The ontogeny of hippocampal local circuits and focal epileptogenesis

Our understanding of the pathophysiological mechanisms underlying the childhood epilepsies is rudimentary at this time. However, results of recent studies in animal models have lead to a number of important hypotheses concerning age-dependent alterations in seizure susceptibility. In area CA3 of hippocampus it appears that during a critical period when this brain area is particularly prone to electrographic seizures, an overabundance of recurrent excitatory synapses may exist. At the same time the synapses themselves appear to be functionally different than their mature counterpart. Age-dependent differences in the properties of postsynaptic NMDA receptors seem to contribute to enhanced seizure susceptibility. In recent years significant progress has been made in unravelling the fundamental processes that underlie the formation of connections between developing neurons. Over-production of early-formed axon collaterals appears to be common-place in the CNS. Moreover, the selection of appropriate patterns of connectivity appear to be dependent in large part on the patterning of neurophysiologic activity. In this regard the NMDA receptor seems to play a pivotal role in synapse consolidation. Based on these observations and the central role recurrent excitation appears to play in hippocampal seizures, it seems entirely plausible that excessive abnormal neuronal discharging that occurs during seizures early in life could result in the consolidation of abnormal numbers of recurrent excitatory synapses. This miswiring of hippocampal networks might be responsible for the marked seizure susceptibility into adulthood and might even contribute to complex partial epilepsy in individuals with a history of childhood seizures.