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Norway

PMID:29362376  

A mouse model of autism implicates endosome pH in the regulation of presynaptic calcium entry.

Julie C Ullman | Jing Yang | Michael Sullivan | Jacob Bendor | Jonathan Levy | Ellen Pham | Katlin Silm | Helia Seifikar | Vikaas S Sohal | Roger A Nicoll | Robert H Edwards
Nature communications | 2018

Psychoactive compounds such as chloroquine and amphetamine act by dissipating the pH gradient across intracellular membranes, but the physiological mechanisms that normally regulate organelle pH remain poorly understood. Interestingly, recent human genetic studies have implicated the endosomal Na+/H+ exchanger NHE9 in both autism spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD). Plasma membrane NHEs regulate cytosolic pH, but the role of intracellular isoforms has remained unclear. We now find that inactivation of NHE9 in mice reproduces behavioral features of ASD including impaired social interaction, repetitive behaviors, and altered sensory processing. Physiological characterization reveals hyperacidic endosomes, a cell-autonomous defect in glutamate receptor expression and impaired neurotransmitter release due to a defect in presynaptic Ca2+ entry. Acute inhibition of synaptic vesicle acidification rescues release but without affecting the primary defect due to loss of NHE9.

Pubmed ID: 29362376

Associated grants

  • Agency: NIDA NIH HHS, United States
    Id: P01 DA010154
  • Agency: NIMH NIH HHS, United States
    Id: F31 MH096447
  • Agency: NIMH NIH HHS, United States
    Id: R01 MH106507
  • Agency: NIMH NIH HHS, United States
    Id: R01 MH070957
  • Agency: NIMH NIH HHS, United States
    Id: R37 MH050712
  • Agency: NIMH NIH HHS, United States
    Id: R01 MH050712
  • Agency: NIMH NIH HHS, United States
    Id: R37 MH038256

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