Regulation of neuronal differentiation by activity-induced calcium influx in striatal neural precursors
Neuronal activity induces Ca2+ influx that regulates neurogenesis and distinct aspects of neuronal differentiation in the embryonic and adult brain. This thesis focusses on the regulation of neuronal differentiation in striatal neural precursors (NPCs) by activity induced Ca2+ influx. Neurons arising from differentiating striatal NPCs show spontaneous Ca2+ transients, which are L type VGCC dependent. Neural activity increases the frequency of L type VGCC dependent Ca2+ transients. It also accelerates neuronal differentiation of striatal NPC derived neurons by promoting GABA expression and neurite outgrowth that are essential steps in establishing neuronal identity and enabling neurons to form functional connections. Although excitatory activity activates CREB, its effects on neuronal differentiation are transcription and translation independent. Furthermore, regulation of GABA expression and neurite outgrowth by neural activity involve distinct signaling pathways. Neurite outgrowth is regulated by NMDAR mediated localized Ca2+ influx that activates MAPK/CaMK and release of sAPP. On the other hand, GABA expression is regulated by PKA and PKC that are activated by VGCC induced global rise in Ca2+. Interestingly, a brief Ca2+ influx through VGCCs, induced by a short depolarizing stimuli, is sufficient to trigger an increase in GABA expression, whereas changes in neurite outgrowth require longer exposure to depolarization. Furthermore, neural activity accelerates GABA expression in neurons restricted to GABAergic fate, suggesting that these neurons express GABA synthesizing enzyme, GAD. Thus, it is conceivable that regulation of GABA expression by VGCC induced Ca2+ influx is achieved via phosphorylation/dephosphorylation of GAD by PKA and PKC. Thus, neural activity modulates NPC differentiation by inducing rapid responses that are transcription independent and that may be important in timely functional integration of newly generated neurons in the mammalian brain.
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