The Impact of Glutamatergic Excitotoxicity on the Differentiation of Cerebellar Neural Stem Cells

The adult cerebellum retains a small Sox2/prominin-1 NSC pool whose fate is shaped by developmental cues and the glutamatergic milieu. We argue that glutamate excitotoxicity is the dominant negative regulator of this niche and Purkinje cell survival because it forms self-reinforcing loops. Spillover activates extrasynaptic GluN2B/2D-NMDARs, silencing CREB/PI3K–Akt and driving sustained \(Ca^{2+}\) influx; mitochondria translate this load into mPTP opening and ROS bursts, creating a \(Ca^{2+}\)–ROS feedback that accelerates death. Oxidative stress and energy failure also depress EAAT1/2 clearance, elevating glutamate and re-activating eNMDARs. Loss of Purkinje cells withdraws Sonic Hedgehog support, shrinking the proliferative granule-precursor pool—another vicious cycle. A countervailing axis (synaptic GluN2A/2C and BDNF/TrkB) is muted by extrasynaptic drive. Cerebellar neurospheres model these gradients and readouts. We outline a triple strategy to break the loops: selective eNMDAR blockade, EAAT enhancement, and Sonic Hedgehog restoration.