Study of NMDA receptor dysfunction in interneurons that express parvalbumin and its role in cognitive and behavioral changes in an epilepsy model

• Grant number: 22/07933-1
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: December 01, 2022
• End date: October 23, 2026
• Field of knowledge: Biological Sciences - Physiology - General Physiology
• Principal Investigator: João Pereira Leite
• Grantee: Ana Carolina Medeiros
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated scholarship(s): 23/14555-6 - Advanced electrophysiological techniques to study hippocampal function in health and disease., BE.EP.DR

Abstract

Cognitive impairments and psychiatric disorders are highly prevalent in patients with temporal lobe epilepsy (TLE), which is characterized precisely by several changes in electroencephalographic activity. In fact, brain oscillatory activity has been correlated with several cognitive functions. Specifically, oscillations in the gamma frequency (30-70 Hz) are observed during the performance of various cognitive tasks. These oscillations are generated by inhibitory neurons, especially interneurons (IN) that express parvalbumin (PV). Specifically, changes in NMDA receptors in these NI can induce cognitive decline and a psychosis-like phenotype in humans. In this sense, our hypothesis is that NMDA receptor dysfunction in IN PV increases susceptibility to status epilepticus (SE) during development and propensity to develop spontaneous seizures, in addition to favoring the emergence of behavioral changes and cognitive impairment associated with morphological changes. and functional. PV-Cre/NR1f/f mice will be used and SE induction will be through pilocarpine injection 17 days after birth. In the chronic phase, the animals will be monitored by video-EEG for the detection of recurrent seizures. For behavioral evaluation, tests with predictive validity will be performed for antidepressants (suspension test by the tail and preference for sucrose), for anxiolytics (elevated plus maze) and tests for memory assessment (object recognition test and T-maze test). ), in addition to tests used to evaluate antipsychotic drugs (open field and PPI). Neuronal (NeuN), microglial (lba1) and astrocytic (GFAP) density analyzes will be performed, as well as cell injury (Fluoro-Jade C) and mossy fiber sprouting (neo-Timm); and quantification by high performance liquid chromatography of monoaminergic transmitters and glutamate. In another experiment, the change in oscillatory activity will be evaluated after optogenetic stimulation of IN that express PV of PV-Cre/NR1f/f epileptic animals in a comparison with control animals. In this way, we hope to understand the role of IN PV NMDA receptors in epilepsy and how they contribute to psychiatric comorbidities and cognitive impairment.