Microglial Presenilin-1 modulates neuronal function and memory-associated behaviors

Microglial cells, the macrophages of the brain parenchyma, are increasingly recognized to play a key role in synaptic plasticity and function. Presenilin 1 (PS1) is an essential protein involved in learning and memory; the loss of neuronal Presenilin function causes cognitive deficits and impaired synapse plasticity in mice. Here we show memory enhancement in male mice lacking PS1 in microglia (PS1 ΔMG ). Leveraging high-throughput RNA sequencing with single-cell deconvolution-analysis, we estimate that PS1 ΔMG increases Cd52-lo microglial population, a proliferative group enriched in AP-1 responsive genes; and increases chemokines Ccl7 and Ccl8 . In silico prediction of binding partners showed that microglial CCL7 may act via inhibition of neuronal CCR5, a receptor known to negatively regulate learning and memory. By profiling active neuronal populations via PhosphoTRAP the data showed a non-autonomous cell effect of microglial PS1 by modulating genes involved in neuronal excitability and synaptic plasticity . Ex vivo electrophysiology and in vivo calcium imaging in freely behaving mice confirm these effects with functional changes in CA1 hippocampus as seen by increased NMDA/AMPA ratios and increased amplitude of neuronal Ca2+ transients in freely behaving animals, respectively. Remarkably, PS1 ΔMG mice exhibited increased memory retention in contextual fear conditioning and novel object recognition. Together, these data suggest a novel mechanism where microglial PS1 negatively regulates neuronal activity through modulation of NMDAR and memory-associated behaviors. Significance Statement Microglia are increasingly recognized as active regulators of neuronal function, yet the molecular mechanisms that constrain their influence on synaptic activity remain incompletely defined. This study identifies microglial Presenilin-1 (PS1) as a key regulator of neuron-microglia signaling that shapes synaptic transmission and learning. We show that loss of microglial PS1 shifts microglia toward a transcriptional and signaling state that enhances NMDA receptor-dependent synaptic activity and improves memory, demonstrating that microglial molecular programs can directly modulate neuronal excitability. These findings establish microglial PS1 as a physiological brake on circuit plasticity and reveal that altering microglial signaling alone is sufficient to influence cognition. Targeting microglial regulatory pathways may therefore provide new strategies to enhance synaptic resilience and cognitive function in brain disorders.