Alzheimer risk-increasing TREM2 variant causes aberrant cortical synapse density and promotes network hyperexcitability in mouse models.

The R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2) increases the risk of Alzheimer's disease (AD). To investigate potential mechanisms, we analyzed knockin mice expressing human TREM2 -R47H from one mutant mouse Trem2 allele. TREM2 -R47H mice showed increased seizure activity in response to an acute excitotoxin challenge, compared to wildtype controls or knockin mice expressing the common variant of human TREM2. TREM2 -R47H also increased spontaneous thalamocortical epileptiform activity in App knockin mice expressing amyloid precursor proteins bearing autosomal dominant AD mutations and a humanized amyloid-β sequence. In mice with or without such App modifications, TREM2 -R47H increased the density of putative synapses in cortical regions without amyloid plaques. TREM2 -R47H did not affect synaptic density in hippocampal regions with or without plaques. We conclude that TREM2-R47H increases AD-related network hyperexcitability and that it may do so, at least in part, by causing an imbalance in synaptic densities across brain regions. • R47H-variant TREM2 exacerbates epileptiform activity after excitotoxin challenge. • TREM2-R47H exacerbates spike-and-wave discharges in App FAD knockin mice. • TREM2-R47H increases synaptic density in the cortex. • Aberrant synaptic connectivity may promote neural network dysfunctions. [ABSTRACT FROM AUTHOR]