Fine-tuning of synaptic upscaling at excitatory synapses by endocannabinoid signaling is mediated via the CB1 receptor.

Yunping Song,Jian Zhang,Chu Chen

doi:10.1038/srep16257

Abstract

The endocannabinoid 2-arachidonoylglycerol (2-AG) functions as a retrograde signaling molecule mediating synaptic transmission and plasticity at both inhibitory and excitatory synapses. However, little is known about whether 2-AG signaling is involved in homeostatic regulation of miniature synaptic events at excitatory synapses in response to activity deprivation. Here, we report that chronic blockade of firing by tetrodotoxin (TTX) for two days resulted in increases both in the frequency and amplitude of spontaneous miniature excitatory postsynaptic currents (mEPSCs) in cultured mouse hippocampal neurons. However, treatment with 2-AG alone or JZL184, a potent and selective inhibitor for monoacylglycerol lipase (MAGL) that hydrolyzes 2-AG, induced a CB1 receptor-dependent reduction of the frequency of mEPSCs, but not the amplitude. The TTX-increased frequency was blunted by 2-AG or JZL184 and this effect was eliminated by pharmacological or genetic inhibition of CB1 receptors. In addition, TTX still increased frequency and amplitude of mEPSCs in the presence of CB1 receptor inhibition. Our results suggest that while endocannabinoids are not required for induction of synaptic scaling at excitatory glutamate synapses after chronic activity deprivation, 2-AG signaling may play a role in fine-tuning of synaptic strengths via presynaptically-expressed CB1 receptors.

Highlights

While homeostatic regulation of synaptic plasticity has been extensively studied, the signaling mechanisms that regulate or tune synaptic scaling are not fully understood[1,2]
To investigate whether 2-AG signaling is required in homeostatic regulation of synaptic strength in response to persistent absence of neuronal activity, whole-cell patch clamp recordings were made to detect miniature excitatory postsynaptic currents (mEPSCs) in cultured mouse hippocampal neurons
We show that endocannabinoid signaling is not required for the induction of synaptic scaling by providing the evidence that both the frequency and amplitude of mEPSCs in cultured mouse hippocampal neurons were elevated by chronic deprivation of firing activity in the absence and presence of CB1 receptors (CB1R) inhibition

Summary

Introduction

While homeostatic regulation of synaptic plasticity has been extensively studied, the signaling mechanisms that regulate or tune synaptic scaling are not fully understood[1,2]. The study of Zhang et al.[9], showed that suppression of mIPSCs in response to the acute absence of mEPSCs (1–3 hours) is dependent on CB1R-mediated 2-arachidonoylglycerol (2-AG) signaling. This suggests that eCBs are involved in scaling of inhibitory synaptic strengths when neural firing or excitatory synaptic activity is absent. It is still not clear whether 2-AG signaling plays a role in synaptic upscaling at excitatory synapses upon chronic activity deprivation. Our results suggest that 2-AG signaling may play a role in CB1R-mediated fine-tuning of synaptic strengths at excitatory synapses when neural network activity is chronically deprived

Methods

Results

Conclusion