CACNB4 overexpression decreases dendritic spine density in sex-specific manner

Parker, E. M.; Kindja, N. L.; DeGiosio, R. A.; Salisbury, R. B.; Krivinko, J. M.; Cheetham, C. E. J.; MacDonald, M. L.; Sweet, R.

doi:10.1101/2022.02.02.478824

bioRxiv · 10.1101/2022.02.02.478824

CACNB4 overexpression decreases dendritic spine density in sex-specific manner

Parker, E. M.·Kindja, N. L.·DeGiosio, R. A.·Salisbury, R. B.·Krivinko, J. M.·Cheetham, C. E. J.·MacDonald, M. L.·Sweet, R.

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Abstract

The canonical voltage-gated calcium channel (VGCC) subunit complex is comprised of the 1 subunit, the ion permeable channel, plus three auxiliary subunits: {beta}, 2{delta} and {gamma}. {beta} is the most extensively studied auxiliary subunit and is necessary for proper forward trafficking of the 1 subunit to the plasma membrane. 1 subunits mediate voltagedependent movement of calcium ions into the cytoplasm of neurons, including at dendritic sites, where increased intracellular calcium initiates signaling cascades that shape structural and functional plasticity of dendritic spines. Genetic studies strongly implicate calcium signaling dysfunction in the etiology of neurodevelopmental disorders including schizophrenia. Dendritic spine density (DSD) is significantly decreased in schizophrenia in primary auditory cortex where DSD is driven by loss of small spines, and small spine loss is associated with increased peptide levels of ALFDFLK found in the VGCC {beta} subunit {beta}4. Overexpessing CACNB4 to increase {beta}4 levels selectively reduced small spine density in cortical neuron cultures. The studies described herein set out to validate this in vitro observation in an intact mammalian system within a neurodevelopmental context. We overexpressed CACNB4 in neurodevelopment and assessed DSD and morphology in cerebral cortex of male and female mice at an adult timpoint. We then characterized {beta} protein levels and {beta}4 protein-protein interactions in male and female mouse cortex. Overexpression selectively reduced small dendritic spine density but this effect was present only in female mice and did not appear to result from estrous stage. Instead, the sex-dependent effect on DSD corresponded to sex differences in the {beta}4 interactome of male versus female mice: the VGCC {beta} subunit {beta}1b was significantly enriched in the {beta}4 interactome of brain tissue of male mice, and thus may have served to mitigate VGCC overexpression-mediated spine loss in male mice.

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Parker, E. M., Kindja, N. L., DeGiosio, R. A., Salisbury, R. B., Krivinko, J. M., Cheetham, C. E. J., MacDonald, M. L., Sweet, R.. 2022-02-03. CACNB4 overexpression decreases dendritic spine density in sex-specific manner. https://doi.org/10.1101/2022.02.02.478824

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