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.
Somatostatin (SST) expressing interneurons are the second most abundant group of inhibitory neurons in the neocortex. They mainly target the apical dendrites of excitatory pyramidal cells and are implicated in feedforward and feedback inhibition. In the present study, we employ a conditional knockout mouse, in which the transcription factor Satb1 is selectively deleted in SST‐expressing interneurons resulting to the reduction of their number across the somatosensory barrel field. Our goal was to investigate the effect of the reduced number of Satb1 mutant SST‐interneurons on (i) the endogenous cortical network activity (spontaneously recurring Up/Down states), and (ii) the transition to epileptiform activity. By conducting LFP recordings in acute brain slices from young male and female mice, we demonstrate that mutant animals exhibit significant changes in network excitability, reflected in increased Up state occurrence, decreased Up state duration and higher levels of extracellular spiking activity. Epileptiform activity was induced through two distinct and widely used in vitro protocols: the low magnesium and the 4‐Aminopyridine (4‐AP) model. In the former, slices from mutant animals manifested shorter latency for the expression of stable seizure‐like events. In contrast, when epilepsy was induced by 4‐AP, no significant differences were reported. We conclude that normal SST‐interneuron function has a significant role both in the regulation of the endogenous network activity, and in the transition to seizure‐like discharges in a context‐dependent manner.
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