Do early life seizures disrupt the maturation and integration of cortical GABAergic interneurons?

Abstract

A single episode of neonatal seizure in rodents is a very promising model for the study of mechanisms underlying social impairment in Autism Spectrum Disorder (ASD), with animals exhibiting autistic-like behavior with no changes in cognition function. The social decision-making (SDM) network is formed by integration of two circuitries, social behavior network and mesolimbic reward system, not limited to the midbrain dopaminergic system. The social decision-making requires the integration of emotional, cognitive and motivational processes in a highly dynamic fashion, being strongly dependent on the activity pattern of the network. Among the factors that interfere in this process, excitation and inhibition (E/I) imbalance in neural circuits has been pointed as key element on behavioral impairment frequently observed in developmental disorders, such as ASD. E/I imbalance can be due to increases in glutamatergic or decreases in GABAergic signaling, which alters the manner of the brain processes information and regulates behavior. Evidences from animal research have been shown that GABAergic system disruption, as reduction in g-Aminobutyric acid (GABA) synthesis or release, impairs sociability and that a single episode of neonatal SE changes GABAergic signaling at the level of GABA receptors. Yet, within this context, little attention has been given to the maturation of GABAergic interneurons, considering their role in defining "critical periods" of brain plasticity. Both inhibitory and excitatory neuronal activity contribute to these changes and many aspects are activity- and NMDAR-dependent. GABAergic interneurons also contribute to spontaneous network activity during early development including both early network oscillations and giant depolarizing potentials. Both of these spontaneous activity patterns are critical to establishing neuronal connectivity and disrupting them can have long term consequences on brain function. Therefore, we hypothesize that early life seizures disrupt the maturation and integration of cortical GABAergic interneurons into cortical networks. The main propose of the proposed study is to understand how early life seizures disrupt interneuron maturation, contributing to later behavioral dysfunction.