Morphogen upregulation following seizure-induced oxidative stress: Implications for hippocampal remodeling and neuronal survival

Moultrie, GA

Introduction: Epileptic seizures arise from abnormal neuronal activity characterized by excessive excitatory signaling and reduced inhibitory control within neural circuits. During seizures, neurons exhibit paroxysmal depolarization shifts, leading to synchronous hyperexcitability and increased glutamate release. Although many seizures do not produce permanent injury, prolonged neuronal hyperactivity, such as status epilepticus or temporal lobe epilepsy, can lead to neuronal death and structural remodeling within the hippocampus. Experimental models demonstrate that seizure activity generates significant oxidative stress and morphological changes within the dentate gyrus, including mossy fiber sprouting, granule cell dispersion, and aberrant neurogenesis. Increasing evidence suggests these changes are mediated by morphogens, a conserved class of signaling proteins that regulate cellular proliferation. Morphogen signaling pathways may respond to oxidative stress and activate cellular mechanisms that promote neuronal survival following seizure-induced injury. This review examines how seizure-induced oxidative stress influences morphogen signaling in the hippocampus, with particular focus on Sonic hedgehog (Shh), Wnt, and fibroblast growth factor (FGF) pathways.

Methods: A narrative literature review was conducted to evaluate experimental studies investigating morphogen signaling in seizure models. Peer-reviewed articles examining Shh, Wnt, and FGF signaling in epilepsy or seizure-induced hippocampal remodeling were identified and analyzed. Included studies utilized established rodent seizure induction models, such as kainic acid-induced status epilepticus, pilocarpine-induced seizures, and electroshock convulsion models, commonly used to investigate epileptogenesis and neuronal injury. Molecular, histological, and signaling pathway analyses from these studies were synthesized to identify patterns of morphogen upregulation and associated neuroprotective mechanisms.

Results: Evidence from multiple experimental models demonstrates that morphogen signaling pathways are significantly altered following seizure activity. Sonic hedgehog signaling is upregulated in mossy cells of the dentate gyrus after seizure induction and promotes neuronal survival through activation of antiapoptotic pathways and paracrine signaling that supports neighboring neurons. Wnt signaling also increases following seizures and regulates neurogenesis and neuronal differentiation through β-catenin-mediated transcriptional pathways. While acute activation of Wnt signaling may support neuroprotective responses, dysregulation of this pathway has been associated with mossy fiber sprouting and abnormal hippocampal circuit remodeling. Fibroblast growth factor signaling similarly increases after seizure induction. Members of the FGF family, including FGF2, FGF5, FGF7, and FGF22, regulate synaptic organization, neuronal proliferation, and inflammatory responses through pathways such as MAPK, PI3K-AKT, and STAT signaling. Among these, FGF2 has demonstrated particularly strong neuroprotective effects by reducing excitotoxicity and promoting neuronal recovery following seizure-related injury.

Discussion: Seizure-induced oxidative stress activates multiple morphogen signaling pathways that influence neuronal survival and hippocampal remodeling. Shh, Wnt, and FGF signaling appear to function as adaptive responses that promote neurogenesis, regulate apoptosis, and facilitate tissue repair following neuronal injury. However, persistent dysregulation of these pathways may also contribute to maladaptive structural changes that sustain epileptogenesis. Improved understanding of morphogen-mediated signaling may provide insight into the molecular mechanisms underlying epilepsy and help identify novel therapeutic targets aimed at reducing neuronal loss and improving treatment strategies for patients with refractory seizure disorders.