Voltage-Gated and Chemogenetic Modulation of Calcium Signaling in Oligodendrocyte Development and Synaptic Integration

Oligodendrocyte progenitor cells (OPCs) are essential for central nervous system (CNS) development and repair, differentiating into mature oligodendrocytes that form myelin sheaths. We established that calcium (Ca²⁺) signaling via voltage-gated Ca²⁺ channels (VGCCs), particularly Cav1.2, regulates OPC proliferation, migration, differentiation, and synaptic integration. We found that conditional deletion of Cav1.2 impaired both myelination and remyelination, while gain-of-function mutations enhanced myelin formation. Previous studies implicated Cav1.2 channels in regulating dendritic spine morphology and postsynaptic stability in neurons through interactions with synaptic proteins. We observed that OPCs formed synaptic-like structures with neurons, integrating glutamatergic and GABAergic inputs via Cav1.2 and associated protein complexes, suggesting that OPCs actively participate in synaptic communication and contribute to neural circuit plasticity. Transcriptomic and imaging analyses confirmed the presence of synaptic proteins such as PSD95 and Homer1 in OPCs, supporting the existence of neuron-OPC synapses. To investigate OPC excitability, we employed chemogenetic tools, including Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). Using transgenic mouse models expressing hM3Dq and hM4Di receptors in the oligodendrocyte lineage, we reversibly modulated OPC activity. Activation of hM3Dq increased Ca²⁺ influx and excitability, while hM4Di suppressed electrical activity, enabling detailed studies of OPC behavior during development and disease. In summary, our findings highlighted the essential role of Ca²⁺ signaling in oligodendrocyte biology and its therapeutic potential for demyelinating diseases. Targeting VGCCs and chemogenetic pathways may accelerate myelin repair and improve functional recovery in CNS disorders. (Figure presented.).