Group 2 innate lymphoid cells drive inhibitory synapse formation with lasting effects on learning and memory.

The immune system provides multiple layers of protection that extend beyond conventional pathogen defense, including context-dependent modulation of behavior. However, the mechanisms driving these immune-mediated behavioral modifications remain incompletely understood. Here, we demonstrate that group 2 innate lymphoid cells (ILC2s) shape hippocampal synaptic development during early postnatal stages, with lasting effects on adult behavior, learning, and memory.Using flow synaptometry, we identified a selective reduction in hippocampal VGAT GABAergic/glycinergic inhibitory synapse frequency at postnatal day 15 in ILC2-deficient mice, while the proportions of inhibitory GABAergic (NL2) or excitatory glutamatergic (GluR1) synapses remained unaltered. These synaptic changes occurred without detectable phenotypical changes in cortical and hippocampal microglia. In adulthood, ILC2-deficient mice displayed significant impairments in hippocampus-dependent tasks, such as active place avoidance and operant conditioning, reflecting deficits in learning and memory.Our findings reveal a critical role for ILC2s in the formation of inhibitory synapses in the hippocampus, highlighting the impact of immune signaling on neuronal network maturation during a crucial period of brain development. This early immune-mediated modulation may have lasting effects on neuronal circuitry and cognitive functions that persist into adulthood, emphasizing the long-term implications of neuro-immune interactions for normal cognitive development and function.