Epilepsy is commonly thought to reflect one of 3 alterations in brain: l) excessive excitatory mechanisms, 2) diminished inhibitory mechanisms, or c) a combination of these. However, preliminary results, involving a model of experimentally induced audiogenic seizure (AGS) susceptibility, suggest increases in inhibitory mechanisms probably occur along with increases in excitatory innervation of inferior colliculus (IC), the site of seizure initiation. This suggests it is the balance between altered levels of both excitation and inhibition which determines pathogenic outcome. Such distinction is of heuristic importance because if the balance could be tipped toward inhibition, the epileptic brain might be rendered less prone to seizures. Certain neonatal treatments appear to have this effect. For example, preliminary results indicate rats experiencing a single seizure as neonates have less severe seizures as adults -- suggesting induction occurs of compensatory inhibitory brain circuitry. It is a putative site-specific increase in inhibition which we wish to study. AGS susceptibility appears to be due to an excitatory hyperinnervation of IC resulting from neonatal hearing deprivation. This abnormal experience appears to prevent the normal developmental use- and NMDA receptor- dependent regression of exuberant excitatory synapses in IC. However, in susceptible rats, the Dorsal nucleus of Lateral Lemniscus (DnLL), has now been found to also exhibit broader patterns of Fos-immunoreactive excitatory responses, suggesting it is also relatively hyperinnervated after hearing deprivation. The DnLL provides 55% of GABAergic inhibition in IC, and probably gates AGS severity by a feedforward inhibitory mechanism. Indeed, transection of GABAergic efferents between DnLL and IC greatly exacerbates seizure severity. We hypothesize excitatory innervation of DnLL also arises by a use- and NMDA receptor-dependent process, but that exuberance of innervation reduces, rather than promotes seizure responses. It is proposed to examine the role of DnLL in AGS severity, the normal development of its excitatory innervation, and whether such development can be selectively altered. Proposed studies focus on behavioral, functional, and anatomical alterations as a function of age, and in adults as a function of neonatal treatments. Neuron tracing and reconstruction techniques will address whether excessive branching of axonal arbors occurs in DnLL's after various neonatal treatments. The principle suggested here, that strength of feedforward inhibition can be selectively and developmentally manipulated, may result in new approaches to the treatment of epilepsies of childhood onset.
