Involvement of glial P2Y1 receptors in cognitive deficit after focal cerebral stroke in a rodent model

Background: Neuroinflammation is associated with many conditions that lead to dementia, such as cerebrovascular disorders or Alzheimer's disease. However, the specific role of neuroinflammation in the progression of cognitive deficits remains unclear. To understand the molecular mechanisms underlying these events we used a rodent model of focal cerebral stroke, which causes deficits in hippocampus-dependent cognitive function. Methods: Cerebral stroke was induced by middle cerebral artery occlusion (MCAO). Hippocampus-dependent cognitive function was evaluated by a contextual fear conditioning test. The glial neuroinflammatory responses were investigated by immunohistochemical evaluation and diffusion tensor MRI (DTI). We used knockout mice for P2Y(1) (P2Y(1)KO), a glial ADP/ATP receptor that induces the release of proinflammatory cytokines, to examine the links among P2Y(1)-mediated signaling, the neuroinflammatory response, and cognitive function. Results: Declines in cognitive function and glial neuroinflammatory response were observed after MCAO in both rats and mice. Changes in the hippocampal tissue were detected by DTI as the mean diffusivity (MD) value, which corresponded with the cognitive decline at 4 days, 1 week, 3 weeks, and 2 months after MCAO. Interestingly, the P2Y(1)KO mice with MCAO showed a decline in sensory-motor function, but not in cognition. Furthermore, the P2Y(1)KO mice showed neither a hippocampal glial neuroinflammatory response (as assessed by immunohistochemistry) nor a change in hippocampal MD value after MCAO. In addition, wild-type mice treated with a P2Y(1)-specific antagonist immediately after reperfusion did not show cognitive decline. Conclusion: Our findings indicate that glial P2Y(1) receptors are involved in the hippocampal inflammatory response. The findings from this study may contribute to the development of a therapeutic strategy for brain infarction, targeting the P2Y(1) receptor.