Short-Term Retrograde Inhibition of GABAergic Synaptic Currents in Rat Purkinje Cells Is Mediated by Endogenous Cannabinoids

Abstract

Depolarization-induced suppression of inhibition (DSI) is a form of short-term plasticity of GABAergic synaptic transmission that is found in cerebellar Purkinje cells and hippocampal CA1 pyramidal cells. DSI involves the release of a calcium-dependent retrograde messenger by the somatodendritic compartment of the postsynaptic cell. Both glutamate and endogenous cannabinoids have been proposed as retrograde messenger. Here we show that, in cerebellar parasagittal slices, type 1 cannabinoid receptors (CB1Rs) are expressed at high levels in axons of GABAergic interneurons and in presynaptic terminals onto Purkinje cells. Application of the cannabinoid antagonist AM-251 (500 nm) leads to the abolition of the DSI of evoked currents (eIPSCs) recorded in paired recordings and to a strong reduction of the DSI of TTX-insensitive miniature events (mIPSCs) recorded from Purkinje cells. Furthermore, the CB1R agonist WIN 55-212,2 (5 microm) induces a presynaptic inhibition of synaptic currents similar to that occurring during DSI, as well as an occlusion of DSI after stimulation of Purkinje cells. Moreover, WIN 55-212,2 reduces the calcium transients evoked in presumed presynaptic varicosities by short trains of action potentials. Our results indicate that DSI is mediated by the activation of presynaptic CB1Rs and that an endogenous cannabinoid is a likely candidate retrograde messenger in this preparation. They further suggest that DSI involves distinct presynaptic modifications for eIPSCs and mIPSCs, including an inhibition of action potential-evoked calcium rises.

Endocannabinoid‐mediated short‐term synaptic plasticity: depolarization‐induced suppression of inhibition (DSI) and depolarization‐induced suppression of excitation (DSE)

“…When restricting their measurements to endocannabinoid-sensitive synaptic connections, found a maximum inhibition during hippocampal DSI close to 90%. A similar value was obtained from paired recordings in the cerebellum (Diana et al, 2002;Figure 2b), whereas in hippocampal cultured cells DSI reaches a somewhat smaller value (about 75% in DSI sensitive pairs: Ohno-Shosaku et al, 2001). In slices, these values correspond to the inhibition obtained with saturating concentration of a cannabinoid exogenous agonist, showing that standard DSI induction protocols are able to saturate presynaptic CBIRs.…”

“…In addition hippocampal DSI was soon shown to be absent in CB1R-deficient mice . In a short period of time, the endocannabinoid-and CB1R-related nature of DSI has been confirmed in the hippocampus and extended to several systems: for GABAergic synapses onto cerebellar Purkinje cells (Kreitzer & Regehr, 2001b;Diana et al, 2002;Yoshida et al, 2002;Figure 2a), cultured rat hippocampal neurons (Ohno-Shosaku et al, 2001), hippocampal dentate granule cells in particular pathological conditions (Chen et al, 2003), cortical pyramidal cells (Trettel & Levine, 2003) and neurons of the substantia nigra (Yanovsky et al, 2003).…”

“…Nearly simultaneously with the Wilson and Nicoll paper, Kreitzer and Regehr (2001a) described DSE for the first time figure. On the right, the effect of blocking the CB1R is shown: mIPSC frequency is unchanged after Purkinje cell depolarization (given at t ¼ 0 in both time plots; from Diana et al, 2002).…”

“…Cerebellar DSI is an example in point. It involves an inhibition of the presynaptic firing rate (Figure 2a; Kreitzer et al, 2002, and Diana & Marty, unpublished data), of evoked inhibitory postsynaptic currents (IPSCs) as measured in paired recordings (Figure 2b; Diana et al, 2002), and of mIPSCs ( Figure 2c; Llano et al, 1991). We recently provided a quantitative evaluation of these three components: they account for 13.4, 23.2 and 63.4%, respectively, of the reduction of the overall afferent GABAergic transmission during DSI (Diana & Marty, 2003).…”

PUFA-derived endocannabinoids: an overview

“…Two forms of short-term synaptic plasticity have been identified so far, named depolarisation-induced suppression of inhibition, which involves GABAergic transmission, and depolarisationinduced suppression of excitation, which involves glutamatergic transmission (54,55) . These processes were found mainly in the hippocampus and cerebellum, where it seems they play an important role in physiological processes such as memory and motor coordination (56)(57)(58) . Additional forms of synaptic transmission involve the induction of long-term synaptic plasticity, named long-term potentiation and long-term depression (59) .…”