Cannabinoid and vanilloid pathways mediate opposing forms of synaptic plasticity in corticotropin-releasing hormone neurons.

Abstract

Activity-dependent release of retrograde signaling molecules form micro-feedback loops to regulate synaptic function in neural circuits. Single neurons can release multiple forms of these signaling molecules, including endocannabinoids and endovanilloids, which act via cannabinoid (CB) receptors and transient receptor potential vanilloid 1 (TRPV1) receptors. In hypothalamic corticotrophin-releasing hormone (CRH) neurons, endocannabinoids acting via CB1 receptors have been shown to play an important role in regulating excitability and hence stress hormone secretion. However, the importance of endovanilloid signaling in CRH neurons is currently unclear. Here, we show that, in response to postsynaptic depolarization, CRH neurons release endocannabinoid/endovanilloid molecules that can activate CB1 and TRPV1 receptors. Activation of CB1 receptors suppresses glutamate neurotransmission whereas activation of TRPV1 enhances spontaneous glutamate transmission. However, the excitatory effects of TRPV1 are normally masked by the inhibitory effects of CB1. When the degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG) was inhibited, this revealed tonic activation of CB1 receptors, suggesting tonic endocannabinoid release. However, we found no evidence for tonic activation of TRPV1 receptors under similar conditions. These findings show that activation of CRH neurons can drive the release of signaling molecules that activate parallel endocannabinoid and endovanilloid receptor pathways to mediate opposing forms of synaptic plasticity.