Hippocampal Meis2+ Interneurons Remodeling Involved in the Chronic Pb Exposure-Induced Learning and Memory Impairment: Single-Nucleus and Spatial Multiomics Evidence

Lead (Pb), recognized as the second greatest global environmental risk factor, is associated with lifelong and irreversible learning and memory impairments resulting from chronic exposure. However, the underlying mechanisms remain incompletely understood. We integrated single-nucleus transcriptomics, spatial multiomics, neuroelectrophysiological, and morphological techniques to systematically delineate the susceptible neuronal cells and their interaction networks within hippocampal subregions following Pb exposure. The results indicated that Pb exposure led to a significant increase in the proportion of Meis2+ interneurons in the CA1 and CA3 regions of the hippocampus, and dysregulated calcium signaling. This subtype may affect PV+ and SST+ IN subtypes as well as CA3 excitatory neurons via abnormal intercellular NRG and EPHA signaling, contributing to E/I imbalance and impairing learning and memory. Moreover, reduced NRG signaling output from oligodendrocytes and microglia to IN subtypes likely exacerbates the impairment. Our findings highlight Meis2+ interneurons as a core IN subtype that may drive a cascade of “transcriptional changes – calcium signaling dysregulation – impaired neuronal interactions – reduced glial support”, offering potential targets for intervening in environmental Pb neurotoxicity.