Physiological effects of sustained blockade of excitatory synaptic transmission on spontaneously active developing neuronal networks--an inquiry into the reciprocal linkage between intrinsic biorhythms and neuroplasticity in early ontogeny.

Spontaneous bioelectric activity (SBA) taking the form of extracellularly recorded spike trains (SBA) has been quantitatively analyzed in organotypic neonatal rat visual cortex explants at different ages in vitro, and the effects investigated of both short- and long-term pharmacological suppression of glutamatergic synaptic transmission. In the presence of APV, a selective NMDA receptor blocker, 1-2- (but not 3-)week-old cultures recovered their previous SBA levels in a matter of hours, although in imitation of the acute effect of the GABAergic inhibitor picrotoxin (PTX), bursts of action potentials were abnormally short and intense. Cultures treated either overnight or chronically for 1-3 weeks with APV, the AMPA/kainate receptor blocker DNQX, or a combination of the two were found to display very different abnormalities in their firing patterns. NMDA receptor blockade for 3 weeks produced the most severe deviations from control SBA, consisting of greatly prolonged and intensified burst firing with a strong tendency to be broken up into trains of shorter spike clusters. This pattern was most closely approximated by acute GABAergic disinhibition in cultures of the same age, but this latter treatment also differed in several respects from the chronic-APV effect. In 2-week-old explants, in contrast, it was the APV+DNQX treated group which showed the most exaggerated spike bursts. Functional maturation of neocortical networks, therefore, may specifically require NMDA receptor activation (not merely a high level of neuronal firing) which initially is driven by endogenous rather than afferent evoked bioelectric activity. Putative cellular mechanisms are discussed in the context of a thorough review of the extensive but scattered literature relating activity-dependent brain development to spontaneous neuronal firing patterns.