Altered GABAA and NMDA receptor subunit expression in the Hypothalamic Paraventricular Nucleus: A possible cause of sympathoexcitation?

Physiology 2012 (Edinburgh) (2012) Proc Physiol Soc 27, C66

Oral Communications: Altered GABAA and NMDA receptor subunit expression in the Hypothalamic Paraventricular Nucleus: A possible cause of sympathoexcitation?

S. C. Cork1, P. L. Chazot1, S. Pyner1

1. School of Biological and Biomedical Sciences, University of Durham, Durham, United Kingdom.

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The autonomic nervous system plays an essential role in cardiovascular regulation, and sympathetic overactivation is characteristic of cardiovascular disease, e.g. hypertension1. In pregnancy, sympathoexcitation is vital for normal foetal development2. The hypothalamic paraventricular nucleus (PVN) is an important site for integration of cardiovascular inputs and autonomic regulation3. GABA elicits inhibitory effects within the PVN through the GABAA receptor, whereas glutamate has an excitatory effect through the NMDA receptor3. Under normal conditions, GABAergic inhibition suppresses autonomic outflow from this nucleus. However in hypertension, glutamatergic activity is potentiated, while GABAergic inhibition is attenuated4. This study investigates whether GABAAR and NMDAR subunit alterations in the PVN are associated with hypertension and/or pregnancy. Experiments conformed to the Animals (Scientific Procedures) Act, 1986. Western blot analysis was performed on PVN micropunches from female Wistar (n=3), female spontaneously hypertensive (SHR; 14wk, n=3) and pregnant Wistar rats (E19, n=3). The protein extract was probed with antibodies against the GluN1, -2A or -2B subunits of the NMDAR or the α1, α2, α5, β1, β3 subunits of the GABAAR. Analysis of protein band density was performed using ImageJ. For immunohistochemical analysis, animals were perfuse-fixed with 4% paraformaldehyde and the brain sectioned to 40μm. Sections were then probed for the same receptor subunits as above. The number of cells immunoreactive for each subunit was counted in the PVN. There was a significant increase (P<0.05) in expression of the GluN2A subunit in the SHR compared with normotensive and late-term pregnant rats. Cell counts revealed this increase to be confined to the medial, dorsal cap and posterior parvocellular subnuclei of the PVN. There was a significant reduction in GABAAα1 (P<0.05) expression in the SHR and late-term pregnant rat compared with normotensive controls. A significant reduction in α5 (P<0.001) subunit expression was also observed in the SHR compared to both normotensive and late-term pregnant rats. We have shown that in the SHR there is a significant decrease in GABAAR α1 and α5 subunit expression, and a significant increase in NMDAR GluN2A expression. The increase in GluN2A expression correlates with regions of the PVN known to influence the cardiovascular system. Conversely, late-term pregnancy is associated with a decrease in GABAAR α1 subunit expression only. We propose that altered subunit expression may explain why sympathetic regulation in hypertension and pregnancy differs from that in a “normal” physiological state.



Where applicable, experiments conform with Society ethical requirements.

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