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bioRxiv · 10.1101/2025.08.22.671714

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

Aljawder, A.·Cummings, D. M.·Wood, J.·Edwards, F. A.
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Abstract

The rare R47H variant of the microglial TREM2 gene increases Alzheimers disease (AD) risk, but its effects on early hippocampal circuitry remain unclear. Trem2 has been reported to be important for microglial-dependent refinement of excitatory synaptic circuits in development. We hypothesized that loss of TREM2 function might result in changes in circuitry due to reduced microglial ability to prune inactive synapses and that this could predispose individuals to later disease. We compared basal synaptic transmission and synaptic density in 3-week-old WT and homozygous Trem2 R47H knockin mice, using in vitro patch clamp recordings and Bassoon-Homer1 immunohistochemistry. Basal synaptic activity, miniature excitatory events, and evoked release probability were unchanged. Synapse density in CA1 and CA3 showed substantial between-mouse variability but no evidence of genotype or regional differences. This variable CA1 synapse density was positively correlated with CA1 miniature excitatory event frequency. Although between-mouse variability in synaptic density could mask subtle changes, these data indicate that early effects of Trem2 R47H in these mice are not sufficient to produce a consistent change in early postnatal hippocampal excitatory synapse density or basal synaptic transmission under these conditions. This supports the view that TREM2-linked AD risk may act primarily through context-dependent mechanisms that become relevant with ageing, neuroinflammatory challenge, or AD pathology.

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Aljawder, A., Cummings, D. M., Wood, J., Edwards, F. A.. 2025-08-22. The Microglial Trem2 R47H Alzheimer's Disease Risk Variant Impairs Early Hippocampal Synaptic Remodeling. https://doi.org/10.1101/2025.08.22.671714

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