Activity-dependent modulation of neuronal sodium channel expression

Action potentials initiate via the voltage-dependent opening of plasma membrane-associated sodium channels. The number and type of sodium channels in a neuronal membrane determine the quantity of sodium current that results from a given stimulus. The expression of sodium channels in neurons is plastic, and is not only altered by injury and disease, but also by subtle changes in physiologic environment. In this dissertation, the effect of neuronal activity level on the expression and function of sodium channels is explored within several neuronal populations. First I examine the response of vasopressin-producing magnocellular neurosecretory cells of the supraoptic nucleus to the hyperosmotic setting of chronic diabetes mellitus. Evidence for up-regulation of sodium channels, and metabolic overactivation leading to apoptosis, in these neurons is presented. Second, I test the effect of electrical stimulation on expression of sodium channels in cultured sensory neurons. And lastly, I demonstrate that there is dysregulated sodium channel expression within cortical neurons in a specific region of the brain in a model of absence epilepsy.; Together, the results of these experiments support the hypothesis that the activity level of a neuron influences its rate of production and expression of sodium channels. Identification of this phenomenon could lead to new therapeutic strategies for (1) limiting end-organ pathogenesis in diabetes (by reducing magnocellular neurosecretory cell sodium channel activity, thereby preventing chronically up-regulated vasopressin secretion), (2) treating pain (by using stimulation to normalize post-injury sodium channel expression and reduce neuronal hyperexcitability), and (3) treating epilepsy (by targeted modulation or block of seizure-initiating sodium channel activity). Development of novel therapeutic approaches will depend on further characterization of the regulatory feedback mechanism that links changes in neuronal activity level with modulation of sodium channel expression.