Deletion of the mouse homolog of CACNA1C disrupts discrete forms of hippocampal dependent memory and neurogenesis with in the dentate gyrus

Abstract

L-type voltage gated calcium channels (LVGCCs) have been implicated in various forms of learning, memory, and synaptic plasticity. Within the hippocampus, the LVGCC subtype, Ca_V1.2 is prominently expressed throughout the dentate gyrus. Despite the apparent high levels of Ca_V1.2 expression in the dentate gyrus, the role of Ca_V1.2 in hippocampal and dentate gyrus associated forms of learning remain unknown. To address this question we examined alternate forms of hippocampal dependent associative and spatial memory in mice lacking the mouse ortholog of CACNA1C (Cacna1c) which encodes Ca_V1.2, with dentate gyrus function implicated in difficult forms of each task. We found that while deletion of Ca_V1.2 did not impair acquisition of fear to a conditioned context, mice lacking Ca_V1.2 exhibited deficits in the ability to discriminate between two contexts, one in which the mice were conditioned and one in which they were not. Similarly, Ca_V1.2 knock-out mice exhibited normal acquisition and recall of the location of the hidden platform in a standard Morris watermaze, but were unable to form a memory of the platform location when the task was made more difficult by restricting the number of available spatial cues. Within the dentate gyrus, pan-neuronal deletion of Ca_V1.2 resulted in decreased cell proliferation and the doublecortin positive adult-born neurons, implicating Ca_V1.2 in adult neurogenesis. These results suggest that Ca_V1.2 is important for dentate gyrus associated tasks and may mediate these forms of learning via a role on adult neurogenesis and cell proliferation within the dentate gyrus.

Significance Statement Recent genome wide association studies have implicated the gene CANA1C which encodes the L-type voltage-gated calcium channel Ca_V1.2 as a risk factor for psychiatric disease. Here we examine mice lacking the mouse ortholog of CANA1C. We find that while seemingly normal, these mice lack the ability to successfully learn tasks that require the discrimination of environmental cues or in which the cues are limited. This type of learning, often referred to as pattern separation/completion, is thought to require the birth and survival of neurons in the dentate gyrus subregion of the hippocampus. Interestingly, mice lacking Ca_V1.2 exhibit reduced neurogenesis in this brain region. Our results suggest an intriguing link between a psychiatric risk allele, neurogenesis and pattern separation/completion.