Data_Sheet_1_Astroglial CD38 impairs hippocampal synaptic plasticity after global cerebral ischemia.DOCX

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 Ca2+-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 impairments following GCI through modulation of GABAergic signaling.

心源性猝发所致的全脑缺血 (GCI) 导致幸存者认知功能严重受损。本研究的前期工作揭示了海马CA1神经元长期增强 (LTP) 的持续性破坏，并与啮齿动物模型中心源性猝发/心肺复苏 (CA/CPR) 导致的学习和记忆缺陷相关。延迟抑制Ca2+-通透性TRPM2离子通道可恢复CA/CPR后的LTP，然而TRPM2激活上游的机制尚不明确。本研究旨在探究CD38作为TRPM2的潜在调节因子，突显出缺血后逆转海马突触可塑性缺陷的新靶点。我们观察到在CA1区域激活的星形胶质细胞中CD38水平在CA/CPR后7天显著升高，无论是在雄性还是雌性小鼠中。延迟抑制CD38可在CA/CPR后的亚急性时间点逆转海马突触可塑性损害，其现象与TRPM2恢复LTP相似。我们先前的研究发现，TRPM2抑制可逆转CA/CPR诱导的GABAΑ受体 (GABAAR) 聚集增强，这有助于持续的LTP缺陷。因此，我们评估了CD38对GABA能抑制性增强的影响，发现抑制CD38以TRPM2依赖的方式逆转GABAAR聚集。在本研究中，我们确定了星形胶质细胞CD38作为TRPM2通道的潜在靶点和上游调节因子，为通过调节GABA能信号通路恢复GCI后的海马突触可塑性损害提供了一种有前景的方法。