Shank3 Regulates L‐Type Voltage‐Gated Ca²⁺ Channels in the Mouse Striatum and Hippocampus at the Early Developmental Stage

Neuronal L‐type (Cav1.2 and Cav1.3) voltage‐gated Ca 2+ channels (VGCCs) are important for neuronal excitability and synaptic plasticity. However, little is known about their regulation during development. SHANK3 is a postsynaptic scaffolding protein that orchestrates postsynaptic signaling and modulates synaptic plasticity. Here, we explored the role of Shank3 in regulating striatal and hippocampal L‐type VGCCs at postnatal 1 week and 12–14 weeks in Shank3b knockout (KO) mice. We found that genetic ablation of Shank3 led to an increase in the somatic Ca 2+ current ( I Ca ) in medium spiny neurons (MSNs) in the striatum at postnatal Week 1, but this effect was reversed at postnatal Weeks 12–14. In addition, the loss of Shank3 led to increased steady‐state inactivation (SSI) of the Ca 2+ current and a leftward shift in voltage dependence at postnatal Week 1, resulting in a significant increase in the Ca 2+ window current. In contrast to the MSNs of the striatum, neither the somatic I Ca density nor the expression level of L‐type Ca 2+ channels in the granule cells of the hippocampal dentate gyrus was altered in Shank3b KO mice. Western blot and immunostaining analyses revealed that the increased I Ca observed at postnatal Week 1 in the striatum of Shank3b KO mice might result from increased Cav1.2 expression. Overall, our data suggest a role for SHANK3 in regulating L‐type VGCCs in the striatum during early development, which may be important for maintaining adequate Ca 2+ influx to ensure appropriate downstream signaling for synapse formation and synaptic plasticity.