Format

Send to

Choose Destination
Nat Commun. 2018 Jan 23;9(1):330. doi: 10.1038/s41467-017-02716-5.

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

Ullman JC1,2,3,4, Yang J1,2,3, Sullivan M1,2,3, Bendor J1,2,3, Levy J2,3,5,6, Pham E1,2,3, Silm K1,2,3, Seifikar H2,3,7, Sohal VS2,3,7, Nicoll RA2,3,5,6, Edwards RH8,9,10,11.

Author information

1
Departments of Neurology and Physiology, UCSF School of Medicine, San Francisco, CA, 94143, USA.
2
Kavli Institute for Fundamental Neuroscience, UCSF School of Medicine, San Francisco, CA, 94143, USA.
3
Weill Institute for Neurosciences, UCSF School of Medicine, San Francisco, CA, 94143, USA.
4
Graduate Program in Molecular and Cellular Biology, UC Berkeley, Berkeley, CA, 94720, USA.
5
Graduate Program in Neuroscience, UCSF School of Medicine, San Francisco, CA, 94143, USA.
6
Department of Cellular and Molecular Pharmacology, UCSF School of Medicine, San Francisco, CA, 94143, USA.
7
Department of Psychiatry, UCSF School of Medicine, San Francisco, CA, 94143, USA.
8
Departments of Neurology and Physiology, UCSF School of Medicine, San Francisco, CA, 94143, USA. robert.edwards@ucsf.edu.
9
Kavli Institute for Fundamental Neuroscience, UCSF School of Medicine, San Francisco, CA, 94143, USA. robert.edwards@ucsf.edu.
10
Weill Institute for Neurosciences, UCSF School of Medicine, San Francisco, CA, 94143, USA. robert.edwards@ucsf.edu.
11
Graduate Program in Neuroscience, UCSF School of Medicine, San Francisco, CA, 94143, USA. robert.edwards@ucsf.edu.

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.

PMID:
29362376
PMCID:
PMC5780507
DOI:
10.1038/s41467-017-02716-5
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center