AUTHOR=Burch Amelia M. , Haas Ami , Orfila James E. , Tiemeier Erika , Gamboa Cassidy De Anda , Chalmers Nicholas , Quillinan Nidia , Herson Paco S. 

TITLE=Astroglial CD38 impairs hippocampal synaptic plasticity after global cerebral ischemia

JOURNAL=Frontiers in Stroke

VOLUME=3

YEAR=2024

URL=https://www.frontiersin.org/journals/stroke/articles/10.3389/fstro.2024.1423887

DOI=10.3389/fstro.2024.1423887

ISSN=2813-3056

ABSTRACT=<p>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<sup>2+</sup>-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 GABA<sub>A</sub> receptor (GABA<sub>A</sub>R) 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 GABA<sub>A</sub>R 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 impairments following GCI through modulation of GABAergic signaling.</p>