Cycle 4 project 7

Role of P2Y1R in mossy fiber sprouting – new strategies to arrest epileptogenesis

 

Xin-Li-XuPhD student: Xin-Li Xu, China
Home Institute: Center for Neurosciences and Cell Biology Coimbra; Principle Investigator: Rodrigues, Ricardo
Host Institute: Bordeaux Neurocampus; Principle Investigator: Rebola, Nelson

 Executive Summary

Several brain disorders involve developmental defects and hence can be explored from the perspective of recapitulating developmental features. Using this rationale, we recently found that glutamate, a major player during seizures, promotes axonal outgrowth and formation of aberrant axons through PKC-GSK3β-CRMP2 pathway in developing hippocampal neurons. We also found in a model of temporal lobe epilepsy (TLE) that this pathway is reactivated, supporting the characteristical hippocampal mossy fiber (MF) axonal sprouting, a cardinal feature of epileptogenesis. We now pursue signalling systems operational during epileptogenesis and capable of modulating axonal outgrowth through CRMP2 modulation, with the ultimate goal to arrest MF sprouting. Preliminary evidence indicates that P2Y1 receptor (P2Y1R) fulfil these criteria. P2Y1Rs are operational during epileptogenesis since: 1) ATP is released particularly at high-frequency stimulations; 2) pharmacological or genetic blockade of P2Y1Rs reduces the severity of SE-induced seizures, 3) attenuates neuronal death and neuroinflammation caused by SE-induction and 4) P2Y1R density increases in the hippocampus upon SE-induction (unpublished data). MF axons contact both pyramidal cells and interneurons in the CA3 area of the hippocampus. P2Y1Rs are present in both neurons and interneurons in the hippocampus and application of P2Y1R agonists has been reported to modulate several important neuronal functions like synaptic plasticity and glutamate release (Rodrigues et al, 2005). Albeit MF synapses release ATP upon high-frequency stimulation (Rebola et al., 2008) no P2R function was found so far, although P2Y1R were reported to be present at these synapses(J.Neurochem., 2008, 106(1):347-60). Finally, it was recently shown that P2Y1Rs bolster axonal growth in developing hippocampal neurons and our preliminary data show that P2Y1R activation modifies the phosphorylation pattern of GSK3β and CRMP2. Thus, this project poses a straightforward working hypothesis that P2Y1R activation contributes to the abnormal MF sprouting in epilepsy through the desinhibition of CRMP2. To explore this promising and relevant hypothesis, three inter-twinned questions will be addressed: 1-Does CRMP2 tether P2Y1Rs activity in axonal outgrowth and axon specification? 2-What is the physiological role of P2Y1R-CRMP2 signalling module in MF synaptic physiology and how is it modified upon SE-induction?; 3- What is the role of P2Y1R-CRMP2 in MF sprouting and subsequent generation of spontaneous recurrent seizures? This multi-disciplinary project, requiring merging Rodrigues’s expertise in the study of the patho-physiological role of P2Rs and neuronal development and Rebola’s expertise in the synaptic physiology of hippocampal MF, poses a working hypothesis supported by a clear straightforward mechanism, which will hopefully allow the design of new therapeutical interventions to prevent epileptogenesis, an unmet medical need. Finally, the wide range of state-of-the-art approaches spanning different levels of analysis (from molecules to physiology and behaviour) and different models with increasing complexity (from cells to in vivo experiments) will provide the candidate with a truly multi-disciplinary training.

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