Thesis Format

Integrated Article

Psychological stress modulates synaptic mechanisms for prostaglandin E2-mediated HPA axis activation

Author

Meagan Wiederman, The University of Western OntarioFollow

Degree

Master of Science

Program

Neuroscience

Supervisor

Inoue, Wataru

Abstract

Immune-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis elevates glucocorticoids, anti-inflammatory hormones, promoting the effective resolution of inflammation. Psychological stress can modulate this anti-inflammatory mechanism, but the mechanisms underlying this modulation remain largely unknown. The immune-induced HPA axis activation is, in large part, mediated by prostaglandin E₂ (PGE₂), an inflammatory mediator. In the brain, PGE₂ attenuates GABAergic synaptic transmission onto corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN) that act as the apex of the HPA axis. The removal of GABA-mediated inhibition (i.e. disinhibition) excites CRH neurons and, consequently, activates the HPA axis. Here, we examined the modulatory effects of psychological stress on this PGE₂-mediated synaptic mechanism for HPA axis activation. To this end, we used whole-cell patch clamp electrophysiology to record GABAergic synaptic transmission onto PVN-CRH neurons as changes in the amplitude of evoked inhibitory post-synaptic current (eIPSCs). We contrasted findings in acute brain slices from mice that have been stressed by restraint (psychological stress) with those of naïve (non-stressed) mice. We first confirmed that, in slices from naïve mice, PGE₂ potently depressed GABAergic synaptic transmission to PVN-CRH neurons. On the other hand, in slices from stressed mice, PGE₂ had heterogeneous effects, potentiating some synapses in addition to depressing others. Using receptor subtype-specific agonists and antagonists, we showed that the EP₃ subtype of the PGE₂ receptor mediated the synaptic depression by inhibiting the release of GABA from the pre-synaptic terminals in naïve slices. On the other hand, the EP₂ and EP₄ receptors mediated the potentiation of GABA release from the pre-synaptic terminals. Acute stress did not alter these mechanisms for bidirectional synaptic plasticity. By contrast, a blockade of EP₁ receptor mimicked the effects of stress, shifting the balance of depression and potentiation toward potentiation. We conclude that EP₁ receptor suppresses EP₂ and EP₄-mediated pre-synaptic potentiation (thus making EP₃-mediated depression dominant) and that psychological stress blocks this EP₁-mediated mechanism. We propose that psychological stress modulates the interplay between different subtypes of EP receptors to ultimately contribute to altering the immune-induced activation of the HPA axis.

Recommended Citation

Wiederman, Meagan, "Psychological stress modulates synaptic mechanisms for prostaglandin E2-mediated HPA axis activation" (2019). Electronic Thesis and Dissertation Repository. 6235.
https://ir.lib.uwo.ca/etd/6235

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This work is licensed under a Creative Commons Attribution 4.0 License.