Context-specific switch from anti- to pro-epileptogenic function of the P2Y1 receptor in experimental epilepsy

Extracellular ATP activates inflammatory responses to tissue injury. It is also implicated in establishing lasting network hyperexcitability in the brain by acting upon independent receptor systems. Whereas the fast-acting P2X channels have well-established roles driving neuroinflammation and increasing hyperexcitability, the slower-acting metabotropic P2Y receptors have received much less attention. Recent studies of P2Y 1 receptor function in seizures and epilepsy have produced contradictory results, suggesting the role of this receptor during seizure pathology may be highly sensitive to context. Here, by using male mice, we demonstrate that the metabotropic P2Y 1 receptor mediates either pro- or anti-convulsive responses, dependent on the time-point of activation in relation to the induction of status epilepticus. P2Y 1 -deficiency or a P2Y 1 antagonist (MRS2500) administered prior to a chemoconvulsant, exacerbates epileptiform activity, while a P2Y 1 agonist (MRS2365) administered at this time point is anticonvulsant. When these drugs are administered after the onset of status epilepticus, however, their effect on seizure severity is reversed, with the antagonist now anticonvulsant and the agonist proconvulsant. This result was consistent across two different mouse models of status epilepticus (intraamygdala kainic acid and intraperitoneal pilocarpine). Pharmacologic P2Y 1 blockade during status epilepticus reduces also associated brain damage, delays the development of epilepsy and, when applied during epilepsy, suppresses spontaneous seizures, in mice. Our data shows a context-specific role for P2Y 1 during seizure pathology and demonstrates that blocking P2Y 1 post-status epilepticus and during epilepsy has potent anti-convulsive effects, suggesting P2Y 1 may be a novel candidate for the treatment of drug-refractory status epilepticus and epilepsy. SIGNIFICANCE STATEMENT This is the first study to fully characterise the contribution of a metabotropic purinergic P2Y receptor during acute seizures and epilepsy. The findings suggest that targeting P2Y 1 may offer a potential novel treatment strategy for drug-refractory status epilepticus and epilepsy. Our data demonstrates a context-specific role of P2Y 1 activation during seizures, switching from a pro-convulsive to an anti-convulsive role depending on physio-pathological context. Thus, our study provides a possible explanation for seemingly conflicting results obtained between studies of different brain diseases where P2Y 1 -targeting has been proposed as a potential treatment strategy and highlights that the timing of pharmacological interventions is of critical importance to the understanding of how receptors contribute to the generation of seizures and the development of epilepsy.