CORTICOSTERONE DISRUPTS MITOCHONDRIAL-ER CONTACTS TO DESYNCHRONIZE HIPPOCAMPAL INHIBITION AND IMPAIR RECOGNITION MEMORY VIA ENDOCANNABINOID SIGNALING

Corticosteroids are key mediators of stress-induced cognitive alterations. However, the mechanisms behind corticosterone (CORT)-induced impairment of novel object recognition (NOR) retrieval remain poorly understood. Here, we show for the first time how CORT changes organellar architecture to disrupt NOR performance and hippocampal GABAergic transmission via endocannabinoid signaling. Mice received a NOR-impairing dose of CORT (10 mg/kg) 30 min before the test session. Pharmacological blockade, Mineralocorticoid receptor (MR)-deletion and local injections of membrane-impermeant CORT-BSA pinpoint the involvement of membrane-bound MRs on hippocampal glutamatergic neurons. Next, using pharmacological manipulations of endocannabinoid levels and conditional mouse mutants for the Cannabinoid Type 1 Receptor (CB1R) we observed that Anandamide and mitochondrial CB1R (mtCB1) in hippocampal PV+ interneurons are required for CORT-induced NOR impairment. Because mtCB1 regulates mitochondrial functions including calcium uptake, and calcium transfer from the endoplasmic reticulum (ER) depends on ER-mitochondria spacing, we examined mitochondrial–ER contact sites (MERCS) in GABAergic cells using a split-GFP-based contact site sensor. CORT reduced the number of MERCS at approximately 20 nm, a distance optimal for calcium transfer, via a CB1-dependent mechanism. Finally, possible synaptic consequences were assessed by ex vivo patch-clamp recordings from CA1 pyramidal neurons. CORT decreased evoked GABAergic transmission, while increasing spontaneous as well as asynchronous GABA release. Ongoing experiments will address whether MERC alterations causally drive these CB1-dependent electrophysiological and behavioral effects. Altogether, these data reveal that MERC structure in interneurons is essential for cognitive processing and its endocannabinoid-mediated disruption contributes to altered synaptic timing and the amnesic effects of stress hormones.