PT  - JOURNAL ARTICLE
AU  - Souhail Djebari
AU  - Guillermo Iborra-Lázaro
AU  - Sara Temprano-Carazo
AU  - Irene Sánchez-Rodríguez
AU  - Mauricio O. Nava-Mesa
AU  - Alejandro Múnera
AU  - Agnès Gruart
AU  - José M. Delgado-García
AU  - Lydia Jiménez-Díaz
AU  - Juan D. Navarro-López
TI  - G-protein-gated inwardly rectifying potassium (Kir3/GIRK) channels govern synaptic plasticity that supports hippocampal-dependent cognitive functions in male mice
AID  - 10.1523/JNEUROSCI.2849-20.2021
DP  - 2021 Jul 14
TA  - The Journal of Neuroscience
PG  - JN-RM-2849-20
4099  - http://www.jneurosci.org/content/early/2021/07/13/JNEUROSCI.2849-20.2021.short
4100  - http://www.jneurosci.org/content/early/2021/07/13/JNEUROSCI.2849-20.2021.full
AB  - The 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’s syndrome, Alzheimer’s and Parkinson’s diseases, psychiatric disorders, epilepsy, drug addiction, or alcoholism. In the hippocampus, GIRK channels decrease excitability of the cells and contribute to resting membrane potential and inhibitory neurotransmission. Here, in order to elucidate the role of GIRK channels activity in the maintenance of hippocampal-dependent cognitive functions, their involvement in controlling neuronal excitability at different levels of complexity was examined in C57BL/6 male mice. For that purpose, GIRK activity in the dorsal hippocampus CA3−CA1 synapse was pharmacologically modulated by two drugs: ML297, a GIRK channel opener, and Tertiapin-Q, a GIRK channel blocker. Ex vivo, using dorsal hippocampal slices, we studied the effect of pharmacological GIRK modulation on synaptic plasticity processes induced in CA1 by Schaffer collateral stimulation. In vivo, we performed acute intracerebroventricular (icv.) injections of the two GIRK modulators to study their contribution to electrophysiological properties and synaptic plasticity of dorsal hippocampal CA3−CA1 synapse, and to learning and memory capabilities during hippocampal-dependent tasks. We found that pharmacological disruption of GIRK channel activity by icv. injections, causing either function gain or function loss, induced learning and memory deficits by a mechanism involving neural excitability impairments and alterations in the 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 StatementCognitive processes of learning and memory that rely on hippocampal synaptic plasticity processes are critically ruled by a finely tuned neural excitability. G-protein-gated inwardly rectifying K+ (GIRK) channels play a key role in maintaining resting membrane potential, cell excitability and inhibitory neurotransmission. Here, we demonstrate that modulation of GIRK channels activity, causing either function gain or function loss, transforms HFS-induced LTP into LTD, inducing deficits in hippocampal-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.