G-Protein-Gated Inwardly Rectifying Potassium (Kir3/GIRK) Channels Govern Synaptic Plasticity That Supports Hippocampal-Dependent Cognitive Functions in Male Mice.
Souhail DjebariGuillermo Iborra-LázaroSara Temprano-CarazoIrene Sánchez-RodríguezMauricio O Nava-MesaAlejandro MúneraAgnès GruartJosé María Delgado-GarcíaLydia Jiménez-DíazJuan de Dios Navarro-LópezPublished in: The Journal of neuroscience : the official journal of the Society for Neuroscience (2021)
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, 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, 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.
Keyphrases
- cerebral ischemia
- high frequency
- spinal cord
- drug induced
- subarachnoid hemorrhage
- traumatic brain injury
- transcranial direct current stimulation
- heart rate variability
- high glucose
- diabetic rats
- brain injury
- heart rate
- cognitive decline
- blood brain barrier
- machine learning
- blood pressure
- oxidative stress
- electronic health record
- physical activity
- working memory
- risk assessment
- emergency department
- mild cognitive impairment
- platelet rich plasma
- artificial intelligence
- deep learning
- cognitive impairment
- sleep quality
- respiratory failure
- prefrontal cortex
- mechanical ventilation
- signaling pathway
- bone marrow
- cell proliferation
- aortic dissection