EFFECTS OF EARLY-LIFE INFLAMMATION ON NDNF+ NEURONS IN CORTICAL LAYER 1

Early-life systemic inflammation is a major risk factor for long-lasting alterations in brain development, yet how immune challenges shape specific cortical circuits remains poorly understood. Cortical layer 1 (L1) represents a unique neuroimmune interface: it lies directly beneath the meninges, is exposed to meningeal-derived immune signals, and contains a sparse population of inhibitory interneurons that regulate dendritic integration and cortical plasticity. These features make L1 interneurons particularly well positioned to sense and respond to inflammatory perturbations during development.Here, we investigated how early-life systemic inflammation affects L1 inhibitory neuron populations. Using a mouse model of neonatal inflammation, we combined single-cell RNA sequencing, immunostaining of synaptic markers, electrophysiology, and behavioral assays to assess the molecular, synaptic, and functional consequences.Our transcriptomic data revealed that NDNF+ neurons are sensitive to early inflammatory exposure, showing marked changes in immune-related pathways, such as interferon-associated signaling. These alterations were largely restricted to NDNF+ neurons when the inflammatory insult was mild during development. However, an additional adult insult resulted in broader transcriptional changes across multiple inhibitory neuron classes. At the synaptic level, we observed increased expression of postsynaptic density–related genes and a corresponding increase in excitatory synaptic contacts onto NDNF+ neurons Together, these results describe molecular and synaptic changes in L1 inhibitory neurons following early-life systemic inflammation and support the relevance of considering layer-specific neuroimmune environments when examining how inflammatory challenges intersect with cortical circuit development.