Developmental neuroplasticity: roles in early life seizures and chronic epilepsy

Both clinical and experimental studies suggest that the immature nervous system is unusually susceptible to seizures during critical periods in postnatal life. A late onset of gamma-aminobutyric acid (GABA)-mediated synaptic inhibition could conceivably play a contributing role in this phenomenon. Numerous studies have shown that neural systems that use GABA in the neonatal brain are different than those of adulthood. GABA is an excitatory neurotransmitter that likely plays a neurotrophic role in neuronal differentiation. Other reports suggest that unique, possibly transient, GABAergic interneuron populations exist in the embryonic and neonatal nervous system. At these early times in development, the immature nervous system is remarkably resistant to seizure generation. However, as the hippocampus and neocortex enter the critical period of enhanced seizure susceptibility, inhibitory GABA systems mature rapidly. At this time, blockade of GABA type A (GABAA) receptors produce unusually severe seizure discharges. In hippocampus, concurrent exuberant outgrowth of recurrent excitatory axon collaterals and synapses appear to play a role in the generation of these seizures. As the hippocampus matures, these axons are morphologically remodeled and nearly 50% of branches within arbors are pruned. This pruning of axon branches corresponds in time with the decrease in seizure susceptibility that characterizes adulthood. Developmental remodeling of neuronal connectivity is a common feature of most areas of the central nervous system. Results from an audiogenic seizure model of early onset epilepsy suggest that prevention of axon arbor remodeling by transient sensory deprivation can lead to a permanent overinnervation of target nuclei and chronic seizure susceptibility. Early life seizures may have a similar effect. Recent results in one model have shown that repeated seizures induced by intrahippocampal injections of tetanus toxin during a critical period results in a chronic epilepsy. Future studies should attempt to determine if the synchronized discharging of early-life seizures prevents the remodeling of neuronal connectivity that normally takes place during postnatal development and results in an overinnervated and chronically hyperexcitable hippocampus.