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The gene CACNA1C , which encodes the pore forming subunit of the L-type calcium channel Ca V 1.2, is associated with increased risk for neuropsychiatric disorders including schizophrenia, autism spectrum disorder, major depression, and bipolar disorder. Previous rodent work identified that loss or reduction of Ca V 1.2 results in cognitive, affective, and motor deficits. Most previous work has either included non-neuronal cell populations (haploinsufficient and Nestin-Cre) or investigated a discrete neuronal cell population (e.g. CaMKII-Cre, Drd1-Cre), but few studies have examined the effects of more broad neuron-specific deletion of Ca V 1.2. Additionally, most of these studies did not evaluate for sex-specific effects or used only male animals. Here, we sought to clarify whether there are sex-specific behavioral consequences of neuron-specific deletion of Ca V 1.2 (neuronal Ca V 1.2 cKO) using Syn1-Cre-mediated conditional deletion. We found that neuronal Ca V 1.2 cKO mice have normal baseline locomotor function but female cKO mice display impaired motor performance learning. Male neuronal Ca V 1.2 cKO display impaired startle response with intact pre-pulse inhibition. Male neuronal Ca V 1.2 cKO mice did not display normal social preference, whereas female neuronal Ca V 1.2 cKO mice did. Neuronal Ca V 1.2 cKO mice displayed impaired associative learning in both sexes, as well as normal anxiety-like behavior and hedonic capacity. We conclude that deletion of neuronal Ca V 1.2 alters motor performance, acoustic startle reflex, and social behaviors in a sex-specific manner, while associative learning deficits generalize across sexes. Our data provide evidence for both sex-specific and sex-independent phenotypes related to neuronal expression of Ca V 1.2.

Genetic variation in , the gene that encodes the pore-forming subunit of the L-type calcium channel Ca 1.3, has been associated with increased risk for neuropsychiatric disorders that display abnormalities in cerebellar structures. We sought to clarify if deletion of Ca 1.3 in mice would induce abnormalities in cerebellar cortex cytoarchitecture or synapse morphology. Since Ca 1.3 is highly expressed in cerebellar molecular layer interneurons (MLIs) and L-type channels appear to regulate GABA release from MLIs, we hypothesized that loss of Ca 1.3 would alter GABAergic synapses between MLIs and Purkinje cells (PCs) without altering MLI numbers or PC structure. As expected, we did not observe changes in the numbers of MLIs or PCs. Surprisingly, Ca 1.3 KO mice do have decreased complexity of PC dendritic arbors without differences in the number or structure of GABAergic synapses onto PCs. Loss of Ca 1.3 was not associated with impaired acquisition of delay eyeblink conditioning. Therefore, our data suggest that Ca 1.3 expression is important for PC structure but does not affect other measures of cerebellar cortex morphology or cerebellar function as assessed by delay eyeblink conditioning.

The gene CACNA1C, which encodes the pore forming subunit of the L-type calcium channel Ca 1.2, is associated with increased risk for neuropsychiatric disorders including schizophrenia, autism spectrum disorder, major depression, and bipolar disorder. Previous rodent work identified that loss or reduction of Ca 1.2 results in cognitive, affective, and motor deficits. Most previous work has either included non-neuronal cell populations (haploinsufficient and Nestin-Cre) or investigated a discrete neuronal cell population (e.g. CaMKII-Cre, Drd1-Cre), but few studies have examined the effects of more broad neuron-specific deletion of Ca 1.2. Additionally, most of these studies did not evaluate for sex-specific effects or used only male animals. Here, we sought to clarify whether there are sex-specific behavioral consequences of neuron-specific deletion of Ca 1.2 (neuronal Ca 1.2 cKO) using Syn1-Cre-mediated conditional deletion. We found that neuronal Ca 1.2 cKO mice have normal baseline locomotor function but female cKO mice display impaired motor performance learning. Male neuronal Ca 1.2 cKO display impaired startle response with intact pre-pulse inhibition. Male neuronal Ca 1.2 cKO mice did not display normal social preference, whereas female neuronal Ca 1.2 cKO mice did. Neuronal Ca 1.2 cKO mice displayed impaired associative learning in both sexes, as well as normal anxiety-like behavior and hedonic capacity. We conclude that deletion of neuronal Ca 1.2 alters motor performance, acoustic startle reflex, and social behaviors in a sex-specific manner, while associative learning deficits generalize across sexes. Our data provide evidence for both sex-specific and sex-independent phenotypes related to neuronal expression of Ca 1.2.

Genetic variation in CACNA1D, the gene that encodes the pore-forming subunit of the L-type calcium channel CaV1.3, has been associated with increased risk for neuropsychiatric disorders that display abnormalities in cerebellar structures. We sought to clarify if deletion of CaV1.3 in mice would induce abnormalities in cerebellar cortex cytoarchitecture or synapse morphology. Since CaV1.3 is highly expressed in cerebellar molecular layer interneurons (MLIs) and L-type channels appear to regulate GABA release from MLIs, we hypothesized that loss of CaV1.3 would alter GABAergic synapses between MLIs and Purkinje cells (PCs) without altering MLI numbers or PC structure. As expected, we did not observe changes in the numbers of MLIs or PCs. Surprisingly, CaV1.3 KO mice do have decreased complexity of PC dendritic arbors without differences in the number or structure of GABAergic synapses onto PCs. Loss of CaV1.3 was not associated with impaired acquisition of delay eyeblink conditioning. Therefore, our data suggest that CaV1.3 expression is important for PC structure but does not affect other measures of cerebellar cortex morphology or cerebellar function as assessed by delay eyeblink conditioning.

Voltage-gated Ca 2+ channels are critical for the development and mature function of the nervous system. Variants in the CACNA2D4 gene encoding the α 2 δ-4 auxiliary subunit of these channels are associated with neuropsychiatric and neurodevelopmental disorders. α 2 δ-4 is prominently expressed in the retina and is crucial for vision, but extra-retinal functions of α 2 δ-4 have not been investigated. Here, we sought to fill this gap by analyzing the behavioral phenotypes of α 2 δ-4 knockout (KO) mice. α 2 δ-4 KO mice (both males and females) exhibited significant impairments in prepulse inhibition that were unlikely to result from the modestly elevated auditory brainstem response thresholds. Whereas α 2 δ-4 KO mice of both sexes were hyperactive in various assays, only females showed impaired motor coordination in the rotarod assay. α 2 δ-4 KO mice exhibited anxiolytic and anti-depressive behaviors in the elevated plus maze and tail suspension tests, respectively. Our results reveal an unexpected role for α 2 δ-4 in sensorimotor gating and motor function and identify α 2 δ-4 KO mice as a novel model for studying the pathophysiology associated with CACNA2D4 variants.

Voltage-gated Ca.sup.2+ channels are critical for the development and mature function of the nervous system. Variants in the CACNA2D4 gene encoding the [alpha].sub.2 [delta]-4 auxiliary subunit of these channels are associated with neuropsychiatric and neurodevelopmental disorders. [alpha].sub.2 [delta]-4 is prominently expressed in the retina and is crucial for vision, but extra-retinal functions of [alpha].sub.2 [delta]-4 have not been investigated. Here, we sought to fill this gap by analyzing the behavioral phenotypes of [alpha].sub.2 [delta]-4 knockout (KO) mice. [alpha].sub.2 [delta]-4 KO mice (both males and females) exhibited significant impairments in prepulse inhibition that were unlikely to result from the modestly elevated auditory brainstem response thresholds. Whereas [alpha].sub.2 [delta]-4 KO mice of both sexes were hyperactive in various assays, only females showed impaired motor coordination in the rotarod assay. [alpha].sub.2 [delta]-4 KO mice exhibited anxiolytic and anti-depressive behaviors in the elevated plus maze and tail suspension tests, respectively. Our results reveal an unexpected role for [alpha].sub.2 [delta]-4 in sensorimotor gating and motor function and identify [alpha].sub.2 [delta]-4 KO mice as a novel model for studying the pathophysiology associated with CACNA2D4 variants.

Voltage-gated Cav Ca2+ channels are critical for the development and mature function of the nervous system. Variants in the CACNA2D4 gene encoding the α2δ-4 auxiliary subunit of these channels are associated with neuropsychiatric and neurodevelopmental disorders. α2δ-4 is prominently expressed in the retina and is crucial for vision, but extra-retinal functions of α2δ-4 have not been investigated. Here, we sought to fill this gap by analyzing the behavioral phenotypes of α2δ-4 knockout (KO) mice. α2δ-4 KO mice (both males and females) exhibited significant impairments in prepulse inhibition that were unlikely to result from the modestly elevated auditory brainstem response thresholds. Whereas α2δ-4 KO mice of both sexes were hyperactive in various assays, only females showed impaired motor learning/coordination in the rotarod assay. Female but not male α2δ-4 KO mice exhibited anxiolytic and anti-depressive behaviors in the elevated plus maze and tail suspension tests, respectively. Our results reveal an unexpected role for α2δ-4 in cognitive and motor function and identify α2δ-4 KO mice as a novel model for studying the pathophysiology associated with CACNA2D4 variants.

The 16p11.2 microduplication (16p11.2dp/+) is associated with several neuropsychiatric disorders including schizophrenia, autism spectrum disorder, bipolar disorder, intellectual disability, and attention deficit/hyperactivity disorder (ADHD). Cerebellar abnormalities have been increasingly implicated in these neuropsychiatric disorders, including those conferred by 16p11.2 microduplication. In 16p11.2dp/+ mouse models, the cerebellum is a site of transcriptional dysregulation, and cerebellar microcephaly has been reported in humans with 16p11.2 microduplication. Despite mounting evidence indicating a role for the cerebellum in neuropsychiatric disorders associated with this CNV, cerebellar cellular structure and cerebellar-dependent behavior in mice with 16p11.2 microduplication remain uncharacterized. To address this, we histologically labeled Purkinje cells (PCs) and molecular layer interneurons (MLIs) in a mouse model of 16p11.2 microduplication. We did not find any structural differences in cerebellar lobule IV/V, nor did we observe impairments in gait or motor coordination, behaviors that are associated with lobule IV/V. In contrast, we discovered a significant increase in calbindin/parvalbumin-positive PCs mislocalized to the granule layer of cerebellar lobule VI in 16p11.2dp/+ mice compared to wild-type (WT) littermates. Additionally, we found a significant decrease in parvalbumin-positive MLIs without a decrease in total DAPI-positive cell counts in lobule VI of 16p11.2dp/+ mice compared to WT littermates. Cerebellar lobule VI is associated with delay eyeblink conditioning, and 16p11.2dp/+ mice are impaired in cerebellum-dependent associative learning on this task. Specifically, 16p11.2dp/+ mice showed deficits in both conditioned response (CR) percentage and CR onset latency relative to WT mice. These results suggest that lobule VI-specific alterations to PC localization and MLI parvalbumin expression in 16p11.2dp/+ mice impair both cerebellar learning and adaptive timing of cerebellar-driven, conditioned responses. Thus, we have identified novel structural and functional alterations in the cerebellum that are associated with 16p11.2 microduplication. Importantly, individuals with schizophrenia and ADHD also show CR acquisition deficits in delay eyeblink conditioning. Together, these data suggest that the behavioral impairments in 16p11.2dp/+ mice resemble impairments seen in neuropsychiatric disorders linked to 16p11.2 microduplication in humans. Further investigation of cerebellar cortex neurons in 16p11.2dp/+ mice may provide insights into the pathogenesis of neuropsychiatric disorders linked to this copy number variant.Competing Interest StatementThe authors have declared no competing interest.