The goal of these studies is to determine how Brain derived neurotrophic factor (BDNF) and its receptor TrkB influence vasopressin release to a progressive physiological challenge, water deprivation. Our data suggest that BDNF may facilitate both glutamate and GABA signaling during water deprivation by causing phosphorylation NR2B and increasing the expression of the chloride transporter KCC2. Increased NR2B phosphorylation would increase NMDA receptor activation enhancing vasopressin release while increased KCC2 activity could increase the inhibitory effects of GABA representing a homeostatic synaptic compensation to increased excitation during water deprivation.
Specific Aim 1 : to determine the role of neurohypophysial BDNF-TrkB signaling and enhanced glutamate action through NR2B phosphorylation during sustained vasopressin release induced by water deprivation. Hypothesis: Phosphorylation of TrkB associated with water deprivation leads to enhanced glutamate activity due to phosphorylation of NR2B NMDA receptor subunits through Fyn kinase, a member of the Src kinase family contributing to NMDA mediated plasticity in MNCs Specific Aim 2: to test the hypothesis that neurohypophysial BDNF-TrkB signaling enhances the inhibitory effects of GABA during water deprivation. Hypothesis: BDNF-TrkB signaling during water deprivation increases KCC2 expression enhancing the inhibitory effects of GABA in MNCs via Src kinase and without the activation of Phospholipase C gamma. Methods: These experiments will for the first time define the roles of BDNF-TrkB signaling in the homeostatic regulation of sustained AVP release. An integrative approach will be employed that includes in vitro and in vivo electrophysiological experiments, whole animal experiments in which TrkB and Src kinase antagonists will be locally applied to the SON, and functional studies of water balance and AVP release in the rat. Benefit: These experiments will address an existing gap in our understanding of the physiological regulation of neurohypophyseal function. The findings of these experiments could potentially alter the way that inappropriate vasopressin release is studied and conceptualized clinically.
Inappropriate vasopressin release related to heart failure or liver failure increases the morbidity and mortality of these patients. Hyponatremia related to vasopressin release is the most common electrolyte disorder and in 2006 the cost of treating hyponatremia in the US was estimated to be $1.6-$3.6 billion per year. The long term goal of this research program is to identify neural networks that control the release of vasopressin from the pituitary and contribute to inappropriate vasopressin release. This proposal will test a novel signaling pathway that regulates the activity of vasopressin neurons in health and disease that could result in a new target for treatment of inappropriate vasopressin release that could be addressed by FDA approved pharmaceuticals.
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|Shell, Brent; Faulk, Katelynn; Cunningham, J Thomas (2016) Neural Control of Blood Pressure in Chronic Intermittent Hypoxia. Curr Hypertens Rep 18:19|
|Choe, Katrina Y; Han, Su Y; Gaub, Perrine et al. (2015) High salt intake increases blood pressure via BDNF-mediated downregulation of KCC2 and impaired baroreflex inhibition of vasopressin neurons. Neuron 85:549-60|
|Saxena, Ashwini; Little, Joel T; Nedungadi, T Prashant et al. (2015) Angiotensin II type 1a receptors in subfornical organ contribute towards chronic intermittent hypoxia-associated sustained increase in mean arterial pressure. Am J Physiol Heart Circ Physiol 308:H435-46|
|Walch, Joseph D; Nedungadi, T Prashant; Cunningham, J Thomas (2014) ANG II receptor subtype 1a gene knockdown in the subfornical organ prevents increased drinking behavior in bile duct-ligated rats. Am J Physiol Regul Integr Comp Physiol 307:R597-607|
|Nedungadi, T Prashant; Cunningham, J Thomas (2014) Differential regulation of TRPC4 in the vasopressin magnocellular system by water deprivation and hepatic cirrhosis in the rat. Am J Physiol Regul Integr Comp Physiol 306:R304-14|
|Saxena, Ashwini; Bachelor, Martha; Park, Yong H et al. (2014) Angiotensin II induces membrane trafficking of natively expressed transient receptor potential vanilloid type 4 channels in hypothalamic 4B cells. Am J Physiol Regul Integr Comp Physiol 307:R945-55|
|Cunningham, J Thomas (2013) Editorial Focus: the brain renin-angiotensin system and hypertension. Focus on: hypertension in mice with transgenic activation of the brain renin-angiotensin system is vasopressin dependent. Am J Physiol Regul Integr Comp Physiol 305:R173-4|