing feedforward inhibition to CA1 pyramidal cells. We recorded from synaptically coupled pairs of anatomically identified NGFCs and CA1 pyramidal cells and found that, strikingly, a single presynaptic action potential evoked a biphasic unitary IPSC (uIPSC), consisting of two distinct components mediated by GABA(A) and GABA(B) receptors. A GABA(B) receptor-mediated unitary response has not previously been observed in hippocampal excitatory neurons. The decay of the GABA(A) receptor-mediated response was slow (time constant = 50 ms), and was tightly regulated by presynaptic GABA(B) receptors. Surprisingly, the GABA(B) receptor ligands baclofen and (2S)-3-{[(1S)-1-(3,4-dichlorophenyl)ethyl]amino-2-hydroxypropyl}(phenylmethyl)phosphinic acid (CGP55845), while affecting the NGFC-mediated uIPSCs, had no effect on action potential-evoked presynaptic Ca2+ signals monitored in individual axonal boutons of NGFCs with two-photon microscopy. In contrast, baclofen clearly depressed presynaptic Ca2+ transients in non-NGF interneurons. Changes in extracellular Ca2+ concentration that mimicked the effects of baclofen or CGP55845 on uIPSCs significantly altered presynaptic Ca2+ transients. Electrophysiological data suggest that GABA(B) receptors expressed by NGFCs contribute to the dynamic control of the excitatory input to CA1 pyramidal neurons from the temporoammonic path. The NGFC-CA1 pyramidal cell connection therefore provides a unique and subtle mechanism to shape the integration time domain for signals arriving via a major excitatory input to CA1 pyramidal cells.

Fluoxetine potentiates GABAergic IPSCs in rat hippocampal neurons

The GABA system is highly involved in the pathophysiology of mood disorders such as depression. Altered GABAergic function is evident in depressed patients and animal models of depression. Currently, the most widely used antidepressants are selective 5-HT reuptake inhibitors, such as fluoxetine. However, the effects of fluoxetine on GABAergic synaptic neurotransmission remain poorly investigated. Whole-cell patch-clamp recordings from cultured rat hippocampal neurons were therefore conducted to investigate the effects of fluoxetine on GABAergic neurotransmission. The spontaneous inhibitory postsynaptic current (sIPSC) was completely blocked by 10 microM bicuculline and reversibly potentiated by 30 microM fluoxetine. The fluoxetine potentiation on either amplitude or frequency of sIPSCs was dose-dependent, with the EC(50) values of 10.96 and 14.26 microM, respectively. This potentiation was also TTX-insensitive, suggesting independence of presynaptic action potentials. The ritanserin (5 microM), a selective 5-HT(2) receptor antagonist, did not alter the fluoxetine potentiation on miniature inhibitory postsynaptic currents. Taken together, our data suggest that fluoxetine can potentiate GABAergic neurotransmission without depending on presynaptic firing of action potentials and its elevating of 5-HT receptor activities. This potentiation by fluoxetine may normalize the hippocampal GABA deficit during depression and in part exert its antidepressant activity.

Active Dendritic Conductances Dynamically Regulate GABA Release from Thalamic Interneurons

Inhibitory interneurons in the dorsal lateral geniculate nucleus (dLGN) process visual information by precisely controlling spike timing and by refining the receptive fields of thalamocortical (TC) neurons. Previous studies indicate that dLGN interneurons inhibit TC neurons by releasing GABA from both axons and dendrites. However, the mechanisms controlling GABA release are poorly understood. Here, using simultaneous whole-cell recordings from interneurons and TC neurons and two-photon calcium imaging, we find that synchronous activation of multiple retinal ganglion cells (RGCs) triggers sodium spikes that propagate throughout interneuron axons and dendrites, and calcium spikes that invade dendrites but not axons. These distinct modes of interneuron firing can trigger both a rapid and a sustained component of inhibition onto TC neurons. Our studies suggest that active conductances make LGN interneurons flexible circuit-elements that can shift their spatial and temporal properties of GABA release in response to coincident activation of functionally related subsets of RGCs.

Nanodomain Coupling between Ca2+ Channels and Ca2+ Sensors Promotes Fast and Efficient Transmitter Release at a Cortical GABAergic Synapse

It is generally thought that transmitter release at mammalian central synapses is triggered by Ca2+ microdomains, implying loose coupling between presynaptic Ca2+ channels and Ca2+ sensors of exocytosis. Here we show that Ca2+ channel subunit immunoreactivity is highly concentrated in the active zone of GABAergic presynaptic terminals of putative parvalbumin-containing basket cells in the hippocampus. Paired recording combined with presynaptic patch pipette perfusion revealed that GABA release at basket cell-granule cell synapses is sensitive to millimolar concentrations of the fast Ca2+ chelator BAPTA but insensitive to the slow Ca2+ chelator EGTA. These results show that Ca2+ source and Ca2+ sensor are tightly coupled at this synapse, with distances in the range of 10-20 nm. Models of Ca2+ inflow-exocytosis coupling further reveal that the tightness of coupling increases efficacy, speed, and temporal precision of transmitter release. Thus, tight coupling contributes to fast feedforward and feedback inhibition in the hippocampal network.

Structural and Single-Channel Results Indicate That the Rates of Ligand Binding Domain Closing and Opening Directly Impact AMPA Receptor Gating

At most excitatory central synapses, glutamate is released from presynaptic terminals and binds to postsynaptic AMPA receptors, initiating a series of conformational changes that result in ion channel opening. Efficient transmission at these synapses requires that glutamate binding to AMPA receptors results in rapid and near-synchronous opening of postsynaptic receptor channels. In addition, if the information encoded in the frequency of action potential discharge is to be transmitted faithfully, glutamate must dissociate from the receptor quickly, enabling the synapse to discriminate presynaptic action potentials that are spaced closely in time. The current view is that the efficacy of agonists is directly related to the extent to which ligand binding results in closure of the binding domain. For glutamate to dissociate from the receptor, however, the binding domain must open. Previously, we showed that mutations in glutamate receptor subunit 2 that should destabilize the closed conformation not only sped deactivation but also altered the relative efficacy of glutamate and quisqualate. Here we present x-ray crystallographic and single-channel data that support the conclusions that binding domain closing necessarily precedes channel opening and that the kinetics of conformational changes at the level of the binding domain importantly influence ion channel gating. Our findings suggest that the stability of the closed-cleft conformation has been tuned during evolution so that glutamate dissociates from the receptor as rapidly as possible but remains an efficacious agonist.

Local Circuit Connections Between Hamster Laminae III and IV Dorsal Horn Neurons

To better understand the role of intrinsic spinal cord circuits in the integration of mechanosensory information, we studied synaptic transmission between neurons in Rexed's laminae III-IV, a major termination zone for cutaneous mechanoreceptor afferents, using dual, simultaneous whole cell electrophysiological recordings in young hamsters. Synaptic connections were detected between 32 of 106 cell pairs (linkage probability of 0.3) and were predominantly unidirectional (91%). Inhibitory connections outnumbered excitatory connections by 2:1. Amplitude of single-axon postsynaptic potentials (PSPs) was independent of postsynaptic cell input resistance. Intracellular labeling suggested that recordings were obtained from local axon interneurons. In connected cell pairs, the percentage of presynaptic action potentials that failed to evoke a postsynaptic response was 44 +/- 29%. Shape indices of PSPs suggested that synaptic contacts were widely distributed along the postsynaptic membrane. Linkage probability was unrelated to intrinsic firing properties, laminar position of the cells or the distance (<160 mum) separating them. However, PSPs in target cells following action potentials in neurons with phasic firing patterns had longer duration and lower failure rates than PSPs activated by neurons with tonic firing patterns. Thus transmission reliability at synapses between lamina III/IV interneurons overall is low, and efficacy of these connections is related to firing properties of the presynaptic cells. The observations also suggest that synaptic organization in LIII-IV is fundamentally different from the superficial dorsal horn (LI-II) where neural circuits may be composed of stereotyped units made from connections between a few functional types of neurons.

Cajal–Retzius cells in the mouse neocortex receive two types of pre‐ and postsynaptically distinct GABAergic inputs

Cajal-Retzius (CR) cells are principal cells of layer I in the developing neocortex. They are able to generate action potentials, make synaptic contacts in layer I and receive excitatory GABAergic inputs before birth. Although CR cells participate in neuronal network activity in layer I, the properties of their synaptic inputs are not yet characterized. We recorded miniature (mIPSCs) and evoked (eIPSCs) postsynaptic currents using the whole-cell patch-clamp technique. Most of CR cells displayed two types of mIPSCs, namely those with fast (mIPSC(F)) and slow (mIPSC(S)) rise kinetics. The mIPSC(F) mean amplitude was significantly larger than that of mIPSC(S), while their decay rates were not different. Peak-scaled non-stationary noise analysis revealed that mIPSC(S) and mIPSC(F) differed in their weighted single-channel conductance. In addition, zolpidem (100 nm), a modulator of alpha(1) subunit-containing GABA(A) receptors, selectively affected mIPSC(S) suggesting that different postsynaptic GABA(A) receptors mediate mIPSC(F) and mIPSC(S). eIPSCs also split into two populations with different rise kinetics. Fast eIPSCs (eIPSC(F)) displayed higher paired-pulse ratio (PPR) and lower GABA release probability than slowly rising eIPSCs (eIPSC(S)). As CGP55845, a GABA(B) receptor antagonist, eliminated the observed difference in PPR, the lower release probability at IPSC(F) connections probably reflects a stronger tonic GABA(B) receptor-mediated inhibition of IPSC(F) synapses. At low (0.1 Hz) stimulation frequency both inputs can effectively convert presynaptic action potentials into postsynaptic ones; however, only IPSC(F) connections reliably transfer the presynaptic activity patterns at higher stimulation rates. Thus, CR cells receive two GABAergic inputs, which differ in the quantal amplitude, the probability of GABA release and the frequency dependence of signal transfer.

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.

Recurrent axon collaterals underlie facilitating synapses between cerebellar Purkinje cells

Morphological studies have provided ample evidence for synaptic connections between cerebellar Purkinje cells (PCs), but the functional properties of these synapses remain elusive. We report on direct recordings of synaptically connected PCs in mice cerebellar slices. In PCs filled with a fluorescent dye to aid axon visualization and postsynaptic target identification, presynaptic action potentials elicited unitary inhibitory postsynaptic currents in neighboring PCs in 10% of potential connections tested. In 11 pairs, postsynaptic currents had a delay onset of 1.62 +/- 0.16 ms with respect to the presynaptic spike, a 10-90% rise time of 2.20 +/- 0.33 ms, and a monoexponential decay with a time constant of 13.3 +/- 1.7 ms. Average values for peak current and variance-to-mean ratio were 55 +/- 14 and 30 +/- 3 pA, respectively. In contrast to the depressing nature of the synapse between PCs and deep cerebellar nuclei neurons, PC-PC synapses exhibited strong facilitation operating within a time window of a few milliseconds; paired-pulse ratios for 3- and 20-ms intervals were 1.79 +/- 0.18 and 1.01 +/- 0.14, respectively (n = 6). The facilitation is of presynaptic nature because it is accompanied by a decrease in failure rate. Trains of action potentials evoked in presynaptic varicosities volume-averaged calcium transients whose peak increased 1.7-fold as the frequency increased from 50 to 166 Hz. We suggest that PC-PC synapses are tuned for high fidelity of transmission during bursts of PC activity and that their operation in the cerebellar circuit modulates synchronized PC firing.

Calcium influx through N-methyl- d-aspartate receptors triggers GABA release at interneuron–Purkinje cell synapse in rat cerebellum

Ca 2+-dependent neurotransmitter release was originally thought to occur only following activation of presynaptic voltage-gated calcium channels after a presynaptic action potential. Recent evidence suggests that not only opening of voltage-gated but also ligand-gated ion channels, such as neurotransmitter receptors, can trigger exocytosis, as well as Ca 2+ release from intracellular Ca 2+ stores. It was shown that activation of N-methyl- d-aspartate (NMDA) receptors on presynaptic interneurons led to increases in GABA release from these neurons onto postsynaptic Purkinje cells in rat cerebellum in the presence of tetrodotoxin (TTX), suggesting a presynaptic location for the underlying NMDA receptors. However, the mechanism for the NMDA-induced increase in GABA release remained unclear. The present study addresses the question whether Ca 2+ influx through presynaptic NMDA receptors alone is sufficient to trigger presynaptic GABA release at this synapse or whether activation of presynaptic NMDA receptors leads to opening of voltage-gated Ca 2+ channels, thereby increasing exocytosis. The results suggest that the NMDA-induced increase in presynaptic GABA release neither requires activation of presynaptic voltage-gated Ca 2+ channels nor Ca 2+ release from presynaptic Ca 2+ stores. It is concluded that Ca 2+ influx through the NMDA receptor alone is sufficient to drive presynaptic GABA release at the rat interneuron–Purkinje cell synapse.