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

Pavlos Rigas,Ani Kaplanian,Charalambos Sigalas,Leonidas Jordan Leontiadis,Charoula Peta,Irini Skaliora,Christos Zlatanos,Aspasia Kapogiannatou,Anna Katri,Maria Nikita,Konstantinos Armaos

doi:10.3389/fnsyn.2018.00043

Pavlos Rigas, Ani Kaplanian + Show 9 more

Open Access

https://doi.org/10.3389/fnsyn.2018.00043

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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.

Highlights

The balance between excitatory and inhibitory synapses in the cortex is critical for normal brain function and adaptive behavior
PTZ injections with a continuum of behaviors categorized into stages ranging from 1 to 6, which we briefly describe as follows in accordance with Luttjohann et al (2009): Stage 1 was characterized by sudden behavioral arrest and/or motionless staring; stage 2 by facial jerking with muzzle or muzzle and eye; stage 3 by neck jerks; stage 4 by clonic seizure in a sitting position; stage 5 by convulsions including clonic and/or tonic–clonic seizures while lying on the belly and/or pure tonic seizures and stage 6 by convulsions including clonic and/or tonic–clonic seizures while lying on the side and/or wild jumping
We investigated the long-term effects of early life seizures (ELS) on spontaneous cortical Up states during adulthood

Summary

Introduction

The balance between excitatory and inhibitory synapses in the cortex is critical for normal brain function and adaptive behavior. Having documented the significant impact of prolonged ELS (60 min status epilepticus, SE) on the adult cortex we wondered if this effect was dependent on the pattern and/or total duration of SE, i.e., whether multiple shorter duration seizures would affect cortical network dynamics as single long-lasting SE did.

Results

Conclusion