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bioRxiv · 10.64898/2025.12.11.693636

The expression level of CACNA1C-encoded CaV1.2 is a tipping point between promotion and inhibition of dendritic growth in neurons

Lanzetti, S.·Mesirca, P.·Diestra, N. P.·Torre, E.·Mari, M.·Haddad, S.·Obermair, G. J.·Campiglio, M.·Folci, A.·Mangoni, M. E.·Di Biase, V.
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Abstract

The CACNA1C gene encodes the CaV1.2 L-type voltage-gated calcium channel, which plays a crucial role in neuronal signaling. CACNA1C is a risk gene for psychiatric conditions involving disruption of neuronal connectivity such as schizophrenia, autism, and bipolar disorders. While genomic studies are consistently reinforcing the notion of CACNA1C as an important locus related to these diseases, the role of CaV1.2 channels in determining neuronal architecture is incompletely understood. Several studies pinpoint the L-type current (ICaL) as regulator of dendritic arborization development. ICaL lays upstream of competing cellular mechanisms leading to both inhibition and promotion of dendritic growth. How signal selectivity is achieved remains an open question. Here, we report that ICaL-dependent dendritic development of murine cultured hippocampal neurons relies on CaV1.2 and is determined by an equilibrium between the level of CaV1.2 protein expression and ICaL activity. Indeed, increasing ICaL enhances dendritic complexity only when CaV1.2 expression level is reduced. In contrast, when channel levels are at baseline, the CaV1.2-dependent growing signal is overcome by the elevation of the dendritic growth inhibiting CaMKII signaling beyond basal conditions. These findings suggest that CaV1.2 expression level acts as a molecular switch between dendritic growing and inhibiting signals. Consequently, altered CaV1.2 expression during early development may alter neuronal structure, potentially impairing neural network formation and increasing susceptibility to psychiatric disorders. SIGNIFICANCE STATEMENTL-type voltage-gated calcium channels (L-VGCCs) allow calcium influx upon membrane depolarization. In neurons, L-VGCCs play a crucial role in regulating gene transcription, synaptic plasticity, and membrane excitability. Our data demonstrate that the L-VGCCs CaV1.2 isoform is a key regulator of early dendritic development. Calcium influx via CaV1.2 is necessary for proper dendritic growth under basal conditions. However, enhanced calcium currents boost dendritic growth only when channel expression levels are reduced. When the amount of CaV1.2 is at baseline, current stimulation antagonizes the growing process by upregulating the CaMKII signaling. Our findings suggest that the number of CaV1.2 available determines whether channel activity leads to aberrant dendritic arborization by sizing the recruitment of growth inhibiting CaMKII cascade.

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Lanzetti, S., Mesirca, P., Diestra, N. P., Torre, E., Mari, M., Haddad, S., Obermair, G. J., Campiglio, M., Folci, A., Mangoni, M. E., Di Biase, V.. 2025-12-13. The expression level of CACNA1C-encoded CaV1.2 is a tipping point between promotion and inhibition of dendritic growth in neurons. https://doi.org/10.64898/2025.12.11.693636

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