Grant: Project Grant

Neuronal networks consist of different types of neurons that all play their own role in order to maintain proper network function. The two main types of neurons segregate in excitatory and inhibitory neurons, which together regulate the flow of information through the network. It has been proposed that changes in the relative strength in these two opposing forces underlie the symptoms observed in many psychiatric disorders, including autism and schizophrenia. Recently downregulation of NHE6 has been associated with with a rare and severe autism-related condition known as Christianson syndrome, generalized autism and Alzheimer's disease. NHE6 regulates the pH of intracellular membrane vesicles called 'recycling endosomes' that play important roles in the targeted delivery of growth factor and neurotransmitter receptors to synapses. Inappropriate trafficking of such cargo inside the synapse results in malformation of the neuronal circuitry in the brain, which can lead to progressive motor impairment (called ataxia), epilepsy (imbalance between excitation and inhibition in the brain), and intellectual disability, all of which have a devastating effect on the wellbeing of the individual. In this grant we build on our previous published work and extensive preliminary data. We will investigate the mechanisms of how lack of NHE6 leads to defects in excitatory inhibitory synapse maturation, and neural circuit formation in the hippocampus an area of the brain involved in learning and memory. We have developed novel tools and assembled a multidisciplined team putting us in a unique position to make groundbreaking discoveries. This work will result in important findings that could directly contribute to our better understanding of neurocircruitry development and shed new insights into the contributions of NHE6 to human health and disease, and identification of efficacious strategies for disease treatment.