Input-specific plasticity at excitatory synapses mediated by endocannabinoids in the dentate gyrus

Abstract

SummaryEndocannabinoids (eCBs) mediate transient and long-lasting synaptic plasticity in several brain structures. In the dentate gyrus, activation of the type 1 cannabinoid receptor (CB1R) by exogenous ligands reportedly depresses excitatory synaptic transmission. However, direct evidence of eCB signaling at excitatory synapses in this region has been lacking. Here, we demonstrate that eCB release can be induced by a brief postsynaptic depolarization of dentate granule cells (DGCs), which potently and transiently suppresses glutamatergic inputs from mossy cell interneurons (MCs) but not from entorhinal cortex via the lateral and medial perforant paths. This input-specific depolarizationinduced suppression of excitation (DSE) is calcium-dependent and can be modulated by agonists of cholinergic and group I metabotropic glutamate receptors. Inhibiting the synthesis of 2-arachidonoyl glycerol (2-AG), one of the most abundant eCBs in the brain, by diacyglycerol lipase (DGL) does not abolish DSE. Moreover, preventing the breakdown of anandamide, the other main eCB, does not potentiate DSE. Thus, eCB signaling underlying DSE in the dentate does not require DGL activity and is unlikely to be mediated by anandamide. Finally, we find that manipulations known to induce eCB-LTD at other central synapses do not trigger LTD at MCF-DGC synapses.

Molecular and Morphological Configuration for 2-Arachidonoylglycerol-Mediated Retrograde Signaling at Mossy Cell–Granule Cell Synapses in the Dentate Gyrus

“…However, it has been controversial as to the role of 2-AG or DGL in eCB-mediated retrograde suppression at MC-GC synapses (Chiu and Castillo, 2008). In the present study, we have demonstrated that DSE and its enhancement by group I mGluR activation were abolished in DGL␣-knock-out mice (Fig.…”

“…The electrode had a tip separation of 40 m and was placed in the supragranular layer within 40 m from the cell body layer. A previous report (Chiu and Castillo, 2008) showed that medial perforant path inputs, but not MC inputs, were sensitive to group II mGluR agonists. Therefore, we checked whether the evoked EPSCs were suppressed by 1 M DCG-IV (group II mGluR agonist), and only the DCG-IV-insensitive EPSCs were analyzed.…”

“…Coronal hippocampal slices (400 m) were prepared from DGL␣-knock-out and wild-type mice at postnatal days 20 -30, as described previously (Chiu and Castillo, 2008). Mice were decapitated under CO 2 anesthesia, and the brain was quickly removed and cooled in an ice-cold, modified external solution containing (in mM) 120 choline-Cl, 2 KCl, 8 MgCl 2 , 28 NaHCO 3 , 1.25 NaH 2 PO 4 , and 20 glucose bubbling with 95% O 2 and 5% CO 2 .…”

“…We made whole-cell recordings from GCs (Chiu and Castillo, 2008) and stimulated MC axons with bipolar electrodes in the inner molecular layer (Ͻ40 m from the GC layer) at which GCs exclusively receive excitatory MC inputs on their dendritic spines (Shepherd, 2004) (see Fig. 3A-F ).…”

Neurobiologia da Cannabis: do sistema endocanabinoide aos transtornos por uso de Cannabis

“…A EC-STD subclassifica-se em: a) supressão da inibição/excitação induzida pela despolarização (depolarization-induced suppression of inhibition/excitation, DSI/DSE), conforme induzida em neurônios inibitórios/excitatórios 24,27,28,38,39,42,47,[51][52][53][54][55] ; b) supressão mediada por receptores ionotrópicos NMDA (NMDA-R-EC-STD) 39,42 ; c) supressão mediada por receptores metabotrópicos (metabotropic-induced suppression of inhibition/excitation, MSI/MSE) 24,38,39,42 ; sobretudo receptores metabotrópicos glutamatérgicos tipo 1 e tipo 5 (mGlu-R 1 /-R 5 ) e receptores metabotrópicos colinérgicos muscarínicos tipo 1 e tipo 3 (mAChR-M 1 /-M 3 ) -mediado, metabotrópico-mediado e comediado) 28,37,38,48,60,63 . O mecanismo metabotrópico--mediado é efetivado pelo 2-AG 38,48,63 , com duas exceções.…”