关键词: 产前酒精暴露, GABA能神经元, 海马, 突触发育, 胎儿酒精谱系障碍

Abstract: Objective To investigate the effects of prenatal alcohol exposure(PAE)on hippocampal GABAergic interneurons in mice. Methods Pregnant C57BL/6 mice were randomly assigned to a pair-fed control(PF-Cont)group or a PAE group.The PAE group received intragastric administration of 4.5 g/kg alcohol from gestational day(GD)5 to 10 and 6.0 g/kg alcohol from GD11 to GD20,while the PF-Cont group received isocaloric maltodextrin solution.On postnatal day(PND)10,spontaneous inhibitory postsynaptic currents(sIPSC)were recorded in hippocampal GABAergic neurons of offspring using the whole-cell patch-clamp technique.Dendritic morphology in hippocampal CA1,CA2/3,and dentate gyrus(DG)regions was quantified via Golgi-Cox staining combined with Sholl analysis.Magnetic resonance imaging(MRI)was performed on male offspring at 72-89 days of age to assess brain morphology.Immunofluorescence staining and stereological methods were used to analyze the density of GABAergic neurons(PV⁺,CR⁺)and total neurons(NeuN⁺)in the hippocampus of male offspring at PND10. Results Male PAE offspring exhibited a significantly higher sIPSC frequency in hippocampal GABAergic neurons than the PF-Cont group(P<0.05).Application of 44 mmol/L alcohol further increased sIPSC frequency in the PAE group(P<0.01),whereas 88 mmol/L alcohol significantly suppressed it(P<0.01).Sholl analysis revealed significantly increased dendritic intersections in PAE male offspring at specific distances from the soma:CA1(10-50 μm),CA2/3(50-140 μm),and DG(100-140 μm)(all P<0.01).Total dendritic length(increased by 31.5% in CA1,38.17% in CA2/3,and 33.2% in DG)and the number of primary dendrites were also significantly elevated(all P<0.05).Adult male PAE offspring showed significantly reduced body weight[(19.64±0.43)vs.(21.32±0.51)g],brain volume[(0.42±0.01)vs.(0.47±0.01)cm³],surface area[(74.81±2.05)vs.(83.05±2.03)mm²],and cortical thickness[(869.54±8.02)vs.(900.32±10.13)μm]compared with the PF-Cont group(all P<0.05).The three-dimensional density of PV⁺ and CR⁺ GABAergic neurons,as well as NeuN⁺ total neurons,was significantly decreased(all P<0.05). Conclusion PAE induces specific impairments of hippocampal GABAergic interneurons in mice,manifesting as aberrant presynaptic excitability(in an alcohol dose-dependent manner),increased dendritic complexity in male offspring,and delayed brain structural development accompanied by reduced density of GABAergic neurons in adulthood.These impairments may constitute a key neurobiological basis for cognitive and behavioral deficits in fetal alcohol spectrum disorders.

Key words: prenatal alcohol exposure, GABAergic neurons, hippocampus, synaptic development, fetal alcohol spectrum disorders