Neuron
Volume 80, Issue 1, 2 October 2013, Pages 97-112
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Article
Christianson Syndrome Protein NHE6 Modulates TrkB Endosomal Signaling Required for Neuronal Circuit Development

https://doi.org/10.1016/j.neuron.2013.07.043Get rights and content
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Highlights

  • NHE6-associated endosomes govern neuronal arborization and circuit strength

  • Loss of NHE6 leads to overacidification of the endosome compartment

  • In NHE6 mutant neurons, BDNF signal is attenuated and TrkB degradation is increased

  • Defects in arborization with loss of NHE6 are reversed by enhanced BDNF treatment

Summary

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.

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These authors contributed equally to this work