Presynaptic mGluRs Control the Duration of Endocannabinoid-Mediated DSI

Abstract

GABA synapses in the brain undergo depolarization-induced suppression of inhibition (DSI) that requires activation of presynaptic cannabinoid type 1 receptors (CB 1 Rs). The brevity of DSI, lasting ϳ1 min in most brain regions, has been ascribed to the transient production of 2-arachidonoylglycerol (2-AG). Here, we propose that the duration of DSI is controlled by heterologous interactions between presynaptic mGluRs and CB 1 Rs. By examining GABA synapses on parvocellular corticotropin-releasing hormone-expressing neurons in the paraventricular nucleus of the hypothalamus (PVN) of male and female mice, we show that DSI decays quickly in experimental conditions in which both GABA and glutamate are released from adjacent nerve terminals. Pharmacological inhibition of group I mGluRs prolongs DSI, whereas prior activation of mGluRs inhibits DSI, collectively suggesting that group I mGluRs quench presynaptic CB 1 R signaling. When photostimulation of genetically identified terminals is used to release only GABA, CB 1 R-dependent DSI persists for many minutes. Under the same conditions, activation of group I mGluRs reestablishes classical, transient DSI. The long-lasting DSI observed when GABA synapses are independently recruited functionally uncouples inhibitory input to PVN neurons. These observations suggest that heterologous interactions between mGluRs and CB 1 Rs control the temporal window of DSI at GABA synapses, providing evidence for a powerful new way to affect functional circuit connectivity in the brain.

A prefrontal-bed nucleus of the stria terminalis circuit limits fear to uncertain threat

“…The PVN contains a high density of cells expressing peptide hormones implicated in stress and fear, notably corticotrophin-releasing hormone (CRH) and oxytocin ( Herman and Tasker, 2016 ; Triana-Del Río et al, 2019 ). Though CRH-expressing neurons in the PVN receive input from the BNST ( Colmers and Bains, 2018 ), it is unclear whether oxytocin-producing cells do so. Interesting nonetheless, we found that mouse PVN oxytocinergic neurons strongly innervate the freezing-regulating vl/PAG, replicating earlier work in cats and naked mole rats ( Holstege, 1987 ; Rosen et al, 2008 ).…”

Neuroprotective and Immunomodulatory Action of the Endocannabinoid System under Neuroinflammation

“…Glutamate spillover may profoundly affect network excitability by shifting the duration of eCB-mediated inhibition at GABA synapses. Metabotropic glutamate receptors are involved in the control of the duration of DSI, most likely through heterologous desensitization of CB 1 [ 106 ]. Thus, glutamate-mediated excitotoxicity can significantly modify establishment of various forms of synaptic plasticity and balance in glutamate-/GABAergic signaling [ 47 ].…”

Bed nuclei of the stria terminalis modulate memory consolidation via glucocorticoid-dependent and -independent circuits

“…The avBST is well-positioned to modulate neuroendocrine responses to stress (25)(26)(27)(28)(29). It provides a GABAergic input to effector neurons in the paraventricular hypothalamic nucleus (PVH) that modulate the hypothalamicpituitary-adrenal (HPA) axis and thereby regulate peripheral glucocorticoid levels in response to a variety of aversive experiences (22,23,(30)(31)(32). Thus, avBST and its projections to the PVH may serve as a critical central regulator of CORT release during the posttraining period of memory consolidation.…”