Elsevier

Neuropharmacology

Volume 54, Issue 1, January 2008, Pages 68-78
Neuropharmacology

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

https://doi.org/10.1016/j.neuropharm.2007.06.026Get rights and content

Abstract

Endocannabinoids (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 depolarization-induced 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.

Introduction

Endocannabinoids (eCB) have recently emerged as key mediators of short-term and long-term synaptic depression at both excitatory and inhibitory synapses in numerous brain structures (recently reviewed in Chevaleyre et al., 2006). Typically, the post-synaptic neuron releases eCBs in response either to depolarization or to bursts of presynaptic afferent activity that engage post-synaptic metabotropic glutamate receptors (Alger, 2002, Chevaleyre et al., 2006, Diana and Marty, 2004, Gerdeman and Lovinger, 2003, Kreitzer and Regehr, 2002). Once released, these messengers rapidly diffuse across the synaptic cleft and bind to type 1 cannabinoid receptors (CB1Rs) on nearby presynaptic terminals, resulting in a reduction of neurotransmitter release that can be transient (i.e. depolarization-induced suppression of inhibition or excitation, DSI/DSE) or long-lasting (i.e. eCB-mediated long-term depression or eCB-LTD). CB1Rs are widely distributed in the brain, and where the receptors are present, exogenous ligands reliably suppress synaptic transmission. In contrast, the magnitude and duration of eCB-mediated synaptic modulation varies widely at different CB1R-containing synapses.

The dentate gyrus has one of the highest levels of CB1R expression in the brain (Herkenham et al., 1990, Katona et al., 2006, Kawamura et al., 2006, Tsou et al., 1998). Exogenous cannabinoids have been shown to moderately reduce synaptic transmission at putative mossy cell fiber (MCF)-dentate granule cell (DGC) synapses (Monory et al., 2006), suggesting that mossy cell terminals may also be modulated by eCBs. However, very little is known about eCB signaling in this area and what potential role it may play. eCBs may have a significant functional impact on this system since, intriguingly, mossy cells excite, and are excited by, dentate granule cells (Buckmaster et al., 1992, Ratzliff et al., 2002, Scharfman, 1995). This positive feedback loop may predispose these cells to excitotoxic cell death. In fact, hilar mossy cells are one of the first cell types to be lost following experimentally-induced epileptiform activity (Buckmaster and Jongen-Relo, 1999, Cavazos et al., 1994), and their loss has been implicated in the development of epilepsy (Sloviter, 1994). In this context, the negative feedback provided by eCB signaling may be especially important. Indeed, recent work suggests that eCB signaling at excitatory synapses may play a protective role against epileptogenesis (Lutz, 2004, Monory et al., 2006, van der Stelt et al., 2002).

Here, we investigate whether excitatory synapses in the dentate gyrus can be modulated by eCBs. We make use of the finding that CB1Rs are highly expressed in the inner-most third of the molecular layer of the dentate gyrus (Katona et al., 2006, Kawamura et al., 2006, Monory et al., 2006, Tsou et al., 1998). This region, called the supragranular layer (SGL), receives excitatory associational/commissural axonal inputs primarily from hilar mossy cells (Buckmaster et al., 1992, Laurberg and Sorensen, 1981, Scharfman, 1995, Witter and Amaral, 2004). We recorded excitatory synaptic responses in DGCs while stimulating the mossy cell fibers (MCFs), the medial perforant path (MPP), or the lateral perforant path (LPP). We were able to induce eCB-mediated short-term synaptic suppression of the mossy cell synaptic input but not the perforant path inputs. Furthermore, we report that eCB-mediated short-term depression at MCF-DGC synapses can be enhanced by agonists of cholinergic and group I metabotropic glutamate receptors. eCB-LTD is not observed at this synapse, perhaps due to mechanistic differences with eCB-LTD-expressing synapses.

Section snippets

Materials and methods

All animal experiments were carried in accordance with the National Institutes of Health guide for the care and use of laboratory animals. Acute hippocampal slices were prepared from postnatal day (P) 16–24 Wistar rats or from P28–30 CB1R−/− mice and CB1R+/+C57BL/6J littermates. Mice were from our colony of Zimmer line CB1R−/− mice (Zimmer et al., 1999) and were maintained as heterozygotes and genotyped by PCR before use as described previously (Takahashi and Castillo, 2006). Animals were

Results

We first investigated whether exogenous activation of CB1Rs could suppress excitatory synaptic transmission onto DGCs. To this aim, we monitored AMPAR-EPSCs evoked by MCF or LPP stimulation before and after bath application of the CB1 receptor agonist WIN 55,212-2 (WIN) (5 μM) (Fig. 2A). We found that 35–45 min following bath application of WIN the EPSC amplitude evoked by MCF stimulation decreased by 68 ± 7% (n = 5, p < 0.0001), while in the same cells EPSCs evoked by LPP stimulation were reduced by

Discussion

In this study we investigated the role of eCBs in regulating excitatory synaptic transmission in the dentate gyrus. We report that inputs from hilar mossy cells (e.g. MCF), but not from entorhinal cortex (i.e. MPP and LPP), can be regulated by eCBs. This finding is entirely consistent with the anatomical localization and functional expression of CB1Rs in the dentate gyrus. Previous studies have shown a stronger CB1R immunolabeling in SGL (the MCF synaptic field) than in the dentate molecular

Acknowledgments

We thank Kanji Takahashi, Vivien Chevaleyre and Boris Heifets for critical reading of the manuscript. CB1+/− mice of the Zimmer line are a gift of Andreas Zimmer (University of Bonn) and were obtained from George Kunos and Sandor Batkai (NIH/NIAAA). We thank Kanji Takahashi for his help in maintaining the Zimmer line and genotyping. This study was supported by NIH/NIDA, the Pew Biomedical Program and Institutional Postdoctoral Training Grant T32 NS 07439.

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