Basal G-protein-gated inwardly rectifying potassium (Kir3/GirK) channels activity governs synaptic plasticity that supports dorsal hippocampus-dependent cognitive functions

G-protein-gated inwardly rectifying potassium (Kir3/GirK) channel is the effector of many G-protein-coupled receptors. Its dysfunction has been linked to the pathophysiology of Down syndrome, Alzheimer and Parkinson diseases, psychiatric disorders, epilepsy, drug addiction, or alcoholism. GirK channels are constitutively activated in the dorsal hippocampus contributing to resting membrane potential, and their synaptic activation compensates any excitation excess. Here, in order to elucidate the role of GirK channels activity in the maintenance of dorsal hippocampus-dependent cognitive functions, their involvement in controlling neuronal excitability at different levels of complexity was examined. For that purpose, basal GirK activity was pharmacologically modulated by two specific drugs: ML297, a GirK channel opener, and Tertiapin-Q, a GirK channel blocker. Ex vivo, using dorsal hippocampal slices, we studied pharmacological GirK modulation effect on synaptic plasticity processes induced in CA1 by Schaffer collateral stimulation. In vivo, we performed acute intracerebroventricular injections of both GirK modulators to study their contribution to CA3-CA1 synapse electrophysiological properties, synaptic plasticity, and learning and memory capabilities during hippocampal dependent tasks. We found that pharmacological disruption of basal GirK activity in dorsal hippocampus, causing either function gain or loss, induced learning and memory deficits by a mechanism involving neural excitability impairments and alterations in induction and maintenance of long-term synaptic plasticity processes. These results support the contention that an accurate control of GirK activity must take place in the hippocampus to sustain cognitive functions. Significance Statement: The dorsal hippocampus mostly performs cognitive functions related to contextual/spatial associations. These functions rely on synaptic plasticity processes that are critically ruled by a finely tuned neural excitability. Being the downstream physiological effectors of a variety of G-coupled receptors, activation of G protein-gated inwardly rectifying K+ (GirK) channels induces neurons to hyperpolarize, contributing to neural excitability throughout the control of excitatory excess. Here, we demonstrate that modulation of basal GirK channels activity, causing either function gain or loss, transforms HFS-induced LTP into LTD, inducing deficits in dorsal hippocampus-dependent learning and memory. Together, our data show a crucial GirK activity-mediated mechanism that governs synaptic plasticity direction and modulates subsequent hippocampal-dependent cognitive functions.