Early striatal dendrite deficits followed by neuron loss with advanced age in the absence of anterograde cortical brain-derived neurotrophic factor
Early striatal dendrite deficits followed by neuron loss with advanced age in the absence of anterograde cortical brain-derived neurotrophic factor
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DOI：
10.1523/jneurosci.3920-03.2004
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发表时间：
2004-04-28
影响因子：
5.3
通讯作者：
Jones, KR
中科院分区：
文献类型：
--
作者：
Baquet, ZC;Gorski, JA;Jones, KR
脑源性神经营养因子 (BDNF) 是神经营养蛋白家族的成员，可调节神经元存活、分化和突触功能。亨廷顿基因突变引起的皮质 BDNF 表达减少被认为在亨廷顿病中观察到的纹状体变性中发挥了作用。在小鼠出生后的最初几周内，皮质中的 BDNF 表达急剧上升。此前，由于 BDNF-/- 小鼠出生后早期致死，因此不可能研究 BDNF 缺失对中枢神经系统结构的具体长期影响。将携带 floxed BDNF 基因的小鼠与 Emx1(IREScre/+) 小鼠交配，产生缺乏皮质 BDNF 但可存活的 Emx-BDNFKO 小鼠。成年 Emx-BDNFKO 小鼠表现出与亨廷顿病小鼠模型中观察到的后肢紧握表型相似。与对照组相比，出生后 Emx-BDNFKO 小鼠的纹状体体积缩小，并且纹状体中最丰富的神经元类型，中型多棘神经元（MSN），在 35 日龄时细胞体缩小，树突变薄，树突棘减少。尽管在出生后 35 或 120 天时未检测到明显的纹状体神经元丢失，但在 1 岁以上的 Emx-BDNFKO 小鼠中，35% 的纹状体神经元缺失。因此，皮质 BDNF 虽然不是 MSN 的产生或近期存活所必需的，但在皮质中 BDNF 表达升高期间，对于正常纹状体神经元树突形态是必需的。此外，还揭示了皮质 BDNF 在支持 MSN 存活方面的长期体内需求。
Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, modulates neuronal survival, differentiation, and synaptic function. Reduced BDNF expression in the cortex caused by mutation of the huntingtin gene has been suggested to play a role in the striatal degeneration observed in Huntington's disease. BDNF expression rises dramatically in the cortex during the first few weeks of postnatal life in mice. Previously, it has been impossible to study the specific long-term effects of BDNF absence on CNS structures because of the early postnatal lethality of BDNF-/- mice. Mice harboring a floxed BDNF gene were bred with Emx1(IREScre/+) mice to generate Emx-BDNFKO mice that lack cortical BDNF but are viable. Adult Emx-BDNFKO mice display a hindlimb clasping phenotype similar to that observed in mouse models of Huntington's disease. The striatum of postnatal Emx-BDNFKO mice was reduced in volume compared with controls, and the most abundant neuron type of the striatum, medium spiny neurons (MSNs), had shrunken cell somas, thinner dendrites, and fewer dendritic spines at 35 d of age. Although significant striatal neuron losses were not detected at 35 or 120 d postnatal, 35% of striatal neurons were missing in Emx-BDNFKO mice aged beyond 1 year. Thus, cortical BDNF, although not required for the generation or near-term survival of MSN, is necessary for normal striatal neuron dendrite morphology during the period when BDNF expression rises in the cortex. Furthermore, a long-term in vivo requirement for cortical BDNF in supporting the survival of MSNs is revealed.