Diazepam-induced loss of inhibitory synapses mediated by PLCδ/ Ca²⁺/calcineurin signalling downstream of GABAA receptors.

ABSTRACT: Benzodiazepines facilitate the inhibitory actions of GABA by binding to γ-aminobutyric acid type A receptors (GABA_ARs), GABA-gated chloride/bicarbonate channels, which are the key mediators of transmission at inhibitory synapses in the brain. This activity underpins potent anxiolytic, anticonvulsant and hypnotic effects of benzodiazepines in patients. However, extended benzodiazepine treatments lead to development of tolerance, a process which, despite its important therapeutic implications, remains poorly characterised. Here we report that prolonged exposure to diazepam, the most widely used benzodiazepine in clinic, leads to a gradual disruption of neuronal inhibitory GABAergic synapses. The loss of synapses and the preceding, time- and dose-dependent decrease in surface level

SUBMITTER: Nicholson MW 

PROVIDER: S-EPMC6232101 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature