TrkA neurotrophin receptor and PI3K-Akt signaling involvement in cranial irradiation-induced memory deficit

e14679 Background: This study aimed to investigate the role of neurotrophin receptor TrkA in cranial radiation-induced memory decline. Methods: Single dose of 10Gy 4MeV electron beam whole brain irradiation (WBI) was given to young male Sprague-Dawley rats (50–60g, day 21). 3 months after WBI, western blot was performed to detect protein level of TrkA and its downstream signaling molecules. The Morris water maze test was performed to evaluate the consequence of WBI on hippocampus-dependent memory formation. Immunohistochemistry was performed to evaluate the consequence of WBI on neurogenesis. For overexpression of TrkA, Adeno-associated virus were injected at the rate of 0.2μl/min (n = 15-20 per group). After that, Morris water maze test was performed again. Results: In Morris water maze test, WBI lead to notable memory deficit, the irradiation rats spent longer latency time than control rats (p < 0.05). In the spatial probe trial, the irradiation rats spent less time in the target quadrant than control rats (p < 0.05). Immunohistochemistry showed that cranial irradiation inhibited proliferation and neurogenesis in hippocampus. The protein level of TrkA expression decreased significantly at 3 months after irradiation compared with control group. Phosphorylation of PI3k, AKT, ERK1/2, CREB were also observed to be significantly inhibited (all p < 0.05). Next, we explored the irradiation-induced apoptotic signal transduction. The increased expression of JNK, caspase-3/9 and reduced expression of BCl2 confirm the irradiation induced apoptosis. After Adeno-associated virus injection, AAV-overexpression TrkA rats showed less escape latency time (p < 0.05) and spent more time (p < 0.05) in the target quadrant than AAV-irradiation rats, but still more escape latency time (p < 0.05) and spent less time (p < 0.05) in the target quadrant than AAV-control rats. Additionally, immunofluorescence staining showed AAV-overexpression-TrkA also rescued radiation-induced neurogenesis impairment Conclusions: TrkA may play a critical role in radiation-induced memory deficit, which indicate the data may have important therapeutic implications.