The T-type Ca Channel Ca3.2 Regulates Differentiation of Neural Progenitor Cells during Cortical Development via Caspase-3.

Here we report that the low-voltage-dependent T-type calcium (Ca) channel Ca3.2, encoded by the CACNA1H gene, regulates neuronal differentiation during early embryonic brain development through activating caspase-3. At the onset of neuronal differentiation, neural progenitor cells exhibited spontaneous Ca activity. This activity strongly correlated with the upregulation of CACNA1H mRNA. Cells exhibiting robust spontaneous Ca signaling had increased caspase-3 activity unrelated to apoptosis. Inhibition of Ca3.2 by drugs or viral CACNA1H knock down resulted in decreased caspase-3 activity followed by suppressed neurogenesis. In contrast, when CACNA1H was overexpressed, increased neurogenesis was detected. Cortical slices from Cacna1h knockout mice showed decreased spontaneous Ca activity, a significantly lower protein level of cleaved caspase-3, and microanatomical abnormalities in the subventricular/ventricular and cortical plate zones when compared to their respective embryonic controls. In summary, we demonstrate a novel relationship between Ca3.2 and caspase-3 signaling that affects neurogenesis in the developing brain.