There is robust evidence that environmental risk factors impact cognitive performance. However, the effect of the environmental risk factor lead (Pb) on susceptibility to non-spatial memory deficits is unknown. Here, it is demonstrated that Pb exposure increases the susceptibility to these deficits, with the impairment of CA1 excitatory neurons as the underlying cause. Furthermore, Pb exposure increased HDAC2 levels in CA1 excitatory neurons, a crucial epigenetic factor for reprogramming synaptic plasticity and memory formation. These non-spatial memory deficit effects could be rescued via Hdac2-cKO in CA1 excitatory neurons. Additionally, Hdac2-cKO reversed reductions in miniature excitatory postsynaptic currents (mEPSC), Ca²⁺ signaling, and spine density caused by Pb in CA1 excitatory neurons. In terms of the mechanistic insight, Hdac2-cKO reversed the downregulation of TRPC6, LRP2, VGLUT1, NMDAR1, NMDAR2B, AMPAR2, and PSD95 in CA1 excitatory neurons. In conclusion, Pb induces non-spatial memory deficits and synaptic plasticity impairments by increasing HDAC2 epigenetic reprogramming in hippocampal CA1 excitatory neurons, providing a new reference for the prevention and treatment of memory deficits induced by environmental cues.

中文翻译：

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CA1 兴奋性神经元中 HDAC2 的表观遗传重编程决定了 Pb 诱导的非空间记忆缺陷

有强有力的证据表明，环境风险因素会影响认知能力。然而，环境风险因素铅 （Pb） 对非空间记忆缺陷易感性的影响尚不清楚。在这里，证明 Pb 暴露增加了对这些缺陷的易感性，其中 CA1 兴奋性神经元的损害是根本原因。此外，Pb 暴露增加了 CA1 兴奋性神经元中的 HDAC2 水平，这是重编程突触可塑性和记忆形成的关键表观遗传因子。这些非空间记忆缺陷效应可以通过 CA1 兴奋性神经元中的 Hdac2-cKO 来挽救。此外，Hdac2-cKO 逆转了 CA1 兴奋性神经元中由 Pb 引起的微型兴奋性突触后电流 （mEPSC） 、 Ca ²⁺ 信号传导和脊柱密度的减少。在机制洞察方面，Hdac2-cKO 逆转了 CA1 兴奋性神经元中 TRPC6 、 LRP2 、 VGLUT1 、 NMDAR1 、 NMDAR2B 、 AMPAR2 和 PSD95 的下调。综上所述，Pb 通过增加海马 CA1 兴奋性神经元的 HDAC2 表观遗传重编程诱导非空间记忆缺陷和突触可塑性损伤，为预防和治疗环境线索诱导的记忆缺陷提供了新的参考。