Cacna1c deficiency in forebrain glutamatergic neurons alters behavior and hippocampal plasticity in female mice.

CACNA1C, coding for the α1 subunit of L-type voltage-gated calcium channel (LTCC) Ca_v1.2, has been associated with multiple psychiatric disorders. Clinical studies have revealed alterations in behavior as well as in brain structure and function in CACNA1C risk allele carriers. These findings are supported by rodent models of Ca_v1.2 deficiency, which showed increased anxiety, cognitive and social impairments as well as a shift towards active stress-coping strategies. These behavioral alterations were accompanied by functional deficits, such as reduced long-term potentiation (LTP) and an excitation/inhibition (E/I) imbalance. However, these preclinical studies are largely limited to male rodents, with few studies exploring sex-specific effects. Here, we investigated the effects of Ca_v1.2 deficiency in forebrain glutamatergic neurons in female conditional knockout (CKO) mice. CKO mice exhibited hyperlocomotion in a novel environment, increased anxiety-related behavior, cognitive deficits, and increased active stress-coping behavior. These behavioral alterations were neither influenced by the stage of the estrous cycle nor by the Nex/Neurod6 haploinsufficiency or Cre expression, which are intrinsically tied to the utilization of the Nex-Cre driver line for conditional inactivation of Cacna1c. In the hippocampus, Ca_v1.2 inactivation enhanced presynaptic paired-pulse facilitation without altering postsynaptic LTP at CA3-CA1 synapses. In addition, CA1 pyramidal neurons of female CKO mice displayed a reduction in dendritic complexity and spine density. Taken together, our findings extend the existing knowledge suggesting Ca_v1.2-dependent structural and functional alterations as possible mechanisms for the behavioral alterations observed in female Ca_v1.2-Nex mice.