Magnocellular neuroendocrine cells in the hypothalamus are responsible for the synthesis and release of vasopressin and oxytocin, neurohormones involved in fluid balance, blood pressure regulation, parturition and lactation. Much of the synaptic regulation of these neurons is under the control of the neurotransmitters glutamate, GABA and norepinephrine. Anatomical studies have shown that the magnocellular neurosecretory systems undergo dramatic neuronal-glial and synaptic reorganization under conditions of dehydration, representing a unique model of physiologically linked structural plasticity in the adult brain. This includes extensive retraction of glial processes from around the magnocellular neurons and the formation of new glutamatergic, GABAergic and noradrenergic synapses. We postulate that these structural changes lead to an increase in the glutamate, GABA and noradrenergic synaptic inputs to the magnocellular neurons as well as to a decrease in their transporter-mediated clearance, resulting in an increase in the ambient extracellular levels of these neurotransmitters. We will test this first hypothesis by comparing in untreated and dehydrated rats the levels of glutamatergic and GABAergic synaptic inputs to magnocellular neurons of the supraoptic nucleus, as well as the modulation of these inputs by activation of presynaptic metabotropic receptors by ambient neurotransmitter levels. We posit that changes in the expression of glutamate may be responsible for the induction of the structural plasticity caused by dehydration, as these receptors have been implicated in the formation and stabilization of synaptic contacts associated with structural plasticity in developing and adult brain. We will test this hypothesis by assessing dehydration-induced changes in the expression of specific glutamate receptor subunits, and by altering subunit expression in normal animals through viral delivery of specific receptor subunit genes in vivo. These studies are designed to accomplish two goals: 1) to determine whether the neuronal-glial structural changes induced by dehydration lead to changes in the synaptic innervation and in the excitability of magnocellular neurons, and 2) to determine whether changes in glutamate receptor expression are causal in the induction of the structural changes associated with dehydration. The successful completion of these studies will reveal the physiological significance of anatomical changes observed under conditions of dehydration, and will provide insight into the molecular mechanisms responsible for these changes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS042081-03
Application #
6873063
Study Section
Special Emphasis Panel (ZRG1-IFCN-2 (01))
Program Officer
Coulombe, James N
Project Start
2003-03-01
Project End
2008-02-28
Budget Start
2005-03-01
Budget End
2006-02-28
Support Year
3
Fiscal Year
2005
Total Cost
$305,900
Indirect Cost
Name
Tulane University
Department
Anatomy/Cell Biology
Type
Schools of Arts and Sciences
DUNS #
053785812
City
New Orleans
State
LA
Country
United States
Zip Code
70118
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Qiu, Jing; Hindmarch, Charles C T; Yao, Song T et al. (2011) Transcriptomic analysis of the osmotic and reproductive remodeling of the female rat supraoptic nucleus. Endocrinology 152:3483-91
Popescu, Ion R; Morton, Linda A; Franco, Alier et al. (2010) Synchronized bursts of miniature inhibitory postsynaptic currents. J Physiol 588:939-51
Di, Shi; Tasker, Jeffrey G (2004) Dehydration-induced synaptic plasticity in magnocellular neurons of the hypothalamic supraoptic nucleus. Endocrinology 145:5141-9
Boudaba, Cherif; Linn, David M; Halmos, Katalin Cs et al. (2003) Increased tonic activation of presynaptic metabotropic glutamate receptors in the rat supraoptic nucleus following chronic dehydration. J Physiol 551:815-23