Impact of acute binge-like ethanol exposure during the third-trimester equivalent on subicular interneurons in mice

<i>Background:</i> In animal models, third-trimester-equivalent acute alcohol exposure (TTAAE) leads to cell death in the subiculum, a hippocampal region critical for long-term memory. Proximal and distal regions of the dorsal subiculum have projections that contribute to different aspects of cognitive processing. GABAergic interneurons regulate excitatory pyramidal neurons in the subiculum, but the long-term effects of TTAAE on these interneurons remain unclear. <i>Objective:</i> To test the hypothesis that TTAAE triggers apoptotic pathways in dorsal subiculum interneurons, leading to a persistent reduction in their numbers and alterations in their functional properties during adolescence. <i>Methods:</i> Postnatal day (P) 7 vesicular GABA transporter (VGAT)-Venus mice were injected (2 × 2.5 mg/kg; subcutaneously, 2 hr apart). Cleaved caspase-3 expression was quantified 8 hr after the last injection. Adolescent neuronal and interneuronal densities were quantified using an anti-NeuN marker and Venus fluorescence. Whole-cell patch-clamp recordings were performed from interneurons and pyramidal neurons. <i>Results:</i> TTAAE activated apoptotic pathways in dorsal subicular interneurons in both regions (proximal, <i>p</i> = .005, g = −1.1; distal, <i>p</i> = .003, g = −1.1). Adolescent neuronal density was significantly decreased in exposed males’ distal dorsal subiculum (<i>p</i> &lt; .0001, g = −0.8). Ethanol exposure decreased instantaneous frequency evoked by 250–400 pA current injection in fast-spiking GABAergic interneurons only in female mice (250: <i>p</i> = .019, g = −1.08; 300–450: <i>p</i> = .038, g = −1.06 to- 1.18) but did not significantly affect spontaneous inhibitory postsynaptic currents (sIPSCs) evoked by interneuronal GABA release onto pyramidal neurons. <i>Conclusion:</i> TTAAE activates apoptotic pathways in subicular interneurons, leading to long-term, sex-specific changes, reducing male neuron density and altering female interneuron function. These effects may underlie memory deficits demonstrated in mice with TTAAE.