TRPM2 and CaMKII Signaling Drives Excessive GABAergic Synaptic Inhibition Following Ischemia.

Autor: Burch AM; Neuronal Injury & Plasticity Program, Department of Anesthesiology, University of Colorado School of Medicine, Aurora, Colorado 80045., Garcia JD; Department of Pharmacology, University of Colorado School of Medicine, Aurora, Colorado 80045., O'Leary H; Neuronal Injury & Plasticity Program, Department of Anesthesiology, University of Colorado School of Medicine, Aurora, Colorado 80045., Haas A; Neuronal Injury & Plasticity Program, Department of Anesthesiology, University of Colorado School of Medicine, Aurora, Colorado 80045., Orfila JE; Department of Neurological Surgery, The Ohio State University College of Medicine, Columbus, Ohio 43210., Tiemeier E; Neuronal Injury & Plasticity Program, Department of Anesthesiology, University of Colorado School of Medicine, Aurora, Colorado 80045., Chalmers N; Neuronal Injury & Plasticity Program, Department of Anesthesiology, University of Colorado School of Medicine, Aurora, Colorado 80045., Smith KR; Department of Pharmacology, University of Colorado School of Medicine, Aurora, Colorado 80045., Quillinan N; Neuronal Injury & Plasticity Program, Department of Anesthesiology, University of Colorado School of Medicine, Aurora, Colorado 80045 paco.herson@osumc.edu nidia.quillinan@cuanschutz.edu., Herson PS; Department of Neurological Surgery, The Ohio State University College of Medicine, Columbus, Ohio 43210 paco.herson@osumc.edu nidia.quillinan@cuanschutz.edu.
Jazyk: angličtina
Zdroj: The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2024 May 08; Vol. 44 (19). Date of Electronic Publication: 2024 May 08.
DOI: 10.1523/JNEUROSCI.1762-23.2024
Abstrakt: Excitotoxicity and the concurrent loss of inhibition are well-defined mechanisms driving acute elevation in excitatory/inhibitory (E/I) balance and neuronal cell death following an ischemic insult to the brain. Despite the high prevalence of long-term disability in survivors of global cerebral ischemia (GCI) as a consequence of cardiac arrest, it remains unclear whether E/I imbalance persists beyond the acute phase and negatively affects functional recovery. We previously demonstrated sustained impairment of long-term potentiation (LTP) in hippocampal CA1 neurons correlating with deficits in learning and memory tasks in a murine model of cardiac arrest/cardiopulmonary resuscitation (CA/CPR). Here, we use CA/CPR and an in vitro ischemia model to elucidate mechanisms by which E/I imbalance contributes to ongoing hippocampal dysfunction in male mice. We reveal increased postsynaptic GABA A receptor (GABA A R) clustering and function in the CA1 region of the hippocampus that reduces the E/I ratio. Importantly, reduced GABA A R clustering observed in the first 24 h rebounds to an elevation of GABAergic clustering by 3 d postischemia. This increase in GABAergic inhibition required activation of the Ca 2+ -permeable ion channel transient receptor potential melastatin-2 (TRPM2), previously implicated in persistent LTP and memory deficits following CA/CPR. Furthermore, we find Ca 2+ -signaling, likely downstream of TRPM2 activation, upregulates Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) activity, thereby driving the elevation of postsynaptic inhibitory function. Thus, we propose a novel mechanism by which inhibitory synaptic strength is upregulated in the context of ischemia and identify TRPM2 and CaMKII as potential pharmacological targets to restore perturbed synaptic plasticity and ameliorate cognitive function.
Competing Interests: The authors declare no competing financial interests.
(Copyright © 2024 the authors.)
Databáze: MEDLINE
Externí odkaz: