Long-Term Effects of Early Life Seizures on Endogenous Local Network Activity of the Mouse Neocortex

Abstract

Understanding the long term impact of early life seizures (ELS) is of vital importance both for researchers and clinicians. Most experimental studies of how seizures affect the developing brain have drawn their conclusions based on changes detected at the cellular or behavioral level, rather than on intermediate levels of analysis, such as the physiology of neuronal networks. Neurons work as part of networks and network dynamics integrate the function of molecules, cells and synapses in the emergent properties of brain circuits that reflect the balance of excitation and inhibition in the brain. Therefore, studying network dynamics could help bridge the cell-to-behavior gap in our understanding of the neurobiological effects of seizures. To this end we investigated the long-term effects of ELS on local network dynamics in mouse neocortex. By using the pentylenetetrazole (PTZ)-induced animal model of generalized seizures, single or multiple seizures were induced at two different developmental stages (P9–15 or P19–23) in order to examine how seizure severity and brain maturational status interact to affect the brain’s vulnerability to ELS. Cortical physiology was assessed by comparing spontaneous network activity (in the form of recurring Up states) in brain slices of adult (>5 mo) mice. In these experiments we examined two distinct cortical regions, the primary motor (M1) and somatosensory (S1) cortex in order to investigate regional differences in vulnerability to ELS. We find that the effects of ELSs vary depending on (i) the severity of the seizures (e.g., single intermittent ELS at P19–23 had no effect on Up state activity, but multiple seizures induced during the same period caused a significant change in the spectral content of spontaneous Up states), (ii) the cortical area examined, and (iii) the developmental stage at which the seizures are administered. These results reveal that even moderate experiences of ELS can have long lasting age- and region-specific effects in local cortical network dynamics.

GABAB‐ and GABAA‐receptor‐mediated regulation of Up and Down states across development

“…In brief, we conducted ex vivo simultaneous extracellular (local field potential, LFP) and whole-cell (intracellular, IC) recordings to study the GABAergic mechanisms shaping the developmental differences of cortical UDS activity during distinct stages of the mouse lifespan. Based on our published data of how UDSs change throughout development (Rigas et al, 2015(Rigas et al, , 2018Sigalas et al, 2017) and on preliminary results (see below), we analysed the activity from three age groups (between-subjects factor): young (18-21 days old), adolescent (42-48 days old) and adults (3-9 months old). We applied the GABA receptor antagonists CGP55845 (CGP; 1 μm) and gabazine (200 nm) to study the differential role of GABA B and GABA A receptors, respectively, on cortical activity.…”