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bFGF Knockdown Inhibits mTOR Signaling by Suppressing Caveolin-1 and Aggravates Cognitive Damage After Arterial
Qiongyi Pang1, Yudan Wu2, Tianyu Jin1
1Department of Rehabilitation Medicine, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, No. 109, Xueyuan West Road, Wenzhou, 325027, Zhejiang, China.
Insights
Basic fibroblast growth factor (bFGF) deficiency impairs cognitive function and neural development in juvenile rats following arterial ischemic stroke (AIS). Loss of bFGF disrupts synaptic plasticity and exacerbates neurological deficits.
Area of Science:
- Neuroscience
- Developmental Biology
- Molecular Biology
Background:
- Pediatric arterial ischemic stroke (AIS) is a major cause of long-term neurological disability in children.
- Basic fibroblast growth factor (bFGF) is known to promote neural development and repair, but its role in pediatric AIS is not well understood.
Purpose of the Study:
- To investigate the role of bFGF in cognitive function and neural plasticity following experimental AIS in juvenile rats.
- To elucidate the molecular mechanisms by which bFGF influences post-ischemic brain injury.
Main Methods:
- Behavioral tests (Morris water maze, three-chamber test) assessed cognitive and social functions.
- Golgi staining and electron microscopy evaluated neuronal morphology and synaptic structure.
- Western blotting measured protein levels (PSD95, synapsin I, mTOR signaling markers).
- Genetic manipulation (knockdown) was used to study bFGF, FGFR1, and caveolin-1 (Cav1) functions.
Main Results:
- bFGF knockdown in juvenile rats with AIS led to impaired spatial learning, memory, and social interaction.
- Reduced bFGF disrupted neuronal axon morphology, synaptic ultrastructure, and decreased key synaptic proteins (PSD95, synapsin I).
- bFGF deficiency inhibited mTOR signaling, reduced autophagy and apoptosis, and increased necrosis markers.
- bFGF interacts with FGFR1 and Cav1; Cav1 knockdown mimicked bFGF deficiency effects on mTOR signaling.
Conclusions:
- bFGF deficiency exacerbates cognitive deficits in juvenile rats after AIS by suppressing Cav1 and inhibiting mTOR signaling.
- These findings highlight the critical role of the bFGF-Cav1-mTOR pathway in mitigating neurological damage and cognitive impairment post-AIS.
- Understanding these mechanisms offers potential therapeutic targets for pediatric AIS.
Abstract:
Pediatric arterial ischemic stroke (AIS) is the leading cause of stroke in children and approximately two-thirds of affected patients experience permanent neurological sequelae. Although basic fibroblast growth factor (bFGF) has positive effects on neural development, axon regeneration, and synaptic reconstruction, its effects in AIS remain unclear. Here, we examined the role of bFGF in post-ischemic cognitive function in juvenile rats. Behavioral assessments using the Morris water maze and the three-chamber test revealed that bFGF knockdown impairs spatial learning, memory, and social interactions. Golgi staining and electron microscopy demonstrated that bFGF knockdown disrupts neuronal axon morphology and synaptic ultrastructure. In the hippocampus of AIS rats, bFGF deficiency significantly reduced PSD95 and synapsin I protein levels. Moreover, bFGF knockdown decreased autophagy and apoptosis markers while increasing necrosis indicators. Mechanistically, loss of bFGF inhibited phosphorylation of mammalian target of rapamycin (mTOR), a process regulated by fibroblast growth factor receptor 1 (FGFR1). We further show that bFGF interacts with FGFR1 and caveolin-1 (Cav1), a membrane scaffold protein; knockdown of Cav1 in the hippocampus similarly attenuated mTOR signaling. Collectively, our results suggest that bFGF deficiency suppresses Cav1, thereby inhibiting mTOR signaling and exacerbating cognitive deficits after AIS in juvenile rats. These findings provide insight into the molecular mechanisms underlying pediatric AIS.
