The role of neural activity in synaptic development and its implications for adult brain function.

In much of the developing nervous system, electrical activity guides the formation of neural connections, with lasting effects on adult brain function. Epilepsy, a defect in neuronal excitability, might result from abnormal patterns of activity in the young brain. Many connections are organized by selective stabilization of synapses when they are activated simultaneously on the same postsynaptic cell during a sensitive period in early life. This process often involves calcium entry through the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. The magnitude of the current passed by this receptor depends on its subunit composition, which varies with age and brain region. Although receptor configurations that admit large calcium currents are permissive of synaptic plasticity, they also increase neural vulnerability to excitotoxic cell death. In most regions of developing brain, activity that can drive NMDA receptors initially is low and increases with maturation. Thus, the replacement of NMDA receptors that flux large calcium currents during early periods of synaptic organization with NMDA receptor subtypes that flux less calcium as synapses become more active, more effective, and less plastic allows maturing neurons to maintain optimal levels of intracellular calcium in the face of drastic developmental changes in their inputs. We have proposed that this transition in NMDA receptors from high to low calcium permeabilities is itself activity dependent. This idea is supported by data showing that many synaptic proteins, including receptor subunits, can be regulated by activity. Cultured cerebellar granule neurons require NMDA receptor stimulation for survival and differentiation, which may replicate the activation provided by the arrival of mossy fiber innervation in vivo. In these cultures, chronic depolarization and glutamate or NMDA treatment induces more mature NMDA receptor subunit expression patterns and function and also increases the expression of several gamma-aminobutyric acid type A (GABAA) receptor subunits, changing that receptor's function. In addition, evidence from in vivo studies indicates that synaptic maturation itself may depend on NMDA receptor activity. During the formation of topographic connections between the retina and superior colliculus (SC) of young rats, chronic local application of the competitive NMDA receptor antagonist +2-amino-5-phosphonovalerate (D-APV) blocks the normal developmental up-regulation of NMDA receptor subunit 1 (NR1) mRNA and nitric oxide synthase activity, as well as maturation of calcium and calmodulin-dependent kinase distribution, activity, and substrate phosphorylation. Together, these recent molecular findings suggest that chronic seizure disorders could result from any of a variety of early developmental events. Any disturbance that locally perturbs regulation of NMDA receptors or the temporal correlations in synaptic activity that drive these receptors has the potential to alter the normal development of local circuitry and the critical balance of inhibition and excitation required to contain seizure activity.