L-type voltage-gated calcium channels are important regulators of neuronal activity and are widely expressed throughout the brain. One of the major L-type voltagegated calcium channel isoforms in the brain is Ca V 1.3. Mice lacking Ca V 1.3 are reported to have impairments in fear conditioning and depressive-like behaviors, which have been linked to Ca V 1.3 function in the hippocampus and amygdala. Genetic variation in Ca V 1.3 has been linked to a variety of psychiatric disorders, including autism and schizophrenia, which are associated with altered motor learning, associative learning and social function. Here, we explored whether Ca V 1.3 plays a role in these behaviors. We found that Ca V 1.3 knockout mice have deficits in rotarod learning despite normal locomotor function. Deletion of Ca V 1.3 is also associated with impaired gait adaptation and associative learning on the Erasmus Ladder. We did not observe any impairments in Ca V 1.3 knockout mice on assays of anxiety-like, depression-like or social preference behaviors. Our results suggest an important role for Ca V 1.3 in neural circuits involved in motor learning and concur with previous data showing its involvement in associative learning.

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OBJECTIVES/GOALS: Genetic variation in L-type voltage-gated calcium channels, including CaV1.3, is associated with increased risk for psychiatric disorders including bipolar disorder and schizophrenia. Additionally, rare mutations in CaV1.3 have been linked to epilepsy, developmental delay, and autism. Deletion of CaV1.3 in mice is associated with impaired consolidation of contextual fear conditioning. Some studies have also observed affective behavior deficits in CaV1.3-deficient mice, but other studies have not found affective phenotypes, perhaps due to differences in genetic backgrounds, sex ratios, or task protocols. CaV1.3 is important for slow afterhyperpolarization in hippocampal and amygdala neurons, which prevents excessive firing in response to sustained excitatory input, and CaV1.3-deficient amygdala neurons exhibit hyperexcitability and impaired LTP. CaV1.3 is also expressed in the cerebellum, but its functional role there is not well understood. Given its importance in shaping neuronal activity in the hippocampus and amygdala, we hypothesized that loss of CaV1.3 would cause abnormalities in motor learning as well as affective and cognitive behaviors. METHODS/STUDY POPULATION: Wild-type (WT), haploinsufficient (Hap), and knockout (KO) mice were maintained on a congenic C57BL/6NTac genetic background and were subjected to behavioral tasks including open field, rotarod, ErasmusLadder, elevated zero maze, forced swim test, and tail suspension test. Data were analyzed with sexes combined and with sexes separated to assess for sex as a biological variable. Studies were analyzed by one-way ANOVA, two-way ANOVA, or generalized linear mixed model, where appropriate. RESULTS/ANTICIPATED RESULTS: CaV1.3 KO was associated with impaired motor learning in the rotarod task (p < 0.05), as well as impaired associative learning in the ErasmusLadder task (p < 0.01), despite intact locomotor function on both tasks. When examined by sex, the rotarod phenotypes were driven by motor learning impairments in males (both Hap and KO, p < 0.05 and p < 0.01, respectively), whereas the ErasmusLadder associative learning phenotypes were present in both sexes only in the KO condition, consistent with previously reported impairments in CaV1.3-deficient mice in consolidation of contextual fear conditioning. Although KO mice learned the motor aspects of the ErasmusLadder task, they learned more slowly. They also failed to learn start cues, which requires intact associative learning. No differences were observed in overall exploration or locomotor activity in open field or elevated zero maze. Analyses from affective tasks are ongoing. DISCUSSION/SIGNIFICANCE OF IMPACT: These preliminary studies provide new evidence that CaV1.3 is important for the function of neural circuits involved in motor learning, and concur with previous data showing its involvement in associative learning. Our data differ slightly from previous studies of CaV1.3 in motor learning, which could be attributable to differences in task protocols and/or genetic background. These results highlight the importance of CaV1.3 in a variety of behaviors, which may help explain why variation in CaV1.3 expression and function has pleiotropic effects in humans.

L-type voltage-gated calcium channels (LVGCCs) are important regulators of neuronal activity and are widely expressed throughout the brain. One of the major LVGCC isoforms in the brain is CaV1.3. Mice lacking CaV1.3 (CaV1.3 KO) have impairments in fear conditioning and depressive-like behaviors, which have been linked to the role of CaV1.3 in hippocampal and amygdala function. Genetic variation in CaV1.3 has been linked to a variety of psychiatric disorders, including autism and schizophrenia, which are associated with motor, learning, and social deficits. Here, we explored whether CaV1.3 plays a role in these behaviors. We found that CaV1.3 KO mice have deficits in rotarod learning despite normal locomotor function. Deletion of CaV1.3 is also associated with impaired associative learning on the Erasmus Ladder. We did not observe any impairments in CaV1.3 KO mice on assays of anxiety-like, depression-like, or social preference behaviors. Our results suggest an important role for CaV1.3 in neural circuits involved in motor learning and concur with previous data showing its involvement in associative learning.