Role of excitatory amino acids in developmental epilepsies

Altered excitatory amino acid (EAA) neurotransmission, mediated primarily by glutamate, is a major cause of the imbalance of excitation and inhibition which characterizes both early development and epileptogenesis. Glutamate's actions are mediated by three classes of receptors: NMDA, non-NMDA (AMPA and kainate), and metabotropic. Several features of normal EAA development contribute to hyperexcitability in the immature brain, making it more prone to development of seizures. These features include increased density of NMDA receptors, differences in NMDA receptor subunit composition and activation kinetics, which result in reduced voltage-dependent Mg(2+) blockade and longer receptor openings in early development. Also, the unique subunit composition of AMPA receptors present at synapses during early development results in increased Ca(2+) influx. These and other differences in EAA signaling, in combination with developmental alterations in inhibitory neurotransmission, contribute to the increased seizure susceptibility seen in young animals and children. In turn, seizures themselves may alter EAA neurotransmission in an age-dependent manner. Age related changes in excitatory neurotransmission may, therefore, lead to differences in basic mechanisms of epileptogenesis between the immature and mature brain, and may also alter the activity and efficacy of antiepileptic drugs in the pediatric age group.