Persistently active cannabinoid receptors mute a subpopulation of hippocampal interneurons

Abstract

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....

Functional Specificity of Mossy Fiber Innervation of GABAergic Cells in the Hippocampus

“…In contrast, IvyCs and RSBCs were less likely to be functionally connected to simultaneously recorded MFs (n ϭ 5 monosynaptic pairs of 30 MF-IvyC pairs, 16.7%; n ϭ 3 monosynaptic pairs of 29 MF-RSBC pairs, 10.3%). The most striking difference in this regard was exhibited by the MFAs (Vida and Frotscher, 2000;Losonczy et al, 2004) that were never observed to receive monosynaptic EPSCs from MFs (n ϭ 0 connection of 30 MF-MFA pairs). Statistical analyses (Pearson's 2 test) of the probability of connections between identified CA3 GABAergic cells and nearby MF terminals indicated significant differences among the cell types ( 2 ϭ 16.8; p ϭ 0.0021).…”

“…6). MFAs are found exclusively in the CA3 area and innervate specifically the stratum lucidum of CA3 (hence the name of the cell type) and the hilus (Vida and Frotscher, 2000;Losonczy et al, 2004) (note that it is the axons, and not the dendrites, that align with the MF termination zone). In agreement with previous studies, most of the axons of identified MFAs within the CA3 in our sample are located in the stratum lucidum, running parallel with the pyramidal cell layer (all MFAs had axons showing the latter property), and also send collaterals to the hilus (19 of 23 cells).…”

Electrical Coupling among Irregular-Spiking GABAergic Interneurons Expressing Cannabinoid Receptors

“…CCK-expressing cells have been shown to be heterogeneous, including subpopulations with different morphology, electrophysiology, and expression of neuropeptides and calcium-binding proteins Cope et al, 2002;Kawaguchi and Kondo, 2002;Pawelzik et al, 2002;Losonczy et al, 2004). Thus, small CCKcontaining neocortical cells are usually positive for VIP and calretinin (Kawaguchi and Kondo, 2002) but lack CB 1 expression (Bodor et al, 2003).…”

Presynaptic Monoacylglycerol Lipase Activity Determines Basal Endocannabinoid Tone and Terminates Retrograde Endocannabinoid Signaling in the Hippocampus

“…Therefore, it is important to elucidate how MGL activity is regulated under physiological conditions. In the hippocampal CA3 area, persistently active CB1 receptors is reported to mute subpopulation of interneurons (Losonczy et al, 2004). It is possible that low MGL activities at presynaptic terminals may underlie persistent activation of CB1 receptors.…”