Molecular physiology of cation-chloride cotransport mechanisms in the nervous system.
GABAergic neurotransmission depends upon the transmembrane Cl concentration gradient that exists at the synapse. The intracellular Cl concentration in CNS and PNS neurons is regulated, in part, by cation-chloride cotransport mechanisms such as Na-K-2Cl and K-Cl cotransporters. For example, the inward Na-K-2Cl cotransporter is highly expressed in immature CNS neurons, resulting in a high intracellular Cl- concentration and GABA depolarizing or excitatory responses. In contrast, mature CNS neurons have low Na-K-2Cl cotransporter and high K-Cl cotransporter leading to low intracellular Cl- and GABA hyperpolarizing or inhibitory responses.
Our laboratory is creating knockouts of the cotransporters and studying their relationship with neurotransmission and behavior. Our work, in collaboration with Drs. Robert MacDonald and Mike McDonald, involves molecular biology, physiology, electrophysiology and behavior. These studies have significance in perception of pain, hyper-excitability and epilepsy, nerve conduction, peripheral neuropathy and paraplegia.