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.