Role of Dendritic Bdnf Synthesis in Adult Neurogenesis and Spine Morphogenesis

Substantial evidence has demonstrated that dendritic protein synthesis is an important source of new protein during the expression of synaptic plasticity. Dendritically synthesized brain-derived neurotrophic factor (BDNF) has been shown to be key in the expression of lasting synaptic plasticity. However little is known about the function of dendritic protein synthesis in other cellular forms of plasticity. Here we investigated the role of dendritic BDNF synthesis in adult neurogenesis and spine morphogenesis. Adult neurogenesis in the subgranular zone (SGZ) of the dentate gyrus is regulated by hippocampal network activity. However the interplay between glutamatergic and GABAergic transmission during adult neurogenesis remains unclear. Here we report that dendritic synthesis of BDNF mediates this interplay. Activation of the N-methyl-D-aspartic-acid receptor (NMDAR) stimulated dendritic BDNF synthesis in hippocampal neurons and the effect of NMDAR antagonism on adult neurogenesis was abolished in mice lacking dendritic BDNF synthesis. These animals also exhibited deficits in GABAergic innervation to the SGZ and differentiation of precursor cells, which was rescued by administration of a GABA A agonist. Furthermore, we observed similar neurogenesis deficits in mice where BDNF signaling was selectively abolished iv in parvalbumin-expressing GABAergic (PV) interneurons. We propose that these data establish a model in which NMDAR activation stimulates dendritic synthesis of BDNF, which facilitates GABA release from PV interneurons, leading to differentiation of precursor cells. A sequence in the Bdnf mRNA long 3'untranslated region (3'UTR) has been shown to be necessary and sufficient to target Bdnf mRNA into the dendrites. Furthermore, an animal model deficient in dendritic Bdnf mRNA exhibits alterations in spine morphogenesis. We investigated what possible role single nucleotide polymorphisms (SNPs) in the human Bdnf 3'UTR might have on Bdnf mRNA trafficking and spine morphogenesis. We found that one of the eight reported SNPs in the human Bdnf 3'UTR impeded dendritic trafficking of Bdnf mRNA in cultured hippocampal neurons. In addition, neurons transfected with these constructs showed impairments in spine morphogenesis. Mature neurons had longer, thinner, more densely clustered spines that resembled immature neuronal spines. These data suggest that humans carrying this SNP may have impairments in dendritic BDNF synthesis and spine morphogenesis. v The research and writing of this thesis is dedicated to everyone who helped along the way. Most of all I must express my gratitude and respect to my mentor Dr. Baoji Xu for all the wonderful guidance and support he has given me. Also, my fellow colleagues in Lanigan, and …