Functional Restoration following Global Cerebral Ischemia in Juvenile Mice following Inhibition of Transient Receptor Potential M2 (TRPM2) Ion Channels.

James E Orfila,J Michael Wyss,Paco S Herson,Nicholas Chalmers,Guying Deng,Nidia Quillinan,Robert M Dietz,Crystal Minjarez,Jose Vigil

doi:10.1155/2021/8774663

Abstract

Hippocampal cell death and cognitive dysfunction are common following global cerebral ischemia across all ages, including children. Most research has focused on preventing neuronal death. Restoration of neuronal function after cell death is an alternative approach (neurorestoration). We previously identified transient receptor potential M2 (TRPM2) ion channels as a potential target for acute neuroprotection and delayed neurorestoration in an adult CA/CPR mouse model. Cardiac arrest/cardiopulmonary resuscitation (CA/CPR) in juvenile (p20-25) mice was used to investigate the role of ion TRPM2 channels in neuroprotection and ischemia-induced synaptic dysfunction in the developing brain. Our novel TRPM2 inhibitor, tatM2NX, did not confer protection against CA1 pyramidal cell death but attenuated synaptic plasticity (long-term plasticity (LTP)) deficits in both sexes. Further, in vivo administration of tatM2NX two weeks after CA/CPR reduced LTP impairments and restored memory function. These data provide evidence that pharmacological synaptic restoration of the surviving hippocampal network can occur independent of neuroprotection via inhibition of TRPM2 channels, providing a novel strategy to improve cognitive recovery in children following cerebral ischemia. Importantly, these data underscore the importance of age-appropriate models in disease research.

Highlights

Successful resuscitation of patients following cardiac arrest (CA) continues to lead to improved rates of survival
Our data are consistent with recent studies showing that global cerebral ischemia in the juvenile brain leads to impairment of synaptic plasticity, e.g., impaired long-term potentiation (LTP) and memory function [11, 34]
FEPSP slope (% of baseline) fEPSP slope (% of baseline) fEPSP slope (% of baseline) stimulation normalized to 20 minutes of baseline recording. (c) Time course of fEPSP slope from female juvenile mice 7 days after sham mice were administered 20 mg/kg tatSCR or tatM2NX 30 minutes after cardiac arrest/cardiopulmonary resuscitation (CA/CPR) and 7 days after CA/CPR mice were administered 20 mg/kg tatSCR or tatM2NX 30 min after CA/CPR. (d) Quantification of change in fEPSP slope 60 minutes after theta burst stimulation (TBS) stimulation normalized to 20 minutes of baseline recording

Summary

Introduction

Successful resuscitation of patients following cardiac arrest (CA) continues to lead to improved rates of survival. We have focused on neuronal networks, such as the hippocampal network, to investigate whether synaptic function can be preserved or rescued in surviving neurons as a primary outcome. In this way, we envision therapeutic targets that can augment compensatory or recovery mechanisms in the brain after injury, termed neurorestoration, which can advance the field of translational ischemia research. Through assessing hippocampal networks in mice after cardiac arrest/cardiopulmonary resuscitation (CA/CPR), deficits in synaptic plasticity and learning and memory have been demonstrated that persist for weeks to months after ischemic injury in adults [5,6,7,8,9,10]. The juvenile brain has shown similar impairments in hippocampal synaptic function after CA/CPR or ischemic stroke models, though endogenous recovery occurs around 1

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Results

Conclusion