Knockdown of adenosine A2A receptors in hippocampal neurons prevents post-TBI fear memory retrieval.

Mar 13, 2023

Experts: Xiao-Qing Cen,Ping Li,Bo Wang,Xing Chen,Yan Zhao,Nan Yang,Yan Peng,Chang-Hong Li,Ya-Lei Ning,Yuan-Guo Zhou

The formation of fear memory is crucial in emotional disorders such as PTSD and anxiety. Traumatic brain injury (TBI) can cause emotional disorders with dysregulated fear memory formation; however, their cross-interaction remains unclear and hurdled the treatment against TBI-related emotional disorders. While adenosine A2A receptor(A2AR) contributes to the physiological regulation of fear memory, this study aimed to evaluate the A2AR role and possible mechanisms in post-TBI fear memory formation using a craniocerebral trauma model, genetically modified A2AR mutant mice, and pharmacological A2AR agonist CGS21680 and antagonist ZM241385. Our finding showed (i) TBI enhanced mice freezing levels (fear memory) at seven days post-TBI; (ii) The A2AR agonist CGS21680 enhanced the post-TBI freezing levels; conversely, the A2AR antagonist ZM241385 reduced mice freezing level; further (iii) Genetic knockdown of neuronal A2AR in the hippocampal CA1, CA3, and DG regions reduced post-TBI freezing levels, while A2AR knockout in DG region yielded the most reduction in fear memory; finally, (iv) AAV-CaMKII-Cre virus-mediated DG deletion of A2AR on excitatory neurons led to a significant decreased freezing levels post-TBI. These findings indicate that brain trauma increases fear memory retrieval post-TBI, and A2AR on DG excitatory neurons plays a crucial role in this process. Importantly, inhibition of A2AR attenuates fear memory enhancement, which provides a new strategy to prevent fear memory formation/enhancement after TBI.
Copyright © 2023. Published by Elsevier Inc.

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ABOUT THE EXPERTS

Xiao-Qing Cen,Ping Li,Bo Wang,Xing Chen,Yan Zhao,Nan Yang,Yan Peng,Chang-Hong Li,Ya-Lei Ning,Yuan-Guo Zhou

Xiao-Qing Cen

The College of Bioengineering, Chongqing University, No.174 Shazheng Street, Shapingba District, Chongqing 400044, China; Department of Army Occupational Disease, State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery and Daping Hospital, Army Medical University, Chongqing, China.

Ping Li

Department of Army Occupational Disease, State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery and Daping Hospital, Army Medical University, Chongqing, China; Institute of Brain and Intelligence, Army Medical University, Chongqing, China.

Bo Wang

Department of Army Occupational Disease, State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery and Daping Hospital, Army Medical University, Chongqing, China.

Xing Chen

Department of Army Occupational Disease, State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery and Daping Hospital, Army Medical University, Chongqing, China.

Yan Zhao

Department of Army Occupational Disease, State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery and Daping Hospital, Army Medical University, Chongqing, China.

Nan Yang

Department of Army Occupational Disease, State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery and Daping Hospital, Army Medical University, Chongqing, China.

Yan Peng

Department of Army Occupational Disease, State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery and Daping Hospital, Army Medical University, Chongqing, China.

Chang-Hong Li

Department of Army Occupational Disease, State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery and Daping Hospital, Army Medical University, Chongqing, China.

Ya-Lei Ning

Department of Army Occupational Disease, State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery and Daping Hospital, Army Medical University, Chongqing, China; Institute of Brain and Intelligence, Army Medical University, Chongqing, China. Electronic address: ylning@outlook.com.

Yuan-Guo Zhou

The College of Bioengineering, Chongqing University, No.174 Shazheng Street, Shapingba District, Chongqing 400044, China; Department of Army Occupational Disease, State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery and Daping Hospital, Army Medical University, Chongqing, China; Institute of Brain and Intelligence, Army Medical University, Chongqing, China. Electronic address: ygzhou@tmmu.edu.cn.