Cortical information processing requires an orchestrated interaction between a large number of pyramidal cells and albeit fewer, but highly diverse GABAergic interneurons (INs). The diversity of INs is thought to reflect functional and structural specializations evolved to control distinct network operations. Consequently, specific cortical functions may be selectively modified by altering the input-output relationship of unique IN populations. Here, we report that persistently active cannabinoid receptors, the site of action of endocannabinoids, and the psychostimulants marijuana and hashish, switch off the output (mute) of a unique class of hippocampal INs. In paired recordings between cholecystokininimmunopositive, mossy fiber-associated INs, and their target CA3 pyramidal cells, no postsynaptic currents could be evoked with single presynaptic action potentials or with repetitive stimulations at frequencies <25 Hz. Cannabinoid receptor antagonists converted these ''mute'' synapses into high-fidelity ones. The selective muting of specific GABAergic INs, achieved by persistent presynaptic cannabinoid receptor activation, provides a state-dependent switch in cortical networks.hippocampus ͉ inhibition ͉ patch-clamp I nformation processing in the hippocampal neuronal network relies on precise, spatiotemporal reciprocal interactions between apparently homogeneous pyramidal cells (PCs) and highly diverse GABAergic interneurons (INs) (1-5). The impact of these nerve cells on their postsynaptic target cells is determined by a variety of factors, including the number and location of synapses on the postsynaptic cell, quantal size, probability of transmitter release (P r ), and short-or long-term synaptic plasticity (6). Many of these factors are highly variable at hippocampal glutamatergic synapses (7,8), despite the apparent uniformity of PCs. In contrast, at GABAergic synapses formed by the extremely diverse INs, many of these critical synaptic parameters seem to be alike. For example, hippocampal INs elicit postsynaptic responses that are highly reliable, of large amplitude, and predominantly show short-term depression (9-15). This type of synaptic transmission may be essential for INs synchronizing a large population of PCs (16). However, variability of these synaptic properties has been suggested to be beneficial for stabilizing the network (17). Furthermore, INs also convey autonomic, motivational, and emotional impact on hippocampal information processing, and this type of inhibition is supposed to be easily modifiable (18). In this article, we tested whether all GABAergic synaptic connections in the rat hippocampus were indeed highly reliable with apparent lack of transmission failures; or whether the output of an IN could be dramatically altered, implying a switch in their contribution to network behaviors. MethodsSlice Preparation and Electrophysiological Recordings. Horizontal hippocampal slices were prepared from 13-to 19-day-old male Wistar rats (15.9 Ϯ 0.3 days, n ϭ 26) as described earlier (19). After 1....

Short-term synaptic plasticity changes the reliability of transmission during repetitive activation and allows different neuronal ensembles to encode distinct features of action potential trains. Identifying the mechanisms and the locus of expression of such plasticity is essential for understanding neuronal information processing. To determine the quantal parameters and the locus of alterations during short-term plasticity of cortical glutamatergic synapses, EPSCs were evoked in hippocampal oriens-alveus interneurons by CA1 pyramidal cells. The robust short-term facilitation of this connection allowed us to examine the transmission under functionally relevant but widely different release probability (P r ) conditions. Paired whole-cell recordings permitted the functional and post hoc morphological characterization of the synapses. To determine the quantal size (q), the P r , and the number of functional release sites (N F ), two independent quantal analysis methods were used. Light and electron microscopy were performed to identify the number of synaptic junctions (N EM ) between the recorded cells. The mean number of functional release sites (N F(f) ϭ 2.9 Ϯ 0.4; n ϭ 8) as inferred from a simple binomial model with no quantal variance agreed well with the mean of N EM (2.8 Ϯ 0.8; n ϭ 6), but N F(f) never matched N EM when they were compared in individual pairs; however, including quantal variance in the model improved the functional prediction of the structural data. Furthermore, an increased P r (4.8 Ϯ 0.8-fold) fully accounted for the marked short-term facilitation of EPSCs (5.0 Ϯ 0.7-fold), and q was independent of P r . Our results are consistent with the "one-release site, one-vesicle" hypothesis.

The amount of neurotransmitter released after the arrival of an action potential affects the strength and the trial-to-trial variability of postsynaptic responses. Most studies examining the dependence of synaptic neurotransmitter concentration on the release probability (P r ) have focused on glutamatergic synapses. Here we asked whether univesicular or multivesicular release characterizes transmission at hippocampal GABAergic synapses. We used multiple probability functional analysis to derive quantal parameters at inhibitory connections between cannabinoid receptor-and cholecystokinin (CCK)-expressing interneurons and CA3 pyramidal cells. After the recordings, the cells were visualized and reconstructed at the light-microscopic level, and the number of boutons mediating the IPSCs was determined using electron microscopy (EM). The number of active zones (AZs) per CCK-immunopositive bouton was determined from threedimensional EM reconstructions, thus allowing the calculation of the total number of AZs for each pair. Our results reveal an approximate fivefold discrepancy between the numbers of functionally determined release sites (17.4 Ϯ 3.2) and structurally identified AZs (3.7 Ϯ 0.9). Channel modeling predicts that a fivefold to sevenfold increase in the peak synaptic GABA concentration is required for the fivefold enhancement of the postsynaptic responses. Kinetic analysis of the unitary IPSCs indicates that the increase in synaptic GABA concentration is most likely attributable to multivesicular release. This change in the synaptic GABA concentration transient together with extremely low postsynaptic receptor occupancy permits a P r -dependent scaling of the postsynaptic response generated at a single hippocampal GABAergic synaptic contact.

The discharge pattern of hippocampal pyramidal cells (PC) varies depending on the behaviour of the animal and on the accompanying network states. During theta activity, PCs fire asynchronously at low rates whereas during sharp waves PCs increase their firing frequency and many cells fire synchronously. In the present study, we addressed how the presynaptic activity of CA1 PCs influences the precise operation of their output synapses. Asynchronous presynaptic discharge was mimicked by activating only a single PC during paired recordings, whereas the highly synchronous presynaptic firing was emulated by extracellularly stimulating the axons of ≈ 70 PCs in acute hippocampal slices. By using low-and high-affinity glutamate receptor competitive antagonists to monitor the synaptic glutamate concentration transient, we show that the synaptic transmitter concentration varies depending on the release probability (P r ) when many Europe PMC Funders Group Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts fibres are synchronously activated. Our kinetic analysis revealed that an 5-fold increase in P r from the beginning to the end of an action potential train resulted in a slowing down of the decay of ≈ evoked EPSCs, suggesting neurotransmitter spillover between neighbouring synapses. In agreement with this prediction, the slowing of the decay was reversed by the application of the low-affinity antagonist γ-D-glutamyl-glycine. In contrast, altering P r had no effect on the kinetics of unitary EPSCs. Our data demonstrate that synapse independence breaks down during synchronous presynaptic activity, but the point-to-point communication is preserved when PCs fire asynchronously.

A-type K+ channels restrain the spread of incoming signals in tufted and apical dendrites of pyramidal neurons resulting in strong compartmentalization. However, the exact subunit composition and functional significance of K+ channels expressed in small diameter proximal dendrites remain poorly understood. We focus on A-type K+ channels expressed in basal and oblique dendrites of cortical layer 3 pyramidal neurons, in ex vivo brain slices from young adult mice. Blocking putative Kv4 subunits with phrixotoxin-2 enhances depolarizing potentials elicited by uncaging RuBi-glutamate at single dendritic spines. A concentration of 4-aminopyridine reported to block Kv1 has no effect on such responses. 4-aminopyridine and phrixotoxin-2 increase supralinear summation of glutamatergic potentials evoked by synchronous activation of clustered spines. The effect of 4-aminopyridine on glutamate responses is simulated in a computational model where the dendritic A-type conductance is distributed homogeneously or in a linear density gradient. Thus, putative Kv4-containing channels depress excitatory inputs at single synapses. The additional recruitment of Kv1 subunits might require the synchronous activation of multiple inputs to regulate the gain of signal integration.