PYRUVATE–INSULIN CO-TREATMENT AFFECTS CA3 GAMMA OSCILLATIONS AND INTERNEURON SYNCHRONY IN YOUNG <EM>APP</EM><SUP>NL-G-F </SUP>MICE

Alzheimer’s disease involves not just amyloid-β (Aβ) and tau pathology but also early disruptions in neuronal network synchronization.
Among the earliest functional deficits observed are impairments in gamma oscillations, crucial rhythmic activities for cognitive functions such as memory encoding and attention. Recent evidence has identified a striking early impairment in spike-gamma coupling of fast-spiking interneurons (FSIs) within the CA3 region of the hippocampus in the App^NL-G-F knock-in mouse model. This desynchronization of FSIs, especially those expressing parvalbumin, occurs as early as 2.5 months of age, before plaque deposition.
We asked whether a combined metabolic intervention, such as pyruvate and insulin supplementation, could rescue this early synchrony deficit. Insulin is known to modulate GABAergic signaling and prevents the development of age-dependent cognitive deficits. However, their combined effect on restoring
gamma synchrony remains unexplored.
Acute hippocampal slices from 2.5-month-old App^NL-G-F and wild-type mice were incubated with insulin and sodium pyruvate. CA3 local field potentials were recorded to quantify gamma power. FSIs were patched with an ATP/GTP-modified internal solution to test metabolic rescue of interneuron function and spike–gamma phase coupling. To connect functional rescue with metabolic signaling, the slices were prepared for anti-monocarboxylate transporter 2 (MCT2) and anti-glucose transporter 3 (GLUT3) immunofluorescence.
Our results show that co-application of insulin and pyruvate affects CA3 gamma power and the FSI spike–gamma coupling in the App^NL-G-F. These data support a mechanism by which insulin signalling and enhanced oxidative substrate availability stabilize interneuron-driven gamma rhythms, complementing emerging gamma-based approaches for very early AD stages.