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ORIGINAL RESEARCH article

Front. Stroke
Sec. Mechanisms, Models, and Biomarkers of Stroke
Volume 3 - 2024 | doi: 10.3389/fstro.2024.1423887
This article is part of the Research Topic Post-Stroke Cognitive Decline and Dementia: Unraveling Mechanisms, Models, and Biomarkers View all articles

Astroglial CD38 impairs hippocampal synaptic plasticity after global cerebral ischemia

Provisionally accepted
Amelia M. Burch Amelia M. Burch 1Ami Haas Ami Haas 1James E. Orfila James E. Orfila 2Erika Tiemeier Erika Tiemeier 1Nicholas Chalmers Nicholas Chalmers 1Nidia Quillinan Nidia Quillinan 1Paco S. Herson Paco S. Herson 2*
  • 1 Department of Anesthesiology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
  • 2 The Ohio State University, Columbus, United States

The final, formatted version of the article will be published soon.

    Cardiac arrest-induced global cerebral ischemia (GCI) results in profound cognitive impairment in survivors. Our prior work demonstrated persistent disruption of long-term potentiation (LTP) in hippocampal CA1 neurons, correlating with learning and memory deficits in a rodent model of cardiac arrest/ cardiopulmonary resuscitation (CA/CPR). Delayed inhibition of the Ca 2+permeable TRPM2 ion channel restored LTP post-CA/CPR, yet the mechanisms upstream of TRPM2 activation remain elusive. This study investigates CD38 as a potential regulator of TRPM2, highlighting a novel target to reverse hippocampal synaptic plasticity deficits after ischemia. We observe elevated levels of CD38 in activated astrocytes in the CA1 region of the hippocampus 7 days following CA/CPR in both male and female mice. Delayed inhibition of CD38 reverses hippocampal synaptic plasticity impairments at subacute timepoints after CA/CPR, phenocopying TRPM2 restoration of LTP. Our previous findings demonstrated that TRPM2 inhibition reverses the CA/CPR-induced enhancement of GABAA receptor (GABAAR) clustering, which contribute to ongoing LTP deficits. We, therefore, assessed the effect of CD38 on GABAergic inhibitory potentiation and find that inhibition of CD38 reverses GABAAR clustering in a TRPM2-dependent manner. In this study, we identify astroglial CD38 as a potential target and upstream regulator of the TRPM2 channel, offering a promising approach to restore hippocampal synaptic plasticity 47 impairments following GCI through modulation of GABAergic signaling.

    Keywords: CD38, Cardiac arrest, Global cerebral ischemia, TRPM2, Hippocampus, LTP

    Received: 26 Apr 2024; Accepted: 18 Jun 2024.

    Copyright: © 2024 Burch, Haas, Orfila, Tiemeier, Chalmers, Quillinan and Herson. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Paco S. Herson, The Ohio State University, Columbus, United States

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