Aberrant neurogenesis and late onset suppression of synaptic plasticity as well as sustained neuroinflammation in the hippocampal dentate gyrus after developmental exposure to ethanol in rats

• Published in: Toxicology (Amsterdam) 2021-10, Vol.462, p.152958-152958, Article 152958
• Main Authors: Takahashi, Yasunori, Yamashita, Risako, Okano, Hiromu, Takashima, Kazumi, Ogawa, Bunichiro, Ojiro, Ryota, Tang, Qian, Ozawa, Shunsuke, Woo, Gye-Hyeong, Yoshida, Toshinori, Shibutani, Makoto
• Format: Article
• Language: English
• Subjects: Animals; Cell Proliferation - drug effects; Dentate Gyrus - drug effects; Dentate Gyrus - pathology; Developmental neurotoxicity; Ethanol (EtOH); Ethanol - toxicity; Female; Hippocampal neurogenesis; Hippocampus - drug effects; Hippocampus - pathology; Interneurons - drug effects; Male; Maternal Exposure - adverse effects; Neurogenesis - drug effects; Neuroinflammation; Neuroinflammatory Diseases - etiology; Neuroinflammatory Diseases - pathology; Neuronal Plasticity - drug effects; Pregnancy; Prenatal Exposure Delayed Effects - physiopathology; Rat; Rats; Rats, Sprague-Dawley; Synaptic plasticity
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/j.tox.2021.152958

•Developmental EtOH exposure disrupted hippocampal neurogenesis at weaning in rats.•Type-3 NPCs were decreased because of altered external neurotransmitter inputs.•Enhanced SGZ cell proliferation increased type-2a NPCs as a compensatory response.•Synaptic plasticity of newborn granule cells was suppressed as a late effect.•Induction of neuroinflammation affects both neurogenesis and synaptic plasticity. Drinking alcohol during pregnancy may cause fetal alcohol spectrum disorder. The present study investigated the effects of maternal oral ethanol (EtOH) exposure (0, 10, or 12.5 % in drinking water) from gestational day 6 until day 21 post-delivery (weaning) on postnatal hippocampal neurogenesis at weaning and in adulthood on postnatal day 77 in rat offspring. At weaning, type-3 neural progenitor cells (NPCs) were decreased in the subgranular zone (SGZ), accompanied by Chrnb2 downregulation and Grin2b upregulation in the dentate gyrus (DG). These results suggested suppression of CHRNB2-mediated cholinergic signaling in γ-aminobutyric acid (GABA)ergic interneurons in the DG hilus and increased glutamatergic signaling through the NR2B subtype of N-methyl-d-aspartate (NMDA) receptors, resulting in NPC reduction. In contrast, upregulation of Chrna7 may increase CHRNA7-mediated cholinergic signaling in immature granule cells, and upregulation of Ntrk2 may cause an increase in somatostatin-immunoreactive (+) GABAergic interneurons, suggesting a compensatory response against NPC reduction. Promotion of SGZ cell proliferation increased type-2a NPCs. Moreover, an increase in calbindin-d-29 K+ interneurons and upregulation of Reln, Drd2, Tgfb2, Il18, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor subunit genes might participate in this compensatory response. In adulthood, reduction of FOS+ cells and downregulation of Fos and Arc suggested suppression of granule cell synaptic plasticity, reflecting upregulation of Tnf and downregulation of Cntf, Ntrk2, and AMPA-type glutamate receptor genes. In the DG hilus, gliosis and hyper-ramified microglia, accompanying upregulation of C3, appeared at weaning, suggesting contribution to suppressed synaptic plasticity in adulthood. M1 microglia increased throughout adulthood, suggesting sustained neuroinflammation. These results indicate that maternal EtOH exposure temporarily disrupts hippocampal neurogenesis and later suppresses synaptic plasticity. Induction of neuroinflammation might ini