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

• Published in: Nature communications Vol. 9; no. 1; pp. 330 - 18
• Main Authors: Ullman, Julie C., Yang, Jing, Sullivan, Michael, Bendor, Jacob, Levy, Jonathan, Pham, Ellen, Silm, Katlin, Seifikar, Helia, Sohal, Vikaas S., Nicoll, Roger A., Edwards, Robert H.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23-01-2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/109; 14; 14/19; 38/39; 631/378/1689/1373; 631/378/87; 64/60; 9/26; 9/30; 9/74; Acidification; Amphetamines; Animals; Attention Deficit Disorder with Hyperactivity - genetics; Attention Deficit Disorder with Hyperactivity - metabolism; Attention Deficit Disorder with Hyperactivity - physiopathology; Attention deficit hyperactivity disorder; Autism; Autism Spectrum Disorder - genetics; Autism Spectrum Disorder - metabolism; Autism Spectrum Disorder - physiopathology; Behavior, Animal; Calcium; Calcium - metabolism; Calcium compounds; Calcium influx; Chloroquine; Deactivation; Defects; Disease Models, Animal; Electroencephalography; Endosomes; Endosomes - metabolism; Endosomes - pathology; Female; Gene Expression; Glutamic Acid - metabolism; Glutamic acid receptors; Hippocampus - metabolism; Hippocampus - physiopathology; Humanities and Social Sciences; Humans; Hydrogen ions; Hydrogen-Ion Concentration; Inactivation; Information processing; Intracellular; Isoforms; Male; Membranes; Mice; Mice, Knockout; multidisciplinary; Na+/H+-exchanging ATPase; Neurons - metabolism; Neurons - pathology; Neurotransmitter release; pH effects; Physiology; Presynaptic Terminals - metabolism; Presynaptic Terminals - pathology; Primary Cell Culture; Science; Science (multidisciplinary); Sensory integration; Sodium-Hydrogen Exchangers - deficiency; Sodium-Hydrogen Exchangers - genetics; Synaptic Transmission - physiology; Synaptic Vesicles - metabolism; Synaptic Vesicles - pathology
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-02716-5

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 Ca
2+
entry. Acute inhibition of synaptic vesicle acidification rescues release but without affecting the primary defect due to loss of NHE9.
The Na
+
/H
+
exchanger NHE9 is proposed to regulate the H
+
electrochemical gradient across endosomal membranes. Here, the authors find that NHE9 knockout mice show autism spectrum disorder-like behaviors and disrupted synaptic vesicle exocytosis due to impaired presynaptic calcium entry.