Epigenetic reprogramming of HDAC2 in CA1 excitatory neurons determines Pb-induced non-spatial memory deficits.

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.