Administration of intramuscular AAV-BDNF and intranasal AAV-TrkB promotes neurological recovery via enhancing corticospinal synaptic connections in stroke rats

Stroke causes long-term disability in survivors. BDNF/TrkB plays an important role in synaptic plasticity and synaptic transmission in the central nervous system (CNS), promoting neurological recovery. In this study, we performed non-invasive treatment methods focused on intramuscular injection into stroke-injured forelimb muscles, or intranasal administration using adeno-associated virus (AAV) vectors carrying genes encoding BDNF or TrkB. In a permanent rat middle cerebral artery occlusion (MCAO) model, we assessed the effects of combination therapy with AAV-BDNF and AAV-TrkB on motor functional recovery and synaptic plasticity of the corticospinal connections. Our results showed that BDNF or TrkB gene transduced in the spinal anterior horn neurons and cerebral cortical neurons. Compared to AAV vector treatment alone, behavioral and electrophysiological results showed that the combination therapy significantly improved upper limb motor functional recovery and neurotransmission efficiency after stroke. BDA tracing, immunofluorescence staining, qRT-PCR, and transmission electron microscopy of synaptic ultrastructure results revealed that the combination therapy not only potently increased the expression of Synapsin I, PSD-95, and GAP-43, but also promoted the axonal remodeling and restoration of abnormal synaptic structures. These findings provide a new strategy for enhancing neural plasticity and a potential means to treat stroke clinically.