The L-type voltage-gated calcium channel CaV1.2 mediates fear extinction and modulates synaptic tone in the lateral amygdala.

Abstract

L-type voltage-gated calcium channels (LVGCCs) have been implicated in both the formation and the reduction of fear through Pavlovian fear conditioning and extinction. Despite the implication of LVGCCs in fear learning and extinction, studies of the individual LVGCC subtypes, CaV1.2 and CaV1.3, using transgenic mice have failed to find a role of either subtype in fear extinction. This discontinuity between the pharmacological studies of LVGCCs and the studies investigating individual subtype contributions could be due to the limited neuronal deletion pattern of the CaV1.2 conditional knockout mice previously studied to excitatory neurons in the forebrain. To investigate the effects of deletion of CaV1.2 in all neuronal populations, we generated CaV1.2 conditional knockout mice using the synapsin1 promoter to drive Cre recombinase expression. Pan-neuronal deletion of CaV1.2 did not alter basal anxiety or fear learning. However, pan-neuronal deletion of CaV1.2 resulted in a significant deficit in extinction of contextual fear, implicating LVGCCs, specifically CaV1.2, in extinction learning. Further exploration on the effects of deletion of CaV1.2 on inhibitory and excitatory input onto the principle neurons of the lateral amygdala revealed a significant shift in inhibitory/excitatory balance. Together these data illustrate an important role of CaV1.2 in fear extinction and the synaptic regulation of activity within the amygdala.