Hyper-excitability is a permissive factor for the genesis of seizures. Aberrant GABAergic neurotransmission may be the cause of inhibition deficits in epilepsy. 30% of epileptic patients became resistant to the treatment. Pharmacoresistance is associated to alterations of GABAA receptor (GABAAR)-mediated neurotransmission. Unpublished results from our laboratory indicate that SE alters GABAARs dynamics with a consequent synaptic downregulation; the underlying molecular mechanisms will be investigated in the project. The downregulation of GABA inhibitory activity may arise from a positive shift in GABAAR reversal potential, due to an alteration in chloride homeostasis. However, the contribution of Cl– gradient alteration in this phenomenon is not yet established. Here will be investigate the role of Cl– homeostasis in the inhibitory synapse alteration during epilepsy, proposing the K+-Cl-cotransporter (KCC2) as therapeutic target for epilepsy.
The aim of this project is to characterize the structural alterations in GABAergic synapses and investigate the molecular mechanisms underlying the alterations in GABAAR distribution at the synapse in epileptogenesis. We will also investigate the role of chloride homeostasis mechanisms in the alteration of inhibitory synapse induced by SE, focusing on the KCC2 K+-Cl- cotransporter as potential target for SE treatment.
PTDC/MED-FAR/30659/2017 / CENTRO-01-0145-FEDER-030659