The Microglial Trem2 R47H Alzheimer’s Disease Risk Variant Impairs Early Hippocampal Synaptic Remodeling

Summary The rare R47H variant of the microglial TREM2 gene increases Alzheimer’s disease (AD) risk, but its effects on early hippocampal circuitry remain unclear. We examined basal synaptic transmission and synaptic density in 3-week-old Trem2 R47H knockin mice using in vitro whole-cell patch clamp recordings and immunohistochemistry. R47H mice displayed increased synaptic density in CA1 and CA3 regions, consistent with a trend towards increased spontaneous excitatory current frequency. Evoked synaptic currents, miniature EPSCs and spontaneous inhibitory current frequency were unaltered. Microglia shape synaptic circuits in early development by removing inactive synapses. Thus, inhibition of this role due to the Trem2 R47H mutation decreases the microglial reshaping of hippocampal connectivity during early postnatal development, without overtly altering basal synaptic activity. With ongoing synaptic plasticity, such early structural changes may predispose neural circuits to later dysfunction, particularly in the context of AD pathology, highlighting the importance of microglial TREM2 in developmental synaptic refinement.