The overall goal of this project is to determine how neurotrophins regulate synaptic transmission in the developing neocortex. In the visual cortex, there is a change in the kinetics of NMDA mediated synaptic responses over the course of development beginning around the time of eye opening (Carmignoto and Vicini 1992). In neonates, the duration of synaptic responses is much longer than in the adult. In the somatosensory cortex (SI), a similar kinetic shift also occurs, but at a slightly earlier age, beginning at P7. Simultaneously, in the somatosensory cortex, the ratio of the peak evoked NMDA to AMPA currents is reduced 5- fold (Crair and Malenka 1995). In this study, I will test the hypothesis that neurotrophins are necessary and sufficient to induce these developmental changes in synaptic transmission. I will examine this question electrophysiologically, using whole cell patch-clamp. The preparation will be organotypic slice cultures which combine the preservation of circuitry of the acute slice with the ability to do extended experimental manipulations of dissociated cell culture. To determine if neurotrophins are sufficient to induce this synaptic maturation, I will apply exogenous neurotrophins and observe the kinetics of synaptic responses. To determine if they are necessary, I will prevent the actions of endogenous neurotrophins with receptor -bodies, chimeric proteins composed of the extracellular domain of the neurotrophin trk receptor and an IgG heavy chain. If neurotrophins cause this developmental change in transmission, then antagonizing their action with receptor bodies should prevent it.
