Exogenous brain-derived neurotrophic factor rescues synaptic dysfunction in Mecp2-null mice.
Exogenous brain-derived neurotrophic factor rescues synaptic dysfunction in Mecp2-null mice.
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DOI：
10.1523/jneurosci.5503-09.2010
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发表时间：
2010-04-14
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影响因子：
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通讯作者：
Katz DM
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文献类型：
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作者：
Kline DD;Ogier M;Kunze DL;Katz DM
脑源性神经营养因子（BDNF）的出生后缺陷被认为有助于Rett综合征（RTT）的发病机制，RTT是一种由编码甲基CpG结合蛋白2（MeCP2）的基因突变引起的进行性神经发育障碍。在Mecp2基因敲除小鼠（RTT模型）中，BDNF缺陷在对自主神经和呼吸控制重要的结构中最为明显，这些功能在RTT患者中受到严重影响。然而，关于这些缺陷如何影响神经元功能或它们如何与特定的RTT内表型相关的知之甚少。为了解决这些问题，我们分析了脑干孤束核（nTS）的突触功能，这是将初级内脏传入输入整合到中枢自主神经通路的主要部位，也是我们发现Mecp2突变体中BDNF水平显着降低的区域。我们的研究结果表明，自发的微型和诱发的EPSC在nTS神经元的幅度显着增加，在Mecp2 null小鼠，因此，突变型细胞比野生型更有可能消防动作电位在初级传入刺激。这些变化的发生没有任何内在神经元兴奋性的增加，是不受抑制性GABA电流的封锁。然而，这种突触病与初级传入通路中BDNF可用性降低有关，并且可以通过应用外源性BDNF来挽救。基于这些研究结果，我们推测nTS的感觉门控改变导致RTT的心肺不稳定，并且nTS是一个恢复正常BDNF信号传导的位点，可以帮助重建正常的稳态控制。
Postnatal deficits in Brain-Derived Neurotrophic Factor (BDNF) are thought to contribute to pathogenesis of Rett syndrome (RTT), a progressive neurodevelopmental disorder caused by mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2). In Mecp2 null mice, a model of RTT, BDNF deficits are most pronounced in structures important for autonomic and respiratory control, functions that are severely affected in RTT patients. However, relatively little is known about how these deficits affect neuronal function or how they may be linked to specific RTT endophenotypes. To approach these issues we analyzed synaptic function in the brainstem nucleus tractus solitarius (nTS), the principal site for integration of primary visceral afferent inputs to central autonomic pathways and a region in which we found markedly reduced levels of BDNF in Mecp2 mutants. Our results demonstrate that the amplitude of spontaneous miniature and evoked EPSCs in nTS neurons is significantly increased in Mecp2 null mice and, accordingly, that mutant cells are more likely than wildtype to fire action potentials in response to primary afferent stimulation. These changes occur without any increase in intrinsic neuronal excitability and are unaffected by blockade of inhibitory GABA currents. However, this synaptopathy is associated with decreased BDNF availability in the primary afferent pathway and can be rescued by application of exogenous BDNF. On the basis of these findings we hypothesize that altered sensory gating in nTS contributes to cardiorespiratory instability in RTT and that nTS is a site at which restoration of normal BDNF signaling could help reestablish normal homeostatic controls.