Abstract
Glucocorticoids rapidly stimulate endocannabinoid synthesis and modulation of synaptic transmission in hypothalamic neuroendocrine cells via a nongenomic signaling mechanism. The endocannabinoid actions are synapse-constrained by astrocyte restriction of extracellular spatial domains. Exogenous cannabinoids have been shown to modulate postsynaptic potassium currents, including the A-type potassium current (IA), in different cell types. The activity of magnocellular neuroendocrine cells is shaped by a prominent IA. We tested for a rapid glucocorticoid modulation of the postsynaptic IA in magnocellular neuroendocrine cells of the hypothalamic paraventricular nucleus (PVN) using whole-cell recordings in rat brain slices. Application of the synthetic glucocorticoid dexamethasone (Dex) had no rapid effect on the IA amplitude, voltage dependence, or kinetics in magnocellular neurons in slices from untreated rats. In magnocellular neurons from salt-loaded rats, however, Dex application caused a rapid suppression of the IA and a depolarizing shift in IA voltage dependence. Exogenously applied endocannabinoids mimicked the rapid Dex modulation of the IA and CB1 receptor antagonists and agonists blocked and occluded the Dex-induced changes in the IA, respectively, suggesting an endocannabinoid dependence of the rapid glucocorticoid effect. Preincubation of control slices in a gliotoxin resulted in the partial recapitulation of the glucocorticoid-induced rapid suppression of the IA. These findings demonstrate a glucocorticoid suppression of the postsynaptic IA in PVN magnocellular neurons via an autocrine endocannabinoid-dependent mechanism, and suggest a possible role for astrocytes in the control of the autocrine endocannabinoid actions.
Significance Statement Stress causes elevated levels of glucocorticoid hormones and rapid and delayed glucocorticoid feedback effects in the brain. Glucocorticoids regulate synaptic inputs to hypothalamic neuroendocrine cells via a non-genomic release of endocannabinoid. We report a non-genomic glucocorticoid modulation of a postsynaptic A-type potassium current in magnocellular neurons via a novel autocrine endocannabinoid mechanism. The A-current modulation by glucocorticoids occurred in neurons from rats subjected to chronic dehydration via salt loading, but not in neurons from normally hydrated rats. Our findings suggest that chronic dehydration leads to an glucocorticoid-induced endocannabinoid autocrine signaling in magnocellular neuroendocrine cells. The neuroplastic mechanisms for this emergent signaling may be related to neuronal-glial structural plasticity or to changes in rapid postsynaptic glucocorticoid and/or endocannabinoid actions.
Footnotes
Authors report no conflict of interest.
HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS) [NS042081]; HHS | NIH | National Institute of Mental Health (NIMH) [MH066958].
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
Jump to comment: