Alterations in the synaptic proteome and in uronal excitability in the pilocarpine model of temporal lobe epilepsy

Overview

Project Summary

Temporal lobe epilepsy (TLE) is the most prevalent type of epilepsy in humans, and despite treatment with anticonvulsant medication, many patients continue to have uncontrolled seizures throughout their lives. Numerous cellular and molecular abnormalities have been described during the intervening latent period that may contribute to epileptogenesis, such as changes in gene expression, alterations in neurotransmitter receptors and ion channels, axonal sprouting and synaptic reorganization. The medications currently used in epilepsy can suppress seizures symptomatically, but there is minimal evidence that existing antiepileptic drugs correct the underlying brain abnormalities causing epilepsy or alter the natural history of epilepsy. Thus, novel therapeutic strategies are required, with true antiepileptogenic actions to prevent or reverse the cellular and molecular mechanisms of epileptogenesis. To develop such treatments, it is required a better understanding of the primary signaling pathways that initially trigger the numerous downstream mechanisms mediating epileptogenesis. In contrast with the large number of studies addressing the changes in synaptic organization in the epileptic brain, in particular in the hippocampus, the changes in the synaptic proteome, which should influence the structure and function of the synapse, have been poorly investigated. Recent studies showing that the protein synthesis regulator mTOR plays a role in epileptogenesis confirm the importance of translation in the increase in neuronal excitability. Furthermore, the available evidence points to a role for BDNF-TrkB signaling and protein synthesis in the epileptogenic process. The effects of BDNF on local translation at the synapse depend on the availability of transcripts that are transported along dendrites in RNA granules. Unpublished results from our laboratory indicate that the RNA-binding protein hnRNPK is a pivotal player in controlling BDNF-induced protein synthesis in the dendritic compartments in hippocampal neurons, including receptors and signaling molecules. Therefore, the function/dysfunction of hnRNPK likely impacts on synaptic structure and function under conditions of hyperexcitability. In this proposal we will investigate the BDNF-TrkB signaling mechanisms coupled to potentiation of excitatory synapses in epileptogenesis, focusing on hnRNPK as a master regulator of the synaptic proteome. The pilocarpine model of TLE will be used to investigate i) the changes in the control of translation by BDNF at hippocampal synapses, ii) how alterations in BDNF signaling regulate synaptic expression of NMDA receptors to enhance neuronal excitability and iii) the role of hnRNP K as a mediator of the effects of BDNF in epileptogenesis. The project will contribute to the understanding of the mechanisms leading to the hyperexcitability that follows the induction of status epilepticus, and may contribute to the development of more effective antiepileptic strategies.

Main Goals

In this proposal we will investigate the BDNF-TrkB signaling mechanisms coupled to potentiation of excitatory synapses in epileptogenesis, focusing on hnRNPK as a master regulator of the synaptic proteome. The pilocarpine model of TLE will be used to investigate i) the changes in the control of translation by BDNF at hippocampal synapses, ii) how alterations in BDNF signaling regulate synaptic expression of NMDA receptors to enhance neuronal excitability and iii) the role of hnRNP K as a mediator of the effects of BDNF in epileptogenesis. The project will contribute to the understanding of the mechanisms leading to the hyperexcitability that follows the induction of status epilepticus, and may contribute to the development of more effective antiepileptic strategies.

Project Details