Alterations in excitatory/inhibitory circuitry in the adult rat brain following postnatal glutamatergic system activation

A critical period for maturation and final organization of excitatory and inhibitory function in the brain occurs during perinatal development when network connections are being formed and refined. In the rat hippocampus, many of these connections reach adult levels by the end of the second postnatal week. Subsequently, insult or injury to the brain at this time may have far-reaching consequences that manifest as changes in behaviour resulting from modifications in underlying neuronal structure and function. It has been previously demonstrated that low daily doses of the glutamate agonist domoic acid (DOM), administered to rat pups throughout the second postnatal week of life, can result in seizure-like behaviours in adulthood similar to temporal lobe epilepsy (TLE) in humans, as well as produce cellular changes in the dentate gyrus and area CA3 of the hippocampus. Now known as the novelty-induced, seizure-like (NIS-L) rat, these animals represent a new developmental model for TLE.

The objective of this dissertation was to further characterize the NIS-L model, thus providing additional information regarding potential alterations in neurologic function and underlying mechanistic properties that may result from early-life glutamate system activation. Subsequently, in vivo studies were performed to provide an electrophysiological assessment of electroencephalogram (EEG) in NIS-L rats. This investigation revealed a distinct EEG waveform pattern during NIS-L manifestation as well as subtle alterations in wave band expression, along with decreased seizure threshold levels and increased mossy fibre sprouting, but no difference in seizure propagation to the rest of the brain. In addition, altered sleep patterns were also reported, similar to what is seen in other animal models of TLE. To assess possible underlying mechanisms responsible for these changes, an immunohistochemical study of inhibitory cells in the hippocampus and amygdala showed region and sex-dependent changes in specific interneuronal subpopulations in the model, as well as decreases in a population of susceptible excitatory neurons, while an in vitro evaluation of field post-synaptic potentials in the dentate gyrus and area CA3 of the hippocampus revealed no differences in baseline activity, but did show a concentration-dependent alteration in response to acute DOM perfusion. A final study investigating possible glutamatergic pathways for DOM-mediated effects indicated no involvement for the N-methyl-D-aspartate (NMDA) receptor, but appeared to implicate α-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (AMPA)-sensitive mechanisms. Additionally, a dramatic and unexpected response to early-life glutamate antagonism was discovered.

These data provide a demonstration of some of the possible changes that may occur in excitatory and inhibitory circuitry in the brain as a result of interference with early developmental processes, and have revealed several underlying mechanisms that may be responsible for these changes. Future studies assessing spontaneity of behavioural seizure expression and evaluating sex-dependent differences in the model, as well as an investigation of the role of GABAergic mechanisms may help further elucidate the possible consequences of interference in the intricate interplay between glutamate and GABA systems during critical developmental stages.