To enable effective responses to a complex and changing world, the neocortex has evolved mechanisms of plasticity that couple patterned neural activity to modification of neural circuitry. Neurotrophins, a family of secreted growth factors, participate in the molecular mechanisms that underly the differentiation and survival of specific neural types, the formation of neural circuitry, the maintenance and plasticity of this circuitry, and the etiology of neural disease. In the cortex, the neurotrophin brain-derived neurotrophic factor (BDNF) is particularly abundant and has been implicated in all of these processes, extending from the initial genesis of cortical neurons through their demise in disease. To precisely identify the necessary functions of BDNF, we have pursued a genetic analysis in the mouse. Because BDNF null mutant mice die during their first weeks of life after retarded postnatal development, interpretation of their forebrain phenotype is complicated. Thus, although BDNF is clearly an important molecule, the specific roles of BDNF in development and maintenance of the cortex are still obscure. Accordingly, we have generated conditional mutations of BDNF that result in loss of BDNF in either the embryo or the adult and begun the analysis of their phenotype. Using these mice, we have found that BDNF is essential for the developmental stabilization of visual cortical layer 2/3 pyramidal neuron dendrite form. This proposal describes further studies of these mice directed toward elucidating specific BDNF functions in the visual cortex. The developmental relationship between dendritic spines, synapses, and defects in dendrite structure will be determined. We will extend our study of cortical dendrites to other layers, and to include adult requirements for BDNF. We will test whether BDNF is necessary for experience-dependent anatomical changes in the cortex. To elucidate directionality of BDNF signaling in the cortex, we will test whether BDNF has cell-autonomous functions. The results of these studies will clarify the roles of BDNF in the development, maintenance, and plasticity of cortical circuitry.
