Master of Science
Physiology and Pharmacology
Dr. Wataru Inoue
The activation of the hypothalamic-pituitary-adrenal (HPA) axis during inflammation is mediated by prostaglandin E2 (PGE2) produced in the brain. However, how PGE2 recruits neuronal mechanisms for HPA axis activation remains unknown. Accumulating evidence indicates that GABA-mediated inhibitory synaptic transmission plays a major role in the HPA axis regulation. That is, GABAergic transmission constitutively constrains the excitability of parvocellular neuroendocrine cells (PNCs) in the paraventricular nucleus of the hypothalamus (the HPA axis output neurons); the removal from this inhibition (i.e. disinhibition) powerfully activates the HPA axis. My thesis examined the actions of PGE2 on GABAergic synaptic transmission to PNCs. Using patch clamp electrophysiology in hypothalamic slices, I found that PGE2 dose-dependently attenuated GABAergic transmission onto PNCs. The analysis of synaptic property changes revealed that PGE2 decreased the release of GABA from the presynaptic terminals whereas it had little, if any, effects on the postsynaptic ionotropic GABA receptors. By using pharmacological approaches, I also identified that the EP3 subtype of the PGE2 receptor mediated the actions of PGE2 on GABA synapses. Finally, because psychological stress is known to influence inflammation-induced HPA axis activation, I examined the effects of psychological stress on PGE2-induced GABA synapse plasticity. I found that restraint stress impaired PGE2-induced suppression of GABA release. Interestingly, however, this modulation by psychological stress was independent of EP3. In summary, my thesis provides a plausible mechanism for how PGE2 activates the HPA axis during inflammation, and a potential mechanism for its modulation by psychological stress.
Khazaeipool, Zahra, "Synaptic Mechanisms for the Hypothalamic-Pituitary-Adrenal Axis Activation by Prostaglandin E2" (2017). Electronic Thesis and Dissertation Repository. 4506.
Available for download on Friday, April 26, 2019