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....