アストロサイトP2Y1受容体を介したニューロン興奮性制御

抄録

Abnormalities of astrocytic roles are implicated in neuronal hyperexcitablity of neurological diseases. In many pathological conditions, astrocytes enhance Ca²⁺ signals by increasing Gq-protein coupled receptors (GqPCR) including P2Y1 receptor. To understand the role of the GqPCR augmentation, we have investigated astrocyte specific overexpression mice model of P2Y1 receptor (P2Y1OE). Performing simultaneous imaging of neurons and astrocytes in the hippocampal CA1 region, we found that electrical stimulation of the Schaffer collateral resulted in fast Ca²⁺ rise in dendrites of neurons followed by slow-onset Ca²⁺ rise in astrocytes. Fast Ca²⁺ rise in dendrites was augmented in P2Y1OE and mediated by ionotropic glutamate receptors. Also, fast dendritic Ca ²⁺ was reduced by inhibition of slow-onset Ca²⁺ rise in astrocytes. Pharmacological data suggest augmented dendritic Ca²⁺ is due to glutamate release. Extracellular glutamate imaging data suggest that the glutamate release is derived from neurons but not astrocytes. Transcriptome analysis of isolated astrocytes from P2Y1OE revealed a novel candidate molecule X as an astrocyte-derived excitatory signal, which could underlie astrocyte P2Y1-mediated neuronal excitation through enhancement of excitatory synaptic transmission.