Upregulation of transmitter release probability improves a conversion of synaptic analogue signals into neuronal digital spikes

ABSTRACT: Action potentials at the neurons and graded signals at the synapses are primary codes in the brain. In terms of their functional interaction, the studies were focused on the influence of presynaptic spike patterns on synaptic activities. How the synapse dynamics quantitatively regulates the encoding of postsynaptic digital spikes remains unclear. We investigated this question at unitary glutamatergic synapses on cortical GABAergic neurons, especially the quantitative influences of release probability on synapse dynamics and neuronal encoding. Glutamate release probability and synaptic strength are proportionally upregulated by presynaptic sequential spikes. The upregulation of release probability and the efficiency of probability-driven synaptic facilitation are strengthened by elevating presynaptic spike frequency and Ca2+. The upregulation of release probability improves spike capacity and timing precision at postsynaptic neuron. These results suggest that the upregulation of presynaptic glutamate release facilitates a conversion of synaptic analogue signals into digital spikes in postsynaptic neurons, i.e., a functional compatibility between presynaptic and postsynaptic partners.     

Electron microscopic autoradiography of the uptake of [H]GABA in dispersed cell cultures of rat cerebellums. II. The development of gabaergic synapses

The formation of GABAergic synapses in dispersed cell cultures of the rat cerebellum was followed from 7 to 21 days in vitro (DIV). The majority of GABAergic synapses appeared between 10 and 14 DIV, and apparently no additional GABAergic synapses formed after 14 DIV.The first step in the development of a GABAergic synapse appeared to be the formation of a large diameter swelling in a GABAergic neuronal process. After the initial contact between the pre- and postsynaptic elements was established, both the number of synaptic vesicles and the thickness of the postsynaptic density increased, while the cross-sectional area of the presynaptic element decreased. The length of the postsynaptic density showed some increase, but no changes were noted in the synaptic cleft thickness, size of the synaptic vesicles or the shape of the synaptic vesicles.Our findings indicate that the formation of GABAergic synapses was not preceded by the formation of other types of junctions or preformed synaptic elements. In addition, the timing and the rate of formation of GABAergic synapses appears not to depend on contact with a single type of postsynaptic neuron, but rather to depend upon intrinsic properties of the development of the GABAergic neuron.     

Feedforward and feedback inhibition in neostriatal GABAergic spiny neurons

There are two distinct inhibitory GABAergic circuits in the neostriatum. The feedforward circuit consists of a relatively small population of GABAergic interneurons that receives excitatory input from the neocortex and exerts monosynaptic inhibition onto striatal spiny projection neurons. The feedback circuit comprises the numerous spiny projection neurons and their interconnections via local axon collaterals. This network has long been assumed to provide the majority of striatal GABAergic inhibition and to sharpen and shape striatal output through lateral inhibition, producing increased activity in the most strongly excited spiny cells at the expense of their less strongly excited neighbors. Recent results, mostly from recording experiments of synaptically connected pairs of neurons, have revealed that the two GABAergic circuits differ markedly in terms of the total number of synapses made by each, the strength of the postsynaptic response detected at the soma, the extent of presynaptic convergence and divergence and the net effect of the activation of each circuit on the postsynaptic activity of the spiny neuron. These data have revealed that the feedforward inhibition is powerful and widespread, with spiking in a single interneuron being capable of significantly delaying or even blocking the generation of spikes in a large number of postsynaptic spiny neurons. In contrast, the postsynaptic effects of spiking in a single presynaptic spiny neuron on postsynaptic spiny neurons are weak when measured at the soma, and unable to significantly affect spike timing or generation. Further, reciprocity of synaptic connections between spiny neurons is only rarely observed. These results suggest that the bulk of the fast inhibition that has the strongest effects on spiny neuron spike timing comes from the feedforward interneuronal system whereas the axon collateral feedback system acts principally at the dendrites to control local excitability as well as the overall level of activity of the spiny neuron.     

The performance of synapses that convey discrete graded potentials in an insect visual pathway.

Synapses from nonspiking neurons transmit small graded changes in potential, but variability in their postsynaptic potential amplitudes has not been extensively studied. At synapses where the presynaptic signal is an all-or-none spike, the probabilistic manner of neurotransmitter release causes variation in the amplitudes of postsynaptic potentials. I have measured the reliability of the operation of synapses that convey small graded potentials between pairs of identified large, second-order neurons in the locust ocellar system. IPSPs are mediated by small rebound spikes, which are graded in amplitude, in the presynaptic neuron. A transfer curve plotting amplitudes of spikes against amplitudes of IPSPs has a characteristic S shape with a linear central portion where IPSP amplitude is between -0.2 and -0.6 as large as spike amplitude but shows appreciable scatter. Approximately half of the scatter is attributable to background noise, most of which originates in photoreceptors and persists in darkness. The remaining noise is intrinsic to the synapse itself and is usually 0.3-0.7 mV in amplitude. It limits the resolution with which two spike amplitudes can be distinguished from one another to approximately 2 mV and, because the linear part of the transfer curve occupies approximately 10 mV in spike amplitudes, limits the number of discrete signal levels that can be conveyed across the synapse to approximately five. The amplitude of the noise is constant throughout the synaptic operating range, which means it is unlikely that presynaptic membrane potential controls transmitter release by setting a single probability level for quantal release.     

Physiological and Ultrastructural Characterization of a Central Synaptic Connection between Identified Motor Neurons in the Locust

An excitatory connection between an extensor and several flexor tibiae motor neurons that innervate antagonistic muscles in the hind leg of a locust has been characterized using physiological and ultrastructural methods. Simultaneous intracellular recordings from the single fast extensor (FETi) motor neuron and up to three flexor motor neurons show that a spike in FETi is followed by a short latency depolarizing synaptic potential in the flexors that is powerful enough to evoke a burst of flexor spikes. The chemically mediated excitatory postsynaptic potential (EPSP) is caused centrally as it persists when sensory feedback from the leg is removed, and has a latency of 1.6-2.0 ms depending upon the position of the recording electrodes in the somata or neuropilar segments of the pre- and postsynaptic neurons. The amplitude of the EPSP declines gradually in a saline containing no calcium but high magnesium, indicating that no spiking interneuron is interposed in the pathway. With repetitive stimulation, the EPSP decrements markedly so that at intervals of 50 ms the second EPSP of a pair is reduced by 90%. The amplitude of the EPSP is also dependent on the amplitude of the presynaptic spike. The physiological evidence suggesting a monosynaptic connection is directly confirmed by electron microscopy of ganglia in which FETi and a flexor were both labelled with horseradish peroxidase. Direct chemical synapses between the two identified neurons, in which FETi is the presynaptic element, occur in three regions of the neuropil examined. At a synapse, the flexor motor neuron may be the only postsynaptic neuron or it may be one element in a dyad. The synaptic arrangements between the two neurons are complex with serial synapses through unlabelled processes linking FETi to flexor motor neurons and with frequent reciprocal synaptic connections between FETi and unlabelled processes. Unidentified processes also make input synapses on both neurons close to the synapses from FETi. The behavioural significance of the connection lies in the mechanical requirements for kicking and jumping. To prepare for these powerful movements the extensor and flexor tibiae muscles must co-contract. The connection from FETi enhances the depolarization and frequency of spikes in the flexors during the co-contraction.     

A specific GABAergic synapse onto oligodendrocyte precursors does not regulate cortical oligodendrogenesis

In the brain, neurons establish bona fide synapses onto oligodendrocyte precursor cells (OPCs), but the function of these neuron‐glia synapses remains unresolved. A leading hypothesis suggests that these synapses regulate OPC proliferation and differentiation. However, a causal link between synaptic activity and OPC cellular dynamics is still missing. In the developing somatosensory cortex, OPCs receive a major type of synapse from GABAergic interneurons that is mediated by postsynaptic γ2‐containing GABA_A receptors. Here we genetically silenced these receptors in OPCs during the critical period of cortical oligodendrogenesis. We found that the inactivation of γ2‐mediated synapses does not impact OPC proliferation and differentiation or the propensity of OPCs to myelinate their presynaptic interneurons. However, this inactivation causes a progressive and specific depletion of the OPC pool that lacks γ2‐mediated synaptic activity without affecting the oligodendrocyte production. Our results show that, during cortical development, the γ2‐mediated interneuron‐to‐OPC synapses do not play a role in oligodendrogenesis and suggest that these synapses finely tune OPC self‐maintenance capacity. They also open the interesting possibility that a particular synaptic signaling onto OPCs plays a specific role in OPC function according to the neurotransmitter released, the identity of presynaptic neurons or the postsynaptic receptors involved.     

Enhanced synaptic transmission at identified synaptic connections in the cerebral ganglion of Aplysia.

The identified A-B neuron synaptic connections in the cerebral ganglion of Aplysia exhibited a novel form of enhanced synaptic transmission. A brief high-frequency train of action potentials (2 s, 10-30 Hz) in the presynaptic A neurons produced a long-lasting increase in the amplitude of excitatory postsynaptic potentials (EPSPs) in B neurons. The increase in synaptic efficacy was termed slow developing potentiation (SDP) since the EPSP amplitude increased slowly with the peak occurring 5 min after the tetanizing train. Peak EPSP amplitudes increased relative to the initial EPSP by an average of greater than 250%. SDP decayed as a single exponential with a time constant of tau = 24 min. The enhanced transmission was neuron specific. Only the connections made by the tetanized A neuron were potentiated. However, potentiation apparently occurred at all the synapses made by the tetanized A neuron. Tetanizing the postsynaptic B neurons neither induced, nor when paired with A neuron tetanization, increased SDP. SDP appears to be primarily due to increased transmitter release by the presynaptic neuron.     

Interaction of inhibition and triplets of excitatory spikes modulates the NMDA‐R‐mediated synaptic plasticity in a computational model of spike timing‐dependent plasticity

Spike timing‐dependent plasticity (STDP) experiments have shown that a synapse is strengthened when a presynaptic spike precedes a postsynaptic one and depressed vice versa. The canonical form of STDP has been shown to have an asymmetric shape with the peak long‐term potentiation at +6 ms and the peak long‐term depression at ?5 ms. Experiments in hippocampal cultures with more complex stimuli such as triplets (one presynaptic spike combined with two postsynaptic spikes or one postsynaptic spike with two presynaptic spikes) have shown that pre–post–pre spike triplets result in no change in synaptic strength, whereas post–pre–post spike triplets lead to significant potentiation. The sign and magnitude of STDP have also been experimentally hypothesized to be modulated by inhibition. Recently, a computational study showed that the asymmetrical form of STDP in the CA1 pyramidal cell dendrite when two spikes interact switches to a symmetrical one in the presence of inhibition under certain conditions. In the present study, I investigate computationally how inhibition modulates STDP in the CA1 pyramidal neuron dendrite when it is driven by triplets. The model uses calcium as the postsynaptic signaling agent for STDP and is shown to be consistent with the experimental triplet observations in the absence of inhibition: simulated pre–post–pre spike triplets result in no change in synaptic strength, whereas simulated post–pre–post spike triplets lead to significant potentiation. When inhibition is bounded by the onset and offset of the triplet stimulation, then the strength of the synapse is decreased as the strength of inhibition increases. When inhibition arrives either few milliseconds before or at the onset of the last spike in the pre–post–pre triplet stimulation, then the synapse is potentiated. Variability in the frequency of inhibition (50 vs. 100 Hz) produces no change in synaptic strength. Finally, a 5% variation in model's calcium parameters (calcium thresholds) proves that the model's performance is robust. © 2012 Wiley Periodicals, Inc.     

Dynamic synapse: A new concept of neural representation and computation

Presynaptic mechanisms influencing the probability of neurotransmitter release from an axon terminal, such as facilitation, augmentation, and presynaptic feedback inhibition, are fundamental features of biological neurons and are cardinal physiological properties of synaptic connections in the hippocampus. The consequence of these presynaptic mechanisms is that the probability of release becomes a function of the temporal pattern of action potential occurrence, and hence, the strength of a given synapse varies upon the arrival of each action potential invading the terminal region. From the perspective of neural information processing, the capability of dynamically tuning the synaptic strength as a function of the level of neuronal activation gives rise to a significant representational and processing power of temporal spike patterns at the synaptic level. Furthermore, there is an exponential growth in such computational power when the specific dynamics of presynaptic mechanisms varies quantitatively across axon terminals of a single neuron, a recently established characteristic of hippocampal synapses. During learning, alterations in the presynaptic mechanisms lead to different pattern transformation functions, whereas changes in the postsynaptic mechanisms determine how the synaptic signals are to be combined. We demonstrate the computational capability of dynamic synapses by performing speech recognition from unprocessed, noisy raw waveforms of words spoken by multiple speakers with a simple neural network consisting of a small number of neurons connected with synapses incorporating dynamically determined probability of release. The dynamics included in the model are consistent with available experimental data on hippocampal neurons in that parameter values were chosen so as to be consistent with time constants of facilitative and inhibitory processes governing the dynamics of hippocampal synaptic transmission studied using nonlinear systems analytic procedures. © 1997 Wiley-Liss, Inc.     

Small vesicle bouton synapses on the distal half of the lateral dendrite of the goldfish Mauthner cell: freeze-fracture and thin section study

To understand principles of synaptic integration, it is necessary to define the types of synapses on a particular neuron and their distribution. Thin sectioning and double replica freeze-fracture techniques were employed to characterize the small vesicle bouton (SVB) synapses on the distal half of the Mauthner (M) cell lateral dendrite, which probably mediate a remote dendritic inhibition. Three morphologically distinct SVB synapses, types A, B, and C, were found. These three SVB synapses form roughly 90% of the synapses on the distal half of the lateral dendrite, with types A and B being most common. The SVB A synapse is characterized by mostly oval and round synaptic vesicles, a discrete presynaptic active zone with a highly variable shape, and a postsynaptic active zone with no apparent particle aggregate in either the E or P face. At the SVB B synapse, most of the synaptic vesicles are flat. A very high particle density is present throughout the presynaptic P face, and vesicle attachment sites are dispersed over much of the presynaptic membrane. Postsynaptic P face particle aggregates are subjacent to the presynaptic vesicle attachment sites, and are often large and anastomosing. The SVB C synapse is characterized by synaptic vesicle profiles that vary from flattened to round. The SVB C cytoplasm was unclouded by the flocculent material that characterized SVBs A and B. The presynaptic active zones at the SVB C synapse are discrete, and macular or oblong. No particle aggregates are apparent in the postsynaptic active zone. Small, macular particle aggregates were found in nonactive zone regions of the postsynaptic E face of all three types of SVBs. Small subsurface cisterns were also observed underlying the M cell membrane at all three types of SVB synapses. Neither the postsynaptic E face aggregates nor the subsurface cisterns were ever observed directly subjacent to presynaptic active zones, but were often seen adjacent to active zones. Short, straight rows of particles and short cylinders were often seen in both pre- and postsynaptic surrounding zone regions of SVB A and C synapses. These structures are thought to represent tight junctions.     

Inhibitory short‐term plasticity modulates neuronal activity in the rat entopeduncular nucleus in vitro

The entopeduncular nucleus (EP) is one of the basal ganglia output nuclei integrating synaptic information from several pathways within the basal ganglia. The firing of EP neurons is modulated by two streams of inhibitory synaptic transmission, the direct pathway from the striatum and the indirect pathway from the globus pallidus. These two inhibitory pathways continuously modulate the firing of EP neurons. However, the link between these synaptic inputs to neuronal firing in the EP is unclear. To investigate this input–output transformation we performed whole‐cell and perforated‐patch recordings from single neurons in the entopeduncular nucleus in rat brain slices during repetitive stimulation of the striatum and the globus pallidus at frequencies within the in vivo activity range of these neurons. These recordings, supplemented by compartmental modelling, showed that GABAergic synapses from the striatum, converging on EP dendrites, display short‐term facilitation and that somatic or proximal GABAergic synapses from the globus pallidus show short‐term depression. Activation of striatal synapses during low presynaptic activity decreased postsynaptic firing rate by continuously increasing the inter‐spike interval. Conversely, activation of pallidal synapses significantly affected postsynaptic firing during high presynaptic activity. Our data thus suggest that low‐frequency striatal output may be encoded as progressive phase shifts in downstream nuclei of the basal ganglia while high‐frequency pallidal output may continuously modulate EP firing.     

Maturation of postsynaptic nicotinic structures on autonomic neurons requires innervation but not cholinergic transmission

Postsynaptic development at the neuromuscular junction depends on nicotinic transmission and secreted components from the presynaptic motor nerve terminal. Similarly, secreted components and synaptic activity are both thought to guide development of glutamatergic synapses in the CNS. Nicotinic synapses on chick ciliary neurons are structurally complex: a large presynaptic calyx engulfs the postsynaptic neuron and overlays a series of discrete mats of receptor-rich somatic spines tightly interwoven and folded against the soma. We used fluorescence imaging of alpha 7-containing nicotinic receptors and the spine constituent drebrin to monitor postsynaptic development. The results show that surgical disruption of the preganglionic input or removal of the ganglionic synaptic target tissue after synapses form in the ganglion does not disrupt the receptor-rich spine mats. Similarly, removal of the target tissue even prior to synapse formation in the ganglion does not prevent subsequent formation of the receptor clusters and associated spine constituents. Postsynaptic development is arrested, however, if normal innervation is prevented by ablating the preganglionic neurons prior to synapse formation. In this case the neurons express reduced levels of nicotinic receptors and cytoskeletal components and organize them only into early-stage clusters. Even low levels of residual innervation, however, can restore much of the normal postsynaptic receptor patterns. Chronic pharmacological blockade of cholinergic synaptic activity fails to replicate the effects of ablating the preganglionic nucleus. The results indicate that ciliary neurons are programmed to express postsynaptic components and can initiate clustering of alpha 7-containing receptors but need presynaptic guidance for maturation of the postsynaptic structure.     

Differential effects of serotonin, FMRFamide, and small cardioactive peptide on multiple, distributed processes modulating sensorimotor synaptic transmission in Aplysia.

At least two processes contribute to the modulation by 5-HT of the connections between sensory neurons and motor neurons in Aplysia. The first involves broadening of the presynaptic spike through modulation of 5-HT-sensitive K+ channels that leads to elevated levels of intracellular Ca2+ and increased release of transmitter. A second process (or set of processes) apparently accounts for the amount of facilitation not produced by presynaptic spike broadening. This spike duration-independent (SDI) process is particularly prominent in depressed synapses. We used a protocol in which spikes were prebroadened into a range of durations in which further spike broadening by itself has little or no effect on facilitation of the EPSP.5-HT produced pronounced facilitation in depressed synapses under these conditions. Another modulatory agent, small cardioactive peptide (SCPb), also broadened spikes in sensory neurons but did not produce facilitation comparable to that produced by 5-HT. These results indicate that 5-HT activates the SDI process whereas SCPb fails to do the same. A 5 min preexposure to the modulatory peptide FMRFamide inhibited 5-HT-induced activation of the SDI process, whereas a 1 min preexposure did not. Another process(es) that may modulate synaptic efficacy in sensorimotor synapses involves changes in the properties of the motor (follower) neuron, such as input resistance. FMRFamide decreased the input resistance of postsynaptic neurons. This action could contribute to the effects of FMRFamide when administered alone, but it did not appear to be responsible for the inhibitory action of FMRFamide on 5-HT-induced facilitation. Neither 5-HT nor SCPb had a clear effect on input resistance. The actions of these three agents, therefore, seem to be differentially distributed among various pre- and postsynaptic processes involved in the modulation of synaptic transmission.     

Mechanisms underlying signal filtering at a multisynapse contact

Visual information must be relayed through the lateral geniculate nucleus before it reaches the visual cortex. However, not all spikes created in the retina lead to postsynaptic spikes and properties of the retinogeniculate synapse contribute to this filtering. To understand the mechanisms underlying this filtering process, we conducted electrophysiology to assess the properties of signal transmission in the Long-Evans rat. We also performed SDS-digested freeze-fracture replica labeling to quantify the receptor and transporter distribution, as well as EM reconstruction to describe the 3D structure. To analyze the impact of transmitter diffusion on the activity of the receptors, simulations were integrated. We identified that a large contributor to the filtering is the marked paired-pulse depression at this synapse, which was intensified by the morphological characteristics of the contacts. The broad presynaptic and postsynaptic contact area restricts transmitter diffusion two dimensionally. Additionally, the presence of multiple closely arranged release sites invites intersynaptic spillover, which causes desensitization of AMPA receptors. The presence of AMPA receptors that slowly recover from desensitization along with the high presynaptic release probability and multivesicular release at each synapse also contribute to the depression. These features contrast with many other synapses where spatiotemporal spread of transmitter is limited by rapid transmitter clearance allowing synapses to operate more independently. We propose that the micrometer-order structure can ultimately affect the visual information processing.     

Visual deprivation increases accumulation of dense core vesicles in developing optic tectal synapses in Xenopus laevis

Despite considerable progress in understanding the molecular components of synapses in the central nervous system, the ultrastructural rearrangements underlying synaptic development remain unclear. We used serial section transmission electron microscopy and three‐dimensional reconstructions of the optic tectal neuropil of Xenopus laevis tadpoles to detect and quantify changes in synaptic ultrastructure over a 1‐week period from stages 39 and 47, during which time the visual system of Xenopus tadpoles becomes functional. Synapse density, presynaptic maturation index, and number of synapses per axon bouton increase, whereas the number of DCVs per bouton decreases, between stages 39 and 47. The width of the synaptic cleft decreased and the diameter of postsynaptic profiles increased between stages 39 and 47 and then remained relatively unchanged after stage 47. We found no significant difference in synapse maturation between GABAergic and non‐GABAergic synapses. To test the effect of visual experience on synaptogenesis, animals were deprived of visual experience for 3 days from stage 42 to 47. Visual deprivation decreased synapse maturation and the number of connections per bouton. Furthermore, visual deprivation increased the number of DCVs per bouton by more than twofold. The visual‐deprivation‐induced decrease in synaptic connections is specific to asymmetric non‐GABAergic synapses; however, both symmetric GABAergic and asymmetric synapses show comparable increases in the number DCVs with visual deprivation. In both the control and the visually deprived animals, the number of DCVs per bouton is highly variable and does not correlate with either synapse maturation or the number of connected partners per bouton. These data suggest that synaptogenesis and DCV accumulation are regulated by visual experience and further suggest a complex spatial and temporal relation between DCV accumulation and synapse formation. J. Comp. Neurol. 518:2365–2381, 2010. © 2010 Wiley‐Liss, Inc.     

Synaptic transmission of graded membrane potential changes and spikes between identified visual interneurons

Several physiological mechanisms allow sensory information to be propagated in neuronal networks. According to the conventional view of signal processing, graded changes of membrane potential at the dendrite are converted into a sequence of spikes. However, in many sensory receptors and several types of mostly invertebrate neurons, graded potential changes have a direct impact on the cells' output signals. The visual system of the blowfly Calliphora vicina is a good model system to study synaptic transmission in vivo during sensory stimulation. We recorded extracellularly from an identified motion-sensitive neuron while simultaneously measuring and controlling the membrane potential of individual elements of its presynaptic input ensemble. The membrane potential in the terminals of the presynaptic neuron is composed of two components, graded membrane potential changes and action potentials. To dissociate the roles of action potentials and graded potential changes in synaptic transmission we used voltage-clamp-controlled current-clamp techniques to suppress the graded membrane potential changes without affecting action potentials. Our results indicate that both the graded potential and the action potentials of the presynaptic neuron have an impact on the spiking characteristics of the postsynaptic neuron. Although a tight temporal coupling between pre- and postsynaptic spikes exists, the timing between these spikes is also affected by graded potential changes. We propose that the control of synaptic transfer of a dynamically complex signal by graded changes in membrane potential and spikes is useful to enable a temporally precise coupling of spikes in response to sudden transitions in stimulus intensity.     

Long‐term depression of inhibitory synaptic transmission induced by spike‐timing dependent plasticity requires coactivation of endocannabinoid and muscarinic receptors

The precise timing of pre‐postsynaptic activity is vital for the induction of long‐term potentiation (LTP) or depression (LTD) at many central synapses. We show in synapses of rat CA1 pyramidal neurons in vitro that spike timing dependent plasticity (STDP) protocols that induce LTP at glutamatergic synapses can evoke LTD of inhibitory postsynaptic currents or STDP‐iLTD. The STDP‐iLTD requires a postsynaptic Ca²⁺ increase, a release of endocannabinoids (eCBs), the activation of type‐1 endocananabinoid receptors and presynaptic muscarinic receptors that mediate a decreased probability of GABA release. In contrast, the STDP‐iLTD is independent of the activation of nicotinic receptors, GABA_BRs and G protein‐coupled postsynaptic receptors at pyramidal neurons. We determine that the downregulation of presynaptic Cyclic adenosine monophosphate/protein Kinase A pathways is essential for the induction of STDP‐iLTD. These results suggest a novel mechanism by which the activation of cholinergic neurons and retrograde signaling by eCBs can modulate the efficacy of GABAergic synaptic transmission in ways that may contribute to information processing and storage in the hippocampus. © 2013 Wiley Periodicals, Inc.     

Freeze fracture study on three types of synapses in the Xenopus spinal cord

Three types of synapses (S-, F- and C-types) were identified in the thin-sectioned Xenopus spinal cord and their structure was analyzed with the freeze-fracturing technique. All three types of synapses showed similar specializations of the presynaptic membrane. This finding suggests that the three types of synapses may release their transmitters by a similar mechanism. By contrast, the three types of synapses revealed different specializations of the postsynaptic membrane. The E-face of the S-type postsynaptic membrane was characterized by a dense aggregate of large intramembrane particles, 12 to 15 nm in diameter. An aggregate of small particles, 8 to 9 nm, was evident on the E-face of the postsynaptic membrane of the F-type synapse. In the C-type synapse, there was a striking aggregate of intramembrane particles, 10 to 14 nm in diameter, on the P-face of the postsynaptic membrane. These characteristics features in the distribution of particles in the three types of postsynaptic membranes may reflect differences in the type of transmitter released or transmitter action on the postsynaptic neuron. The overall size of the area of aggregated particles on the P-face of the C-type postsynaptic membrane was coextensive with the underlying subsurface cistern (SSC) which showed partial occulsion of the lumen. This fact supports the view that the SSC is closely related to the C-type synaptic action which might be distinct from the other synaptic types.     

Mixed inhibitory synaptic balance correlates with glutamatergic synaptic phenotype in cerebellar unipolar brush cells

Inhibitory synapses display a great diversity through varying combinations of presynaptic GABA and glycine release and postsynaptic expression of GABA and glycine receptor subtypes. We hypothesized that increased flexibility offered by this dual transmitter system might serve to tune the inhibitory phenotype to the properties of afferent excitatory synaptic inputs in individual cells. Vestibulocerebellar unipolar brush cells (UBC) receive a single glutamatergic synapse from a mossy fiber (MF), which makes them an ideal model to study excitatory-inhibitory interactions. We examined the functional phenotypes of mixed inhibitory synapses formed by Golgi interneurons onto UBCs in rat slices. We show that glycinergic IPSCs are present in all cells. An additional GABAergic component of large amplitude is only detected in a subpopulation of UBCs. This GABAergic phenotype is strictly anti-correlated with the expression of type II, but not type I, metabotropic glutamate receptors (mGluRs) at the MF synapse. Immunohistochemical stainings and agonist applications show that global UBC expression of glycine and GABA(A) receptors matches the pharmacological profile of IPSCs. Paired recordings of Golgi cells and UBCs confirm the postsynaptic origin of the inhibitory phenotype, including the slow kinetics of glycinergic components. These results strongly suggest the presence of a functional coregulation of excitatory and inhibitory phenotypes at the single-cell level. We propose that slow glycinergic IPSCs may provide an inhibitory tone, setting the gain of the MF to UBC relay, whereas large and fast GABAergic IPSCs may in addition control spike timing in mGluRII-negative UBCs.