Chronic GIRK2 disruption in the weaver mouse selectively alters hippocampal excitability without affecting sharp wave-ripple dynamics.

Abstract

Sharp wave-ripple complexes (SWRs) are intrinsic hippocampal network patterns fundamentally involved in memory processing and are sensitive to changes in excitation-inhibition balance. G protein-gated inwardly rectifying potassium (GIRK) channels regulate neuronal excitability, but their role in shaping SWR dynamics at the network level remains incompletely understood. The weaver mutation (Kcnj6^wv/wv) disrupts the GIRK2 channel's function and provides a model of chronic GIRK alteration. Here, we examined how the weaver mutation affects SWR dynamics along the dorsoventral hippocampal axis and whether these effects resemble those of acute GIRK blockade. Extracellular local field potentials and multiunit activity (MUA) were recorded from dorsal and ventral hippocampal slices of wild-type (WT) and weaver mice. SWR incidence, amplitude, ripple properties, and SWR-associated firing were quantified. The effects of the GIRK blocker tertiapin-Q were also assessed. SWR occurrence was strongly determined by dorsoventral location, with higher event rates in the ventral hippocampus, and was not affected by genotype. Similarly, SWR amplitude was region-dependent and preserved in weaver mice. Ripple oscillation properties were largely preserved, with no consistent genotype-dependent differences. In contrast, baseline neuronal activity (MUA-Base) was significantly increased in weaver mice, indicating enhanced intrinsic excitability, whereas SWR-associated firing (MUA-SWR) showed a tendency toward reduction. Acute GIRK blockade with tertiapin-Q did not significantly alter SWR parameters in either genotype, nor did it interact with genotype effects. Together, these findings indicate that chronic GIRK disruption produces selective alterations in the hippocampal network's function that are not mimicked by acute pharmacological inhibition of these channels. While the basic features of SWR generation are preserved, increased baseline excitability and altered neuronal recruitment suggest circuit-level adaptations that reshape hippocampal dynamics beyond direct GIRK channel effects.