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Mirtazapine, among other antidepressants, is commonly used to treat prenatal depression. Even though mirtazapine is generally considered safe for pregnant women, its effect on the offspring brain have not been sufficiently investigated. The present study aimed to examine the effects of chronic unpredictable stress (CUS) in pregestational rats, perinatal mirtazapine treatment, and their combination, on offspring behavior and brain function. We assessed offspring anxiety levels during the elevated plus maze (EPM) test, the expression of pro-neuroplastic proteins in the offspring brain, the excitability of brainstem monoamine and hippocampal glutamate neurons, and the expression and activity of ryanodine receptors (RyR2). Surprisingly, maternal pregestational stress induced an anxiolytic-like effect in the offspring. This anxiolytic effect was associated with an increased excitability of serotonin (5-HT) neurons and detected in the offspring of the vehicle-, but not mirtazapine-treated dams. Perinatal mirtazapine, however, elevated expression of the brain-derived neurotrophic factor (BDNF); this effect was detected in the female offspring of the stressed dams. Regarding the offspring glutamate and dopamine neurons, the combination of maternal stress and mirtazapine inhibited their burst firing, potentially, due to decreased expression of the glutamate receptors. Even though calcium signaling is important for the burst firing of the neurons, the effects of maternal stress and mirtazapine on the burst activity of the offspring glutamate and dopamine might not be mediated via mechanism(s) involving the RyR2. Summarizing, mirtazapine may diminish the negative influence of maternal stress and depression on the offspring brain, via mechanism(s) putatively involving 5-HT neurotransmission and BDNF.<\/jats:p>","DOI":"10.1038\/s41380-025-03161-3","type":"journal-article","created":{"date-parts":[[2025,8,25]],"date-time":"2025-08-25T13:18:19Z","timestamp":1756127899000},"page":"726-738","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Effects of pre-gestational exposure to the stressors and perinatal mirtazapine administration on the excitability of hippocampal glutamate and brainstem monoaminergic neurons, hippocampal neuroplasticity, and anxiety-like behavior in rats"],"prefix":"10.1038","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-6647-2368","authenticated-orcid":false,"given":"Ruslan","family":"Paliokha","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9061-1099","authenticated-orcid":false,"given":"Mireia","family":"Vi\u00f1as-Noguera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1830-2837","authenticated-orcid":false,"given":"Stanislava","family":"Bukatov\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0950-0170","authenticated-orcid":false,"given":"Daniil","family":"Grinchii","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9540-7169","authenticated-orcid":false,"given":"Jana","family":"Gaburj\u00e1kov\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9300-0688","authenticated-orcid":false,"given":"Marta","family":"Gaburj\u00e1kov\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hande","family":"\u00d6zba\u015fak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1382-3897","authenticated-orcid":false,"given":"Roman","family":"Dekhtiarenko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5434-9775","authenticated-orcid":false,"given":"Talah","family":"Khoury","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9207-0978","authenticated-orcid":false,"given":"\u013dubica","family":"Lacinov\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8103-8577","authenticated-orcid":false,"given":"Eliyahu","family":"Dremencov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5631-918X","authenticated-orcid":false,"given":"Michal","family":"Dubovick\u00fd","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,8,25]]},"reference":[{"key":"3161_CR1","doi-asserted-by":"publisher","first-page":"2008","DOI":"10.1007\/s12031-020-01754-x","volume":"71","author":"T Rana","year":"2021","unstructured":"Rana T, Behl T, Sehgal A, Srivastava P, Bungau S. 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