Department of Molecular Biology, Cell Biology and Biochemistry, and Institute for Brain Science, Brown University, Laboratory for Molecular Medicine, 70 Ship Street, Providence, RI 02903, USA.
Departments of Molecular Pharmacology, Physiology and Biotechnology, and Neuroscience, Brown University, Providence, Rhode Island 02912, USA.
Neuron. 2013 Oct 2;80(1):97-112. doi: 10.1016/j.neuron.2013.07.043. Epub 2013 Sep 12.
Neuronal arborization is regulated by cell-autonomous and nonautonomous mechanisms including endosomal signaling via BDNF/TrkB. The endosomal Na⁺/H⁺ exchanger 6 (NHE6) is mutated in a new autism-related disorder. NHE6 functions to permit proton leak from endosomes, yet the mechanisms causing disease are unknown. We demonstrate that loss of NHE6 results in overacidification of the endosomal compartment and attenuated TrkB signaling. Mouse brains with disrupted NHE6 display reduced axonal and dendritic branching, synapse number, and circuit strength. Site-directed mutagenesis shows that the proton leak function of NHE6 is required for neuronal arborization. We find that TrkB receptor colocalizes to NHE6-associated endosomes. TrkB protein and phosphorylation are reduced in NHE6 mutant neurons in response to BDNF signaling. Finally, exogenous BDNF rescues defects in neuronal arborization. We propose that NHE6 mutation leads to circuit defects that are in part due to impoverished neuronal arborization that may be treatable by enhanced TrkB signaling.
神经元树突分支由细胞自主和非自主机制调节，包括通过 BDNF/TrkB 的内体信号。内体 Na⁺/H⁺交换器 6（NHE6）在一种新的与自闭症相关的疾病中发生突变。NHE6 的功能是允许质子从内体漏出，但其导致疾病的机制尚不清楚。我们证明，NHE6 的缺失会导致内体隔室过度酸化和 TrkB 信号减弱。NHE6 功能缺失的小鼠大脑显示出轴突和树突分支、突触数量和回路强度减少。定点突变显示，NHE6 的质子泄漏功能对于神经元树突分支是必需的。我们发现 TrkB 受体与 NHE6 相关的内体共定位。在 BDNF 信号作用下，NHE6 突变神经元中的 TrkB 蛋白和磷酸化减少。最后，外源性 BDNF 可挽救神经元树突分支的缺陷。我们提出，NHE6 突变导致回路缺陷，部分原因是神经元树突分支减少，而增强 TrkB 信号可能对此有治疗作用。
