Compartment-Specific Modulation of GABAergic Synaptic Transmission by TRPV1 Channels in the Dentate Gyrus

Abstract

The transient receptor potential TRPV1 or vanilloid receptor is a nonselective ligand-gated channel highly expressed in primary sensory neurons where it mediates nociception. TRPV1 is also expressed in the brain where its activation depresses excitatory synaptic transmission. Whether TRPV1 also regulates inhibitory synapses in the brain is unclear. Here, using a combination of pharmacology, electrophysiology, and an in vivo knockdown strategy, we report that TRPV1 activation by capsaicin or by the endocannabinoid anandamide depresses somatic, but not dendritic inhibitory transmission in both rat and mouse dentate gyrus. The effect on somatic inhibition was absent in TRPV1 knock-out mice and was also eliminated by two different TRPV1 shRNAs expressed in dentate granule cells, strongly supporting a functional role for TRPV1 in modulating GABAergic synaptic function. Moreover, TRPV1-mediated depression occurs independently of GABA release, requires postsynaptic Ca 2ϩ rise and activation of calcineurin, and is likely due to clathrin-dependent internalization of GABA receptors. Altogether, these findings reveal a novel form of compartment-specific regulation whereby TRPV1 channels can modify synaptic function in the brain.

The endocannabinoid system in guarding against fear, anxiety and stress

“…Stimulation of the mtCB1R leads to inhibition of mitochondrial oxidative phosphorylation and ATP production in the mitochondria and can modulate neurotransmitter release through mechanisms that are still unknown (indicated by the question mark) 146 . AEA can also activate the postsynaptic non-selective cation channel transient receptor potential cation channel subfamily V member 1 (TRPV1) 71,72,178,179 , leading to an increase in postsynaptic current, whereas 2-AG can also stimulate postsynaptic GABA A receptors 180 . On depolarization of the postsynaptic terminal, for example, by activation of metabotropic receptors (metabotropic glutamate receptor 1 (mGluR1; also known as GRM1), mGluR5, muscarinic receptor type 1 (M 1 ) or M 2 ) 8,14 , 2-AG is postsynaptically synthesized ‘on-demand’ by diacylglycerol lipase-α (DAGLα) in dendritic spines of excitatory synapses 181–183 .…”

Expression of TRPV1 channels by Cajal‐Retzius cells and layer‐specific modulation of synaptic transmission by capsaicin in the mouse hippocampus

“…2010), and to reduce perisomatic GABAergic inputs (Chávez et al . 2014). In the hippocampus proper, Gibson et al .…”

“…In fact, while Cavanaugh et al (2011) have suggested that CRs are the only hippocampal neuronal type expressing TRPV1, other studies indicate a more widespread expression, including several other neuronal types (i.e. pyramidal cells, GABAergic interneurons, and granule cells; see Toth et al 2005;Cristino et al 2006;Gibson et al 2008;Chávez et al 2010Chávez et al , 2014Puente et al 2015;Canduela et al 2015;Lee et al 2015;Eguchi et al 2016;Hurtado-Zavala et al 2017; see also review by Kauer & Gibson, 2009). Thus, application of capsaicin might trigger some form of network activity, which would result, indirectly, in responses in CRs.…”

“…Several groups have provided evidence for network-related effects following the activation of TRPV1 in the hippocampus. For example, TRPV1 expressed by postsynaptic dentate granule cells has been shown to control synaptic plasticity of medial perforant path excitatory inputs (Chávez et al 2010), and to reduce perisomatic GABAergic inputs (Chávez et al 2014). In the hippocampus proper, Gibson et al (2008) have reported that the stimulation of TRPV1 located on the presynaptic terminals of the Schaffer collaterals decreases evoked excitatory synaptic transmission on stratum radiatum interneurons, and induces long-term depression.…”

GABA type a receptor trafficking and the architecture of synaptic inhibition

“…NMDA receptor mediated calcium entry and CaN activation was further shown to decrease surface α2‐containing receptors during in vitro epileptiform activity by live‐cell imaging techniques (Eckel et al, ). Activation of the transient receptor potential cation channel subfamily V member 1 also appears to cause GABA A R endocytosis in the dentate gyrus of rodents dependent on calcium influx, CaN, and dynamin‐activity (Chavez et al, ). In addition, inflammation and release of the proinflammatory cytokine tumor necrosis factor‐α (TNFα) stimulates GABA A R internalization (α1/2/5, β3, γ2) in a CaN‐independent pathway in cultured hippocampal neurons (Pribiag and Stellwagen, ).…”