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

Abstract

Neuronal L-type (Cav1.2 and Cav1.3) voltage-gated Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ current and a leftward shift in voltage dependence at postnatal Week 1, resulting in a significant increase in the Ca²⁺ window current. In contrast to the MSNs of the striatum, neither the somatic I_Ca density nor the expression level of L-type Ca²⁺ 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 Ca²⁺ influx to ensure appropriate downstream signaling for synapse formation and synaptic plasticity.