Prenatal betamethasone exposure increases corticotropin-releasing hormone expression along with increased hippocampal slice excitability in the developing hippocampus.

Melissa J Benson, Marcela Lauková, Karin Borges, Jana Velíšková, Libor Velíšek

Epilepsy research 2020 Feb

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The objective of this study was to determine whether prenatal exposure to betamethasone alters hippocampal expression of corticotropin-releasing hormone (CRH) and resultant hippocampal circuit excitability. Real time (RT)-PCR and western blots were used to determine CRH mRNA and protein expression levels, respectively, in hippocampal extracts of two-week old rat pups prenatally primed with betamethasone or saline on gestational day 15. The data were compared to changes in epileptiform activity induced by kainic acid (KA) or depletion of [Mg2+]0 in combined hippocampus-entorhinal cortex slices. RT-PCR analysis showed 3-fold increased levels of CRH mRNA in hippocampal extracts from prenatally betamethasone-primed pups compared to saline controls (p < 0.05), but no changes in mRNA expression of CRH receptors (1 and 2). Changes in CRH protein isoform ratio in hippocampal extracts suggest 30 % increase in mature CRH levels in betamethasone-primed hippocampi (p < 0.05). No changes in mRNA expression in CRH feedback loop associated genes, GR and FKBP51, were found. Compared to saline-exposed pups, slices from betamethasone-primed pups had faster onset of epileptiform-like activity (inter-ictal discharges and seizure-like-events) after bath application of 4 μM KA (p < 0.05) suggesting a "more hyperexcitable" state. The epileptiform-like activity after KA application was significantly reduced following bath application of a CRH R2 antagonist (p < 0.05) but CRH R1 antagonist had no effect (p > 0.05). Also in the low-Mg2+-induced epileptiform activity, there was increased excitability, in the form of enhanced inter-ictal discharges, in slices from betamethasone primed compared to saline exposed rat pups (p < 0.05). Our study suggests a possible mechanistic link to prenatal betamethasone priming-induced increase in postnatal hippocampal excitability that involves enhanced expression of CRH acting at CRH R2. This is important in regards to the links between prenatal stress/corticosteroid-exposure and syndromes, such as epilepsy, autism spectrum disorders and other psychiatric disorders associated with neuronal hyperexcitability. Copyright © 2020 Elsevier B.V. All rights reserved.

Citation

Melissa J Benson, Marcela Lauková, Karin Borges, Jana Velíšková, Libor Velíšek. Prenatal betamethasone exposure increases corticotropin-releasing hormone expression along with increased hippocampal slice excitability in the developing hippocampus. Epilepsy research. 2020 Feb;160:106276