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

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

doi:10.1016/j.expneurol.2023.114378

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

Exp Neurol. 2023 Jun:364:114378. doi: 10.1016/j.expneurol.2023.114378. Epub 2023 Mar 11.

Authors

Xiao-Qing Cen¹, Ping Li², Bo Wang³, Xing Chen³, Yan Zhao³, Nan Yang³, Yan Peng³, Chang-Hong Li³, Ya-Lei Ning⁴, Yuan-Guo Zhou⁵

Affiliations

¹ 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.
² 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.
³ 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.
⁴ 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.
⁵ 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.

PMID: 36907351
DOI: 10.1016/j.expneurol.2023.114378

Abstract

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.

Keywords: Adenosine A2A receptor; Fear memory; Hippocampal; Traumatic brain injury.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain Injuries, Traumatic* / drug therapy
Fear
Hippocampus / metabolism
Mice
Mice, Inbred C57BL
Neurons / metabolism
Receptor, Adenosine A2A* / genetics
Receptor, Adenosine A2A* / metabolism

Substances

2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine
Receptor, Adenosine A2A