Mutations in the Presenilin genes are the major genetic cause of Alzheimer's disease (AD). Presenilin (PS) is highly expressed in the hippocampus, which is particularly vulnerable in AD. Previous studies of PS function in the hippocampus, however, focused exclusively on excitatory neurons. Whether PS regulates inhibitory neuronal function remained unknown. In the current study, we investigate PS function in GABAergic neurons by performing whole-cell and field-potential electrophysiological recordings using acute hippocampal slices from inhibitory neuron-specific PS conditional double knockout (IN-PS cDKO) mice at 2 months of age, before the onset of age-dependent loss of interneurons. We found that the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) is reduced in hippocampal CA1 neurons of IN-PS cDKO mice, whereas the amplitude of sIPSCs is normal. Moreover, the efficacy of inhibitory neurotransmission as assessed with synaptic input/output relations for evoked mono- and di-synaptic IPSCs is markedly lowered in hippocampal CA1 neurons of IN-PS cDKO mice. Consistent with these findings, IN-PS cDKO mice display enhanced paired-pulse facilitation, frequency facilitation and long-term potentiation in the Schaffer collateral-CA1 pathway. Interestingly, depletion of intracellular Ca2+ stores by inhibition of sarcoendoplasmic reticulum Ca2+ ATPase results in a reduction of IPSC amplitude in control hippocampal neurons but not in IN-PS cDKO neurons, suggesting that impaired intracellular calcium homeostasis in the absence of PS may contribute to the deficiencies in inhibitory neurotransmission. Furthermore, the amplitude of IPSCs induced by short trains of presynaptic stimulation and paired-pulse ratio are decreased in IN-PS cDKO mice. These findings show that inactivation of PS in interneurons results in decreased GABAergic responses and enhanced synaptic plasticity in the hippocampus, providing additional evidence for the importance of PS in the regulation of synaptic plasticity and calcium homeostasis.

中文翻译：

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抑制性神经元中早老素的失活导致 GABA 反应降低并增强突触可塑性


早老素基因突变是阿尔茨海默病 (AD) 的主要遗传原因。早老素 (PS) 在海马体中高度表达，海马体在 AD 中尤其脆弱。然而，之前对海马 PS 功能的研究仅集中于兴奋性神经元。 PS 是否调节抑制性神经元功能仍不清楚。在当前的研究中，我们通过使用 2 个月龄抑制性神经元特异性 PS 条件双敲除 (IN-PS cDKO) 小鼠的急性海马切片进行全细胞和场电位电生理记录，研究 GABA 能神经元的 PS 功能。年龄依赖性中间神经元损失的开始。我们发现 IN-PS cDKO 小鼠海马 CA1 神经元自发抑制性突触后电流 (sIPSC) 的频率降低，而 sIPSC 的幅度正常。此外，通过诱发单突触和双突触 IPSC 的突触输入/输出关系评估的抑制性神经传递功效在 IN-PS cDKO 小鼠的海马 CA1 神经元中显着降低。与这些发现一致的是，IN-PS cDKO 小鼠在 Schaffer 侧支 CA1 通路中表现出增强的配对脉冲促进、频率促进和长期增强。有趣的是，通过抑制肌内质网 Ca2+ ATPase 来消耗细胞内 Ca2+ 储备，会导致对照海马神经元中的 IPSC 振幅降低，但 IN-PS cDKO 神经元中不会降低，这表明在缺乏 PS 的情况下，细胞内钙稳态受损可能会导致这些缺陷。在抑制性神经传递中。此外，在 IN-PS cDKO 小鼠中，短序列突触前刺激和配对脉冲比诱导的 IPSC 振幅降低。 这些发现表明，中间神经元中PS的失活会导致海马中GABA能反应的减少和突触可塑性的增强，这为PS在突触可塑性和钙稳态调节中的重要性提供了额外的证据。