The proposed projects investigate the role of neurotransmitter receptor regulation, using a model system the rat whisker barrel cortex and GABA-A receptors, which mediate synaptic transmission for GABA, the major inhibitory neurotransmitter. A developmental peak in GABA-A receptors occurs before the major wave of GABA synaptogenesis, and at a time when the cortex is most vulnerable to excitation. We will test the hypothesis that GABA-A blockade during development will lead to: (1) neuron death, due to excitotixicty; and (2) fewer GABA-A receptors per neuron, because receptors are needed to establish effective synapses. GABA-A regulation in sensory deprivation may have a similar role in restoring the balance between excitation and inhibition that is necessary for proper cortical functioning. We have found that simply trimming a row of whiskers results in down-regulation GABA-A receptors in the corresponding cortical barrels, 3-4 synapses away. This decerase apparently has functional implications; whisker trimming and GABA-A blockade lead to the same neurophysiological signs of disinhibition. To investigate the cascade of events triggered by sensory deprivation, we will first work at the receptor end, examining whether GABA-A receptors change in number, subunit composition, or gene regulation. Finally, in considering what mediates the effects of sensory input on cortical GABA receptors, we propose brain-derived neurotrophic factor (BDNF) as an excellent candidate. We will test whether whisker trimming decreases BDNF, and whether mutant mice deficient in BDNF are compromised in their ability to regulate cortical GABA systems in response to sensory deprivation.
