MICROGLIA GABA<SUB>B1</SUB> SIGNALING LINKS PARVALBUMIN INTERNEURON HYPERACTIVITY TO SYNAPTIC PATHOLOGY IN ALZHEIMER DISEASE

Memory formation depends on synaptic plasticity, which is disruption in Alzheimer’s disease (AD). In AD models GABAergic parvalbumin-positive (PV⁺) interneurons are hyperactive and, through fast phasic peri-somatic inhibition, critically affect theta–gamma oscillations, mediating cognitive dysfunctions. Microglia can sense GABA transmitter via GABA_B1 receptors and interact with peri-somatic PV synaptic terminals complement protein C1q, but whether this mechanism contributes to early circuit pathology in AD remains unknown.
We hypothesized that PV interneuron hyperactivity activates the microglial GABA_B1 receptor, triggering C1q-dependent microglial interactions with PV⁺ peri-somatic terminals. To test this, we examined anatomical, electrophysiological, and molecular changes in the pyramidal layer of the hippocampal CA1 region in App^NL-G-F mice and age-matched controls at asymptomatic (2 and 4 months) and symptomatic (6 months) stages.
We discovered a significant increase in microglial surface expression of the GABA_B1 receptor already at 2 months of age, with a further increase at 6 months in the App^NL-G-F mice. At 2 months, microglial displayed and activated, pro-inflammatory phenotype marked by increased CD68 and C1q levels. Consistent with an early PV hyperexcitability, we observed enhanced spontaneous inhibitory input onto CA1 pyramidal neurons at 2 months, increased peri-somatic PV synaptic density, and elevated microglial engulfment of PV⁺ terminals. Notably, microglial GABA_B1 membrane expression correlated with cytosolic C1q levels, suggesting GABA-dependent activation of complement-mediated synaptic interactions.
Together, these findings identify GABA-sensing microglia as active modulators of inhibitory synapses in the CA1 during early presymptomatic AD and reveal a potential for GABA_B1 receptors as a novel therapeutic target.