Studies have identified a large number of genes that contribute to autism, and many affect communication between neurons, known as synaptic transmission. However, we do not understand the mechanisms responsible for the genes’ effects on synaptic transmission or how these effects give rise to abnormal behavior. To elucidate these mechanisms, Robert Edwards and his group at the University of California, San Francisco plan to study a protein of known biochemical function that has been implicated in autism and determine its role in synaptic physiology and behavior.
A subset of individuals with autism have mutations in the gene that encodes intracellular sodium/hydrogen exchanger 9 (NHE9). NHE9 belongs to a family of transport proteins that regulate the pH of the cell and intracellular organelles by replacing hydrogen ions with either sodium or potassium ions. Mutations in the closely related NHE6 also produce severe developmental delay and features associated with autism. Although the role of plasma membrane NHEs in regulating cytoplasmic pH is well known, the physiological role of intracellular isoforms remains poorly understood.
Edwards and his team previously showed that intracellular NHE activity has an important role in neurotransmitter release1. NHE activity influences the pH gradient and electrical force that drive the filling of synaptic vesicles with neurotransmitters, a process required for release.
However, NHE9 may affect other aspects of synaptic transmission as well. To characterize the role of NHE9, Edwards and his colleagues aim to study its effects on organelle pH and synaptic physiology. By manipulating the effects they observe, the researchers will be able to determine which are most relevant for behavior and suggest avenues for therapeutic intervention.