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 and Robert H. Edwards ()
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Julie C. Ullman: UCSF School of Medicine
Jing Yang: UCSF School of Medicine
Michael Sullivan: UCSF School of Medicine
Jacob Bendor: UCSF School of Medicine
Jonathan Levy: UCSF School of Medicine
Ellen Pham: UCSF School of Medicine
Katlin Silm: UCSF School of Medicine
Helia Seifikar: UCSF School of Medicine
Vikaas S. Sohal: UCSF School of Medicine
Roger A. Nicoll: UCSF School of Medicine
Robert H. Edwards: UCSF School of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-18

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-017-02716-5

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