Astrocytic GDNF ameliorates anesthesia and surgery-induced cognitive impairment by promoting hippocampal synaptic plasticity in aged mice

Xiaowan Lin; Peng Ren; Ziyi Xue; Xiao Liu; Ying Cao; Tianzuo Li; Huihui Miao

doi:10.1016/j.neuint.2024.105765

Astrocytic GDNF ameliorates anesthesia and surgery-induced cognitive impairment by promoting hippocampal synaptic plasticity in aged mice

Neurochem Int. 2024 Jul:177:105765. doi: 10.1016/j.neuint.2024.105765. Epub 2024 May 13.

Authors

Xiaowan Lin¹, Peng Ren², Ziyi Xue³, Xiao Liu⁴, Ying Cao⁴, Tianzuo Li⁵, Huihui Miao⁶

Affiliations

¹ Department of Anesthesiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; Department of Anesthesiology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.
² Beijing Institute of Basic Medical Sciences, Beijing, China.
³ Department of Anesthesiology, Peking University First Hospital, Beijing, China.
⁴ Department of Anesthesiology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.
⁵ Department of Anesthesiology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China. Electronic address: sjmzltz@163.com.
⁶ Department of Anesthesiology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China. Electronic address: iverymhh@hotmail.com.

PMID: 38750960
DOI: 10.1016/j.neuint.2024.105765

Abstract

Background: Perioperative neurocognitive disorders (PND) are common complications after surgery in older patients. However, the specific mechanism of this condition remains unclear. Glial cell line-derived neurotrophic factor (GDNF) is an important neurotrophin that abundantly expressed throughout the brain. It can enhance synaptic plasticity and alleviate learning and memory impairments. Thus, the purpose of this study was to investigate the role of GDNF in PND and the mechanisms involved.

Methods: The PND animal model was established by performing left tibial fracture surgery on 18-month-old C57BL/6 mice under sevoflurane anesthesia. Recombinant adeno-associated virus (rAAV)-GDNF or empty vectors were injected bilaterally into the hippocampal CA1 region of aged mice 3 weeks before anesthesia/surgery. The open field and fear conditioning test were used to assess the behavior changes. Golgi staining and electrophysiology were utilized to evaluate the morphological and functional alterations of neuronal synaptic plasticity. Western blot analysis was carried out to measure the proteins expression levels and immunofluorescence staining was performed to probe the cellular localization of GDNF.

Results: Mice with surgery and anesthesia showed a significant decrease in hippocampus-dependent learning and memory, accompanied by a decline in hippocampal synaptic plasticity. Anesthesia/surgery induced a reduction of GDNF, which was colocalized with astrocytes. Overexpression of GDNF in astrocytes could ameliorate the decline in cognitive function by improving hippocampal synaptic plasticity, meanwhile astrocytic GDNF rescued the anesthesia/surgery-induced decrease in GFRα1 and NCAM.

Conclusion: The study concludes that astrocytic GDNF may improve anesthesia/surgery-induced cognitive impairment by promoting hippocampal synaptic plasticity in aged mice via the GFRα1/NCAM pathway.

Keywords: Aged; Astrocytes; Glial cell line-derived neurotrophic factor; Perioperative neurocognitive disorders; Synaptic plasticity.

MeSH terms

Aging
Anesthesia
Animals
Astrocytes* / metabolism
Cognitive Dysfunction* / metabolism
Glial Cell Line-Derived Neurotrophic Factor* / metabolism
Hippocampus* / drug effects
Hippocampus* / metabolism
Male
Mice
Mice, Inbred C57BL*
Neuronal Plasticity* / drug effects
Neuronal Plasticity* / physiology

Substances

Glial Cell Line-Derived Neurotrophic Factor
Gdnf protein, mouse