<h3>Purpose/Objective(s)</h3> This study is the first to propose the use of the whole-brain radiation-induced brain injury model in mice, proteomics and animal behavior methods were used to clarify the effect and mechanism of homer1a on nerve cells through AMPAR-CREB pathway after radiation-induced brain injury. <h3>Materials/Methods</h3> The adeno-associated virus overexpression vector and interference expression vector of homer1a were used to inject into the hippocampal CA1 region to create homer1a overexpression and interference expression mice, respectively to establish the mouse whole brain radiation injury model. The expression and spatial distribution of GluR, p-CaMKII, PKA, PKC, p-ERK, p-CREB and other AMPAR-CREB pathway-related molecules in the mouse hippocampus were detected by Real-time PCR, western blot and immunohistochemistry. The stem and wet weight of brain, HE staining, and TUNEL apoptotic cell staining were used to evaluate the degree of brain tissue damage. Neurological function scores, water maze and open field test were used to detect the movement, sensation and cognition of mice. To clarify the role and molecular mechanism of homer1a regulating AMPAR-CREB pathway on neurological function after whole brain radiation injury in mice. <h3>Results</h3> Radiation-induced brain injury can cause brain edema and neurological dysfunction. The results of HE staining showed that the number of dead neuronal cells in the hippocampus of mice increased significantly at 24 hours after injury. The results of TUNEL staining showed that the number of TUNEL positive cells also increased significantly. Western blot results showed that the expression of homer1a increased after radiation-induced brain injury, and the results of immunofluorescence and immunohistochemistry were the same as above. Cognitive and animal behavioral tests (water maze, elevated plus maze, Y-maze and open field test) showed that radiation-induced brain injury could cause damage to the learning and memory function of mice and produce severe depression. By up-regulating homer1a, the degree of brain edema and neurological function score in mice could be effectively reduced. Interfering with the expression of homer1a could aggravate the degree of brain edema and neurological dysfunction in mice. Behavioral results showed that up-regulation of homer1a reversed the learning and memory impairment and anxiety caused by brain injury to a certain extent, while down-regulation of homer1a did the opposite. <h3>Conclusion</h3> Homer1a has neuroprotective function after radiation brain injury, homer1a significantly reduce the degree of brain edema and neurological function score after radiation brain injury, homer1a can reverse the learning and memory impairment and anxiety caused by radiation brain injury to a certain extent, and inhibit neurological cell death. Homer1a may serve as a potential molecular target in the diagnosis and treatment of radiation-induced brain injury.