Endosomal NHE6 in long-range connectivity and autism

  • Awarded: 2012
  • Award Type: Research
  • Award #: 239834

Perturbed neuronal arborization, or branching, and defects in long-range connectivity are likely to be shared mechanisms in many forms of severe autism. Neurotrophic factors (proteins that play a role in the growth and maintenance of neurons) and their cognate receptors, such as brain-derived neurotrophic factor (BDNF) and TrkB, respectively, govern the development of neuronal circuitry, in part, through signaling at the level of intracellular organelles known as endosomes. The protein NHE6 localizes within the cell membranes that form endosomes. Moreover, through its role in mediating the transport of protons (H+) out of endosomes in exchange for the import of sodium (Na+) ions, it contributes to modulating endosome acidity.

Mutations in NHE6 have been implicated in an autism-related condition known as Christianson syndrome. Eric Morrow and his colleagues tested the concept that NHE6 mediates proper neuronal arborization and neuronal circuit formation through mechanisms relating to its role in the regulation of endosome acidity. Mutations in NHE6 might then disrupt these processes, resulting in neurocognitive disorders such as autism.

In imaging of mouse neurons from an NHE6-knockout mouse, which they generated, Morrow’s group found that NHE6 deficiency leads to over-acidification of endosomes and impoverished neuronal arborization and formation of synapses, the junctions between neurons. Additional biochemical studies revealed a perturbation of BDNF/TrkB signaling in NHE6-deficient cells associated with the neuronal circuitry defects. Adding BDNF peptides to cultures of neurons isolated from NHE6-mutant mice reversed some of these defects1. In a separate study conducted by Morrow’s group, which involved meta-analysis of autism brain transcriptome data, his team discovered that the gene encoding NHE6 is down-regulated in the brains of a sizable proportion of individuals with autism2.

Taken together, results from these studies suggest that a subset of severe autism and related conditions may be associated with perturbed neurotrophin signaling, which leads to impoverished arborization and synapse formation. Furthermore, disruption of pathways and cellular processes in which NHE6 plays a key role may represent a common underlying pathophysiology for these disorders. The recent insights Morrow and his colleagues gained regarding NHE6 function and the cellular effects of NHE6 deficiency are revealing new therapeutic avenues with potential for developing treatments for autism and related disorders.



1.Ouyang Q. et al. Neuron 80, 97-112 (2013) PubMed
2.Schwede M. et al. Mol. Psychiatry 19, 277-279 (2014)  PubMed
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