TRPM3 regulates fear memory encoding and seizure susceptibility in the lateral amygdala

TRPM3 is best known for its role as a peripheral sensor of pain and heat. Recent studies reporting gain-of-function TRPM3 mutations in patients with neurodevelopmental and epilepsy-associated disorders suggest a previously unrecognized role of this channel in the brain. However, the function of TRPM3 in neurons of the brain remains largely unexplored.

Using a battery of in vivo and in vitro electrophysiological and histological experiments, we studied the effect of TRPM3 channel on amygdala-related functions.

Here, we identify TRPM3 expression in excitatory neurons of the lateral nucleus of the amygdala (LA), a brain region critical for fear learning also implicated in neuropsychiatric and epileptic disorders. We demonstrate that TRPM3 is functionally active in LA neurons and regulates their intrinsic electrophysiological properties. Consistent with this role, genetic ablation of TRPM3 in mice impairs fear memory formation. Moreover, in a kainic acid-induced epilepsy model, loss of TRPM3 reduces seizure severity, whereas pharmacological activation of the channel exacerbates seizure phenotypes. Finally, we demonstrate the presence of TRPM3 transcripts in neurons of the human LA.

Together, these findings uncover a central role for TRPM3 in amygdala function and identify this ion channel as a modulator of fear memory and seizure susceptibility.