Activity-Dependent Regulation of Glutamate Receptor Function

Mechanisms that can titrate glutamate receptor function as the brain matures are important because excessive glutamatergic activity produces seizures and cell death while too little glutamate receptor function impedes normal synaptic and circuit development. In addition, glutamate receptor down-regulation which occurs as a normal correlate of maturation is frequently associated with a marked decrease in structural plasticity. Thus a cellular and molecular understanding of receptor down-regulation should suggest approaches to upregulating plasticity in select regions of mature brain to facilitate recovery from trauma-induced dysfunction or from genetic or environmentally induced abnormalities in early brain activity. Our studies are focused on normal mice and rats, and mice with mutations in molecules necessary for glutamate neurotransmission. Recently we have found that glutamatergic and GABAergic synaptic development are quite tightly coupled and balanced. We have also shown that abnormally low levels of NMDAR receptor function retards glutamatergic synaptic development, whereas complete blockade has only minor effects.