Deletion of N-type Ca2+ Channel Cav2.2 Results in Hyperaggressive Behaviors in Mice

Voltage-dependent N-type Ca2+ channels play important roles in the regulation of diverse neuronal functions in the brain, but little is known about its role in social aggressive behaviors. Mice lacking the alpha 1B subunit (Ca(v)2.2) of N-type Ca2+ channels showed markedly enhanced aggressive behaviors to an intruder mouse in the resident-intruder test. The dorsal raphe nucleus (DRN), which contains serotonin neurons, is known to be involved in aggression in animals. We thus examined the DRN neurons in the Ca(v)2.2-deficient (Cav2.2(-/-)) mice. Microinjection of omega-conotoxin GVIA, an N-type Ca2+ channel-specific blocker, into the DRN of wild type mice resulted in escalated aggression, mimicking the phenotypes of Ca(v)2.2(-/-). Electrophysiological analysis showed increased firing activity of serotonin neurons with a reduced inhibitory neurotransmission in the Ca(v)2.2(-/-) DRN. Ca(v)2.2(-/-) mice showed an elevated level of arginine vasopressin, an aggression-related hormone, in the cerebrospinal fluid. In addition, Ca(v)2.2(-/-) mice showed an increase of serotonin in the hypothalamus. These results suggest that N-type Ca2+ channels at the DRN have a key role in the control of aggression.