CSF1R inhibition exacerbates gamma oscillation disruption and induces network hyperexcitability in APP/PS1 mice.

Alzheimer's Disease is the most common neurodegenerative disease worldwide, but significant gaps in pathophysiological understanding have hampered development of disease-modifying therapies. In Alzheimer's disease, neurophysiological function is impaired, with gamma frequency oscillations - thought to be essential for higher-order cognitive processes - disrupted in both patients and animal models. However, the mechanisms driving these disruptions are unclear and, in particular, the role of neuroinflammation in these changes is poorly understood. In this study, we investigated neuronal network dynamics in acute brain slices from APP/PS1 transgenic mice. Gamma frequency oscillations had significantly reduced amplitude in APP/PS1 brain slices at 9-11 months, accompanied by an increase in beta frequency power and heightened epileptiform activity. This is suggestive of a slowing in neuronal oscillations, considered a neurophysiological hallmark of Alzheimer's disease. Immunohistochemical analysis revealed a reduction in parvalbumin- and somatostatin-positive inhibitory interneuron populations. Treatment with gabazine demonstrated increased network sensitivity to GABAA receptor antagonism, further indicating compromised inhibitory control in APP/PS1. As these altered oscillatory dynamics correlated with microglial reactivity, we hypothesised a causal role for microglia. Administration of the CSF1R inhibitor GW2580 reduced microglial proliferation, attenuated development of the disease-associated microglial phenotype and partially rescued synaptic loss; but, had no significant impact on amyloid plaque burden or cognitive deficits. Unexpectedly, GW2580 treatment exacerbated neuronal network hyperactivity and the incidence and complexity of epileptiform activity. Microglia in GW2580-treated mice showed reduced CD68 expression and decreased engulfment of synaptic elements, potentially facilitating the persistence of hyperexcitable synapses. These findings support a role of microglia in regulating neuronal network homeostasis and caution against indiscriminate suppression of microglial activity in Alzheimer's disease. Therapeutic strategies targeting microglia must account for their homeostatic functions to avoid adverse effects on neuronal network stability.