BDNF Roles in Regulating Cortical Dendrite Structure

描述（由申请人提供）：为了能够对复杂和变化的世界做出有效反应，新皮层已经进化出可塑性机制，其将模式化神经活动与神经回路的修改相耦合。神经营养因子是一类分泌性生长因子，参与特定神经类型的分化和存活、神经回路的形成、该回路的维持和可塑性以及神经疾病的病因学的分子机制。在皮质中，神经营养因子脑源性神经营养因子（BDNF）特别丰富，并且参与了所有这些过程，从皮质神经元的最初发生延伸到疾病中的死亡。为了精确地确定BDNF的必要功能，我们在小鼠中进行了遗传分析。由于BDNF无效突变小鼠在出生后发育迟缓后的第一周内死亡，因此对其前脑表型的解释是复杂的。因此，尽管BDNF显然是一种重要的分子，但BDNF在皮质发育和维持中的具体作用仍然不清楚。因此，我们已经产生了BDNF的条件突变，导致胚胎或成人中BDNF的丢失，并开始分析其表型。使用这些小鼠，我们发现BDNF是必不可少的视觉皮层第2/3层锥体神经元树突形式的发育稳定。该建议描述了这些小鼠的进一步研究，旨在阐明视皮层中特定的BDNF功能。树突棘、突触和树突结构缺陷之间的发育关系将被确定。我们将把我们对皮质树突的研究扩展到其他层，包括成人对BDNF的需求。我们将测试是否BDNF是必要的经验依赖性的解剖学变化在皮层。为了阐明BDNF信号在皮层的方向性，我们将测试BDNF是否具有细胞自主功能。这些研究的结果将阐明BDNF在皮层回路的发育、维持和可塑性中的作用。

DESCRIPTION (provided by applicant): 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.