Programmed neural circuit formation constitutes the foundation for normal brain functions. Axon guidance cues play crucial roles in neural circuit establishment during development. Whether or how they contribute to maintaining the stability of networks in mature brains is seldom studied. Upon injury, neural rewiring could happen in adulthood, of which mossy fiber sprouting (MFS) is a canonical example. Here, we uncovered a novel role of axon guidance molecule family Sema3F/Npn-2 signaling in MFS and epileptogenesis in a rat model of epilepsy. Dentate gyrus-specific Npn-2 knockdown increased seizure activity in epileptic animals along with increased MFS. Hippocampal culture results suggested that Npn-2 signaling modulates MFS via regulating axon outgrowth and collateral formation. In addition, we discovered that Sema3F/Npn-2 signal through CRMP2 by regulating its phosphorylation in the process of MFS. Our work illustrated that Npn-2 signaling in adult epilepsy animals could potentially modulate seizure activity by controlling MFS. MFS constitutes the structural basis for abnormal electric discharge of neurons and recurrent seizures. Therapies targeting Npn-2 signaling could potentially have disease-modifying anti-epileptogenesis effects in epilepsy treatment.
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