G-Protein-Gated Inwardly Rectifying Potassium (Kir3/GIRK) Channels Govern Synaptic Plasticity That Supports Hippocampal-Dependent Cognitive Functions in Male Mice
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Abstract
The G-protein-gated inwardly rectifying potassium (Kir3/GIRK) channel is the effector of many G-protein-coupled receptors (GPCRs). Its dysfunction has been linked to the pathophysiology of Down syndrome, Alzheimer9s and Parkinson9s 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, 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 (TQ), 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 (i.c.v.) 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 i.c.v. 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 STATEMENT Cognitive 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 high-frequency stimulation (HFS)-induced long-term potentiation (LTP) into long-term depression (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.
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In hippocampal and cortical circuits, GIRK-dependent inhibition supports forms of plasticity that require stable excitability set points, and selective perturbation of GIRK activity in CA1 pyramidal neurons disrupts learning.
“In hippocampal and cortical circuits, GIRK-dependent inhibition supports forms of plasticity that require stable excitability set points, and selective perturbation of GIRK activity in CA1 pyramidal neurons disrupts learning, highlighting its role in cognitive control [304,305,309].”
From Synaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery (2026) · cites this paper as [304]
The GIRK-activity and plasticity section links GIRK regulation of excitability to hippocampal LTP/LTD, and the learning section reports deficits after GIRK-modulating intracerebroventricular injections. The paper does not establish the claim for cortical circuits or stable excitability set points, and its learning experiments did not selectively perturb GIRK activity in CA1 pyramidal neurons. Page numbers were unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe outward K+ flux through GIRK restores baseline tone during sustained neuromodulatory input and prevents runaway firing during high synaptic load.
“The resulting outward K+ flux restores baseline tone during sustained neuromodulatory input and prevents runaway firing during high synaptic load [302,304,305].”
From Synaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery (2026) · cites this paper as [304]
The Introduction (page unavailable) says GPCR activation of GIRK channels can hyperpolarize neurons and contribute to resting membrane potential and excitability. The results also link increased GIRK activity to decreased CA3–CA1 synaptic excitability. Our copy does not establish that outward K+ flux restores baseline tone during sustained neuromodulatory input or prevents runaway firing under high synaptic load. (LLM, conf=0.84)
Experimental — accuracy not yet measuredBy reinstating a K+-dependent safety brake, GIRK channels rebalance hyperactive pyramidal ensembles and dampen circuit noise that degrades computation.
“By reinstating a K+-dependent safety brake, GIRK channels rebalance hyperactive pyramidal ensembles and dampen circuit noise that degrades computation [304,305].”
From Synaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery (2026) · cites this paper as [304]
The Introduction (page not provided) describes GIRK channels as potassium channels that hyperpolarize neurons and regulate excitability. The section on CA3–CA1 excitability and synaptic plasticity (page not provided) reports that increasing GIRK conductance decreases excitability, but also impaired long-term potentiation. It does not establish that reinstating GIRK activity rebalances hyperactive pyramidal ensembles or dampens computationally harmful circuit noise. (LLM, conf=0.87)
Experimental — accuracy not yet measuredExcessive GIRK drive can perturb plasticity, but calibrated GIRK enhancement reliably dampens limbic excitability and supports restorative sleep states in preclinical systems.
“Balanced activation remains essential, as excessive GIRK drive can perturb plasticity; nevertheless, calibrated GIRK enhancement reliably dampens limbic excitability and supports restorative sleep states in preclinical systems [304,322].”
From Synaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery (2026) · cites this paper as [304]
In the sections on CA3–CA1 synaptic plasticity and ex vivo LTP (page unavailable), the paper reports that enhancing GIRK conductance decreased hippocampal excitability and blocked LTP, supporting the plasticity concern and a narrower excitability claim. It does not establish that calibrated enhancement reliably dampens limbic excitability across preclinical systems or supports restorative sleep states. (LLM, conf=0.88)
Experimental — accuracy not yet measured
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Jeremic, D., Jiménez-Díaz, L., & Navarro-López, J. D. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101496 · Cited by 306 · see citing works
Self-citationRodríguez-Giraldo, M., González-Reyes, R. E., Ramírez-Guerrero, S., Bonilla-Trilleras, C. E., Guardo-Maya, S., & Nava-Mesa, M. O. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232113630 · Cited by 118 · see citing works
Self-citationJeremic, D., Sanchez-Rodriguez, I., Jimenez-Diaz, L., & Navarro-Lopez, J. D. (2021) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2021.107808 · Cited by 89 · see citing works
Self-citationNeuronal G protein-gated K<sup>+</sup> channels
Luo, H., Marron Fernandez de Velasco, E., & Wickman, K. (2022) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00102.2022 · Cited by 62 · see citing works
Chen, X., Feng, Y., Quinn, R. J., Pountney, D. L., Richardson, D. R., Mellick, G. D., & Ma, L. (2023) · Pharmacological Reviews · doi:10.1124/pharmrev.122.000743 · Cited by 44 · see citing works
Alfaro‐Ruiz, R., Martín‐Belmonte, A., Aguado, C., Hernández, F., Moreno‐Martínez, A. E., Ávila, J., & Luján, R. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222011106 · Cited by 32 · see citing works
Recognition Memory Induces Natural LTP-like Hippocampal Synaptic Excitation and Inhibition
Sánchez‐Rodríguez, I., Temprano‐Carazo, S., Jeremic, D., Delgado-Garcia, J. M., Gruart, A., Navarro‐López, J. D., & Jiménez‐Díaz, L. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231810806 · Cited by 27 · see citing works
Self-citationShedding light on cholecystokinin’s role in hippocampal neuroplasticity and memory formation
Asim, M., Wang, H., & Chen, X. (2024) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2024.105615 · Cited by 21 · see citing works
Role of Ion Channels in Alzheimer’s Disease Pathophysiology
Bhoi, R., Mitra, T., Tejaswi, K., Manoj, V., & Ghatak, S. (2025) · The Journal of Membrane Biology · doi:10.1007/s00232-025-00341-8 · Cited by 19 · see citing works
Jiménez‐Herrera, R., Contreras, A., Djebari, S., Mulero‐Franco, J., Iborra‐Lázaro, G., Jeremic, D., Navarro‐López, J. D., & Jiménez‐Díaz, L. (2023) · Biology of Sex Differences · doi:10.1186/s13293-023-00545-4 · Cited by 17 · see citing works
Self-citationIborra‐Lázaro, G., Djebari, S., Sánchez‐Rodríguez, I., Gratacòs‐Batlle, E., Sánchez-Fernández, N., Radošević, M., Casals, N., Navarro‐López, J. D., Soto, D., & Jiménez‐Díaz, L. (2023) · The Journal of Physiology · doi:10.1113/jp284248 · Cited by 12 · see citing works
Self-citationImpairments in hippocampal oscillations accompany the loss of LTP induced by GIRK activity blockade
Contreras, A., Djebari, S., Temprano‐Carazo, S., Múnera, A., Gruart, A., Delgado-Garcia, J. M., Jiménez‐Díaz, L., & Navarro‐López, J. D. (2023) · Neuropharmacology · doi:10.1016/j.neuropharm.2023.109668 · Cited by 10 · see citing works
Self-citationLuo, H., de Velasco, E. M. F., Gansemer, B. M., Frederick, M. H., Aguado, C., Luján, R., Thayer, S. A., & Wickman, K. D. (2024) · Science Signaling · doi:10.1126/scisignal.ado4132 · Cited by 11 · see citing works
Martinez, J. D., Brancaleone, W. P., Peterson, K. G., Wilson, L. G., & Aton, S. J. (2023) · Sleep · doi:10.1093/sleep/zsac301 · Cited by 11 · see citing works
Temprano‐Carazo, S., Contreras, A., Saura, C. A., Navarro‐López, J. D., & Jiménez‐Díaz, L. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232113444 · Cited by 10 · see citing works
Self-citationAn, D., Pinheiro-Júnior, E. L., Béress, L., Gladkikh, I. N., Leychenko, E. V., Undheim, E. A. B., Peigneur, S., & Tytgat, J. (2022) · Marine Drugs · doi:10.3390/md20020140 · Cited by 11 · see citing works
GIRK2 Channels in Down Syndrome and Alzheimer’s Disease
Kleschevnikov, A. M. (2022) · Current Alzheimer Research · doi:10.2174/1567205020666221223122110 · Cited by 10 · see citing works
Song, Z., Luo, G., Han, C., Jia, G., & Zhang, B. (2022) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2022/3607053 · Cited by 9 · see citing works
Cognitive rejuvenation through partial reprogramming of engram cells
Berdugo‐Vega, G., Sierra, C., Astori, S., Calati, V., Orsat, J., Scoglio, M. J., Sandi, C., & Gräff, J. (2026) · Neuron · doi:10.1016/j.neuron.2025.11.028 · Cited by 8 · see citing works
An, X., & Cho, H. (2023) · Scientific Reports · doi:10.1038/s41598-023-50088-2 · Cited by 7 · see citing works
Nunzio, M. P. D., & Montani, F. (2022) · Entropy · doi:10.3390/e24101384 · Cited by 6 · see citing works
Rana, Z. S., Pathania, C., Modgil, A., & Punnakkal, P. (2025) · Neuroscience · doi:10.1016/j.neuroscience.2025.04.016 · Cited by 5 · see citing works
Djebari, S., Jiménez‐Herrera, R., Iborra‐Lázaro, G., Jiménez‐Díaz, L., & Navarro‐López, J. D. (2025) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2025.117914 · Cited by 5 · see citing works
Self-citationMulero-Franco, J., Jimenez-Herrera, R., Contreras, A., Djebari, S., Jiménez-Díaz, L., & Navarro-López, J. D. (2025) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2025.118247 · Cited by 4 · see citing works
Self-citationExploring the role of synaptic plasticity in the frequency-dependent complexity domain
Nunzio, M. P. D., Tenti, J. M., Arlego, M., Rosso, O. A., & Montani, F. (2025) · Chaos An Interdisciplinary Journal of Nonlinear Science · doi:10.1063/5.0239820 · Cited by 4 · see citing works
Miranda-Riestra, A., Cercós, M. G., Trueta, C., Oikawa‐Sala, J., Argueta, J., Constantino-Jonapa, L. A., Cruz‐Garduño, R., Benítez‐King, G., & Estrada‐Reyes, R. (2024) · Molecular Pharmacology · doi:10.1124/molpharm.124.000890 · Cited by 4 · see citing works
Luo, H., Frederick, M. H., de Velasco, E. M. F., Oltmanns, J. R. O., Wright, C. J., & Wickman, K. D. (2024) · Learning & Memory · doi:10.1101/lm.054022.124 · Cited by 4 · see citing works
Martín‐Belmonte, A., Aguado, C., Alfaro‐Ruiz, R., & Luján, R. (2025) · PubMed · doi:10.14670/hh-18-822 · Cited by 2 · see citing works
Djebari, S., Contreras, A., Castro-Andres, V., Jiménez‐Herrera, R., Iborra‐Lázaro, G., Sánchez‐Campusano, R., Jiménez‐Díaz, L., & Navarro‐López, J. D. (2026) · The Journal of Physiology · doi:10.1113/jp286196 · Cited by 3 · see citing works
Self-citationDjebari, S., Contreras, A., Jiménez‐Herrera, R., Castro-Andres, V., Iborra‐Lázaro, G., Sánchez‐Campusano, R., Jiménez‐Díaz, L., & Navarro‐López, J. D. (2023) · Research Square · doi:10.21203/rs.3.rs-3791891/v1 · Cited by 2 · see citing works
Self-citationGuiding G protein signaling by target enhancement of GPCRsPreprint
Mücher, B., Garrido‐Charles, A., Cyganek, L., Bruegmann, T., Dalkara, D., Siveke, I., & Herlitze, S. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.02.06.636923 · Cited by 2 · see citing works
Luo, H., de Velasco, E. M. F., Kim, J. J., Yang, P., Mermelstein, P. G., Bonventre, J. V., Cooke, P. S., & Wickman, K. D. (2025) · Biology of Sex Differences · doi:10.1186/s13293-025-00776-7 · Cited by 1 · see citing works
Behavior of KCNQ Channels in Neural Plasticity and Motor Disorders
Singh, S. P., William, M., Malavia, M., & Chu, X. (2022) · Membranes · doi:10.3390/membranes12050499 · Cited by 1 · see citing works
Identification and Interaction of Key Genes in Alzheimer's Disease via Bioinformatics Analysis
Zheng, Y., Huang, S., Zhou, H., Zhou, W., Jin, G., Liu, Q., & Wu, Y. (2022) · Indian Journal of Pharmaceutical Sciences · doi:10.36468/pharmaceutical-sciences.spl.583 · Cited by 1 · see citing works
Jiménez‐Herrera, R., Contreras, A., Iborra‐Lázaro, G., Jeremic, D., Djebari, S., Navarro‐López, J. D., & Jiménez‐Díaz, L. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.05.09.539973 · Cited by 1 · see citing works
Self-citationJeremic, D., Jiménez‐Díaz, L., & Navarro‐López, J. D. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.05.13.653795 · Cited by 1 · see citing works
Self-citationSynaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery
Tanaka, M. (2026) · Biomedicines · doi:10.3390/biomedicines14061265
Temprano‐Carazo, S., Contreras, A., Saura, C. A., Navarro‐López, J. D., & Jiménez‐Díaz, L. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.05.20.492780
Self-citationMartinez, J. D., Brancaleone, W. P., Peterson, K. G., Wilson, L. G., & Aton, S. J. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.07.15.500268
Role of neural oscillations modulating long term potentiation to Alzheimer's Disease
Liu, Y. (2023) · Theoretical and Natural Science · doi:10.54254/2753-8818/22/20230990
Ren, L., Yu, J. H., Chen, H., Luo, J., Lv, F., & Min, S. (2024) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2024.1365119
Mulero‐Franco, J., Jiménez‐Herrera, R., Contreras, A., Djebari, S., Jiménez‐Díaz, L., & Navarro‐López, J. D. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.11.05.622060
Self-citationZhang, C., Sun, Z., Chen, X., Yang, H., Chen, J., Ding, Z., & Zhen, X. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.03.10.625121
The Effect of Dopamine on Neuroplasticity in Spinal Cord Injury
Chesnokov, A. A., Kalinina, D. S., Makhortykh, A. E., Khuzin, D. V., & Евгеньевич, М. П. (2025) · Journal of Evolutionary Biochemistry and Physiology · doi:10.1134/s0022093025040015
Jiménez-Herrera, R., Contreras, A., Djebari, S., Mulero‐Franco, J., Iborra‐Lázaro, G., Jeremic, D., Navarro‐López, J. D., & Jiménez‐Díaz, L. (2024) · Figshare · doi:10.6084/m9.figshare.26617762
Self-citationFrom encounter to memory: molecular dynamics of heterospecifc recognition in cleaner wrassePreprint
Schunter, C., & Romeo, D. (2026) · Research Square · doi:10.21203/rs.3.rs-8312257/v1
Jeremic, D., Jiménez‐Díaz, L., & Navarro‐López, J. D. (2026) · Journal of Molecular Graphics and Modelling · doi:10.1016/j.jmgm.2026.109417 · Cited by 1 · see citing works
Self-citationMücher, B., Garrido‐Charles, A., Wietek, J., Köhler, I., Grömmke, M., Frischmuth, T., Cyganek, L., Rost, B. R., Bruegmann, T., Schmitz, D., et al. (2026) · Science Signaling · doi:10.1126/scisignal.adw4374
- Authors
- Djebari, S., Iborra-Lázaro, G., Temprano-Carazo, S., Sánchez-Rodríguez, I., Nava-Mesa, M. O., Múnera, A., Gruart, A., Delgado-García, J. M., Jiménez-Díaz, L., & Navarro-López, J. D.
- Affiliations
- University of Castilla-La Mancha (ES)
- Universidad Nacional de Colombia (CO)
- Universidad Pablo de Olavide (ES)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2021-07-14
- Volume
- 41
- Issue
- 33
- Pages
- 7086-7102
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC8372024
- OpenAlex
- W3179034397
- Cited by
- 48
- References
- 85
- Citations by year
- 2026: 6 · 2025: 11 · 2024: 7 · 2023: 8 · 2022: 13 · 2021: 3
- FWCI
- 3.57
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- RUIdeRA - Institutional University Repository (University of Castilla-La Mancha) (submittedVersion, other-oa)
- Funders
- Ministerio de Economía y Competitividad
- Universidad de Castilla-La Mancha
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- GIRK channels, inwardly rectifying potassium channels, synaptic plasticity, hippocampus, learning and memory, neuronal excitability, long-term potentiation, long-term depression, CA3-CA1 synapses, tertiapin-Q, intracerebroventricular administration, Schaffer collateral stimulation, G protein-coupled receptors
- MeSH terms
- Animals, Conditioning, Operant, Emotions, Hippocampus, Learning, Male, Mice, Inbred C57BL, Motor Activity, Nerve Tissue Proteins, Neuronal Plasticity, Psychomotor Performance, Long-Term Potentiation, Excitatory Postsynaptic Potentials, Mice, G Protein-Coupled Inwardly-Rectifying Potassium Channels
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