Analysis of ischemic neuronal injury in Ca_V2.1 channel α₁ subunit mutant mice

We studied the physiological role of Ca_V2.1α₁ in ischemic neuronal injury using mutants. Rolling Nagoya and leaner mouse brains showed similar Ca_V2.1α₁ expression patterns. MCAO model showed more severe ischemic area in rolling Nagoya than in leaner mice. Higher [Ca²⁺]i was induced in rolling Nagoya than in leaner mice. When examining ischemic mechanisms, comparison of allelic variants was useful. One of the main instigators leading to cell death and brain damage following ischemia is Ca²⁺ dysregulation. Neuronal membrane depolarization results in the activation of voltage-gated Ca²⁺ (Ca_V) channels and intracellular Ca²⁺ influx. We investigated the physiological role of the Ca_V2.1 (P/Q-type) channel in ischemic neuronal injury using Ca_V2.1 channel α₁ subunit mutant mice, rolling Nagoya and leaner mice. The in vivo ischemia model with a complete occlusion of the middle cerebral artery showed that the infarct area at 24h was significantly smaller in rolling Nagoya (27.1±3.5% of total brain volume) and leaner (20.1±3.5%) mice compared to wild-type (42.9±4.5%) mice. In an in vitro Ca²⁺ imaging study, oxygen-glucose deprivation using a hippocampal slice induced a significantly slower rate of increase in intracellular Ca²⁺ concentration ([Ca²⁺]i) in rolling Nagoya (0.083±0.007/min) and leaner (0.062±0.006/min) mice compared to wild-type (0.105±0.008/min) mice. These results demonstrate that the mutant Ca_V2.1 channel in rolling Nagoya and leaner mice plays a different protective role in a ([Ca²⁺]i)-dependent manner in ischemic models and indicate that Ca_V2.1 channel blockers may be used preventively against ischemic injury.