Treadmill Running Regulates Adult Neurogenesis, Spatial and Non-spatial Learning, Parvalbumin Neuron Activity by ErbB4 Signaling

Exercise can promote adult neurogenesis and improve symptoms associated with schizophrenia and other mental disorders via parvalbumin (PV)-positive GABAergic interneurons in the dentate gyrus ErbB4 is the receptor of neurotrophic factor neuregulin 1, expressed mostly in PV-positive interneurons. Whether ErbB4 in PV-positive neurons mediates the beneficial effect of exercise and adult neurogenesis on mental disorder needs to be further investigation. Here, we first conducted a four-week study on the effects of AG1478, an ErbB4 inhibitor, on memory and neurogenesis. AG1478 significantly impaired the performance in several memory tasks, including the T -maze, Morris water maze, and contextual fear conditioning, downregulated the expression of total ErbB4 (T-ErbB4) and the ratio of phosphate-ErbB4 (p-ErbB4) to T-ErbB4, and associated with neurogenesis impairment. Interestingly, AG1478 also appeared to decrease intracellular calcium levels in PV neurons, which could be reversed by exercise. These results suggest exercise may regulate adult neurogenesis and PV neuron activity through ErbB4 signaling. Overall, these findings provide further evidence of the importance of exercise for neurogenesis and suggest that targeting ErbB4 may be a promising strategy for improving memory and other cognitive functions in individuals with mental disorders. Graphical Abstract Treadmill running and ErbB4 signaling: AG1478 downregulated the expression of T-ErbB4 and the ratio of p-ErbB4 to T-ErbB4, while treadmill running enhanced neurogenesis, increased spatial learning and memory, non-spatial working, and reference memory and promoted the intracellular Ca 2+ levels in PV neurons.