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Interactions between epilepsy and homeostatic plasticity: how seizures recurrence modulates homeostatic plasticity and how parvalbuminergic hypofunction facilitates seizures induction.

Grant number: 18/18014-1
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): January 01, 2019
Effective date (End): December 31, 2021
Field of knowledge:Biological Sciences - Physiology
Principal Investigator:João Pereira Leite
Grantee:Ana Paula Crestani
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated research grant:16/17882-4 - Drug-resistant epilepsies: diagnostic challenges, associated comorbidities and new experimental approaches, AP.TEM

Abstract

The homeostatic synaptic plasticity keeps the patterns of neuronal activity within a physiological range, acting through negative feedback in situations of neuronal hypoactivity or hyperactivity. This kind of plasticity controls the postsynaptic response through of receptors expression and dendritic spines density (synaptic scaling), besides modulates the inhibitory control mediated by interneurons. Considering that during an epileptic seizure occurs an increase in the neuronal activity, we intend to evaluate how the recurrent afterdischarges similar to an epileptic seizure interfere with the homeostatic plasticity and whether the homeostatic imbalance caused by the inhibitory hypofunction facilitates the epileptogenesis. These alterations in the homeostatic plasticity induced by the afterdischarges will be verified using parameters that feature the synaptic scaling. The alteration will be classified as (i) long-lasting or (ii) transitory modifications. In the first experiment of phase 1, it will be performed the electrophysiological characterization of the postsynaptic response (unitary and field recordings) after the induction of the recurrent afterdischarges. Additionally, it will be evaluated the long-lasting alterations caused by the afterdischarges in the Hebbian plasticity induction (LTP and LTD), in the cognitive performance, in the density and morphology of the dendritic spines, as well as in the AMPA receptors expression in the postsynaptic density. In the second experiment, it will be examined the transitory modifications in the homeostatic plasticity through quantification of dendritic spines and AMPA receptors expression in the same period where it was electrophysiologicaly observed the synaptic scaling in the experiment 1. In phase 2, it will be investigated the readiness for afterdischarge induction, the behavioral performance and the characterization of the synaptic scaling (electrophysiological, morphological and molecular) in animals that have hypofunction in the parvalbuminergic interneurons (PV-Cre/NR1f/f). In this way, we believe that this project will clarify how seizures modify the homeostatic plasticity and how the imbalance in one of the mechanisms that control the homeostatic plasticity (parvalbuminergic interneurons) influences in the seizures induction.