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Hippocampal Inhibitory Synapsis Deficits Induced by α5-Containing GABAA Receptors Mediate Chronic Neuropathic Pain–Related Cognitive Impairment

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Abstract

Chronic neuropathic pain often leads to cognitive impairment, but the exact mechanism remains unclear. Gamma-aminobutyric acid A receptors (GABAARs) are the major inhibitory receptors in the brain, of which the α5-containing GABAARs (GABAARs-α5) are implicated in a range of neuropsychiatric disorders with cognitive deficits. However, whether GABAARs-α5 are involved in chronic neuropathic pain-related cognitive impairment remains unknown. In this study, the rats with chronic neuropathic pain induced by right sciatic nerve ligation injury (SNI) exhibited cognitive impairment with declined spontaneous alternation in Y-maze test and discrimination index in novel object recognition test. The GABAARs-α5 expressing on parvalbumin and somatostatin interneurons increased remarkably in hippocampus, resulting in decreased mean frequency of spontaneous inhibitory postsynaptic currents in hippocampal pyramidal neurons. Significantly, antagonizing the GABAARs-α5 by L655708 rescued weakened inhibitory synaptic transmission and cognitive impairment induced by chronic neuropathic pain. Taken together, these data suggest that the GABAARs-α5 play a crucial role in chronic neuropathic pain-induced cognitive impairment by weakening inhibitory synaptic transmission, which may provide insights into the pharmacologic treatment of chronic neuropathic pain-related cognitive impairment.

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Data Availability

The datasets used during the present study are available from the corresponding author upon reasonable request.

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Funding

This work was supported by the National Natural Science Foundation of China (grant number: 82071196), the Jiangsu Commission of Health (grant number: z201949) and the Basic Research Grant of Southeast University.

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  1. Xuechun Cai, Lili Qiu, and Chaoran Wang contributed equally.

Authors and Affiliations

  1. Department of Anesthesiology and Perioperative Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China

    Xuechun Cai, Chaoran Wang, Hang Yang, Zhenhui Zhou, Yunqing Zhu & Wei Zhu

  2. Department of Anesthesiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, Jiangsu, People’s Republic of China

    Lili Qiu, Wenlan Cai & Jie Sun

  3. Department of Anesthesiology, Department of Anesthesiology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China

    Meng Mao

  4. Department of Anesthesiology, Nanjing Maternity and Child Health Care Hospital, Nanjing, Jiangsu, People’s Republic of China

    Yazhou Wen

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  1. Xuechun Cai
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Contributions

Xuechun Cai, Jie Sun, and Wei Zhu contributed to study design; Xuechun Cai, Jie Sun, and Wei Zhu contributed to manuscript editing; Lili Qiu, Chaoran Wang, Hang Yang, Zhenhui Zhou, Meng Mao, and Yunqing Zhu contributed to experimental studies; Xuechun Cai, Lili Qiu, Chaoran Wang, Yazhou Wen, and Wenlan Cai contributed to data analysis. All authors read and approved the final manuscript.

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Correspondence to Wei Zhu or Jie Sun.

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Cai, X., Qiu, L., Wang, C. et al. Hippocampal Inhibitory Synapsis Deficits Induced by α5-Containing GABAA Receptors Mediate Chronic Neuropathic Pain–Related Cognitive Impairment. Mol Neurobiol 59, 6049–6061 (2022). https://doi.org/10.1007/s12035-022-02955-8

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