Environmental enrichment implies GAT-1 as a potential therapeutic target for stroke recovery
| Autor: | Hui Xiao, Chun-Xia Luo, Hai-Yin Wu, Yu-Hui Lin, Yanyu Sun, Meng-Cheng Yao, Huan-Yu Ni, Jian Dong, Yan Liu, Xiao-Lin Kou, Di Yang, Shi-Ying Cao, Feng Wu, Jun Li, Dong-Ya Zhu, Jin Wu, Lei Chang |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
GAT-1 GABA Plasma Membrane Transport Proteins functional recovery medicine.medical_treatment Medicine (miscellaneous) Optogenetics In Vitro Techniques Mice Neuroplasticity Medicine GABA transporter Tonic (music) Animals Humans Molecular Targeted Therapy Precision Medicine Pharmacology Toxicology and Pharmaceutics (miscellaneous) Stroke gamma-Aminobutyric Acid Mice Knockout Neurons Environmental enrichment Neuronal Plasticity biology business.industry Recovery of Function medicine.disease stroke Mice Inbred C57BL Disease Models Animal plasticity Corticospinal tract biology.protein environmental enrichment Female business Stroke recovery Neuroscience Signal Transduction Research Paper |
| Zdroj: | Theranostics |
| ISSN: | 1838-7640 |
| Popis: | Rationale: Stroke is a leading cause of adult disability worldwide, but no drug provides functional recovery during the repair phase. Accumulating evidence demonstrates that environmental enrichment (EE) promotes stroke recovery by enhancing network excitability. However, the complexities of utilizing EE in a clinical setting limit its translation. Methods: We used multifaceted approaches combining electrophysiology, chemogenetics, optogenetics, and floxed mice in a mouse photothrombotic stroke model to reveal the key target of EE-mediated stroke recovery. Results: EE reduced tonic gamma-aminobutyric acid (GABA) inhibition and facilitated phasic GABA inhibition in the peri-infarct cortex, thereby promoting network excitability and stroke recovery. These beneficial effects depended on GAT-1, a GABA transporter regulating both tonic and phasic GABA signaling, as EE positively regulated GAT-1 expression, trafficking, and function. Furthermore, GAT-1 was necessary for EE-induced network plasticity, including structural neuroplasticity, input synaptic strengthening in the peri-infarct cortex, output synaptic strengthening in the corticospinal tract, and sprouting of uninjured corticospinal axons across the midline into the territory of denervated spinal cord, and functional recovery from stroke. Moreover, restoration of GAT-1 function in the peri-infarct cortex by its overexpression showed similar beneficial effects on stroke recovery as EE exposure. Conclusion: GAT-1 is a key molecular substrate of the effects of EE on network excitability and consequent stroke recovery and can serve as a novel therapeutic target for stroke treatment during the repair phase. |
| Databáze: | OpenAIRE |
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