Grant: Project Grant

The human brain has one of the highest rates of consumption of biochemical fuel (i.e., glucose) needed to sustain neuronal electrical activity. This in turn produces significant levels of metabolic ionic byproducts, such as protons (acid), bicarbonate and phosphates (bases) that must be effectively buffered, recycled for other purposes, or removed in order to maintain a suitable acid-base (pH) milieu for optimal brain function. Abnormal disturbances in brain pH balance are associated with the progression of various pathophysiological conditions, including newborn asphyxia, stroke, epilepsy, intellectual disability, and neuropsychiatric disorders - debilitating conditions that have an enormous human and economic impact on society. However, the molecular and cellular mechanisms that control brain pH levels are not fully understood. This project examines the roles of one major class of pH-regulating ion transport proteins called alkali cation/proton exchangers (i.e., SLC9A gene family), with a specific focus on the SLC9A6 transporter that is located in mobile membrane-bound vesicles located inside most brain cell types. Recent studies have identified mutations in SLC9A6 that cause an increasing diagnosed form of severe intellectual disability, epilepsy and autistic behaviour called Christianson Syndrome. We have isolated the SLC9A6 gene and are currently studying the effects the mutations have on neuronal function. We hypothesize that these defects impair the proper pH and functioning of vesicles that carry neurotransmitter receptors and other proteins to synapses of neurons, which in turn affects brain electrical activity and function. This assumption will be tested using a range of molecular, cellular, genetic and electrophysiological techniques in cultured cells and mouse animal models; thereby shedding new insights into the contributions of SLC9A6 to human health and disease, and identification of efficacious strategies for disease treatment.