Axon Initial Segment Structural Plasticity is Involved in Seizure Susceptibility in a Rat Model of Cortical Dysplasia

Abstract

Cortical dysplasia is the most common etiology of intractable epilepsy. Both excitability changes in cortical neurons and neural network reconstitution play a role in cortical dysplasia epileptogenesis. Recent research shows that the axon initial segment, a subcompartment of the neuron important to the shaping of action potentials, adjusts its position in response to changes in input, which contributes to neuronal excitability and local circuit balance. It is unknown whether axon initial segment plasticity occurs in neurons involved in seizure susceptibility in cortical dysplasia. Here, we developed a "Carmustine"- "pilocarpine" rat model of cortical dysplasia and show that it exhibits a lower seizure threshold, as indicated by behavior studies and electroencephalogram monitoring. Using immunofluorescence, we measured the axon initial segment positions of deep L5 somatosensory neurons and show that it is positioned closer to the soma after acute seizure, and that this displacement is sustained in the chronic phase. We then show that Nifedipine has a dose-dependent protective effect against axon initial segment displacement and increased seizure susceptibility. These findings further our understanding of the pathophysiology of seizures in cortical dysplasia and suggests Nifedipine as a potential therapeutic agent.

Refractory psychiatric symptoms and seizure associated with Dandy-Walker syndrome: A case report and literature review

“…[ 17 ] Patients with pathological focal lesion and cortical dysplasia had lower seizure threshold. [ 18 ] Hydrocephalus can cause neuronal damage in the cortex by disturbing activity of the dopaminergic and noradrenergic neuronal system as well as to synaptogenesis, in advanced hydrocephalus, morphological deformation of cortical neurons are accompanied by variation in neurofilament immunoreactivity, since the neurofilament is the key component of the neuronal cytoskeleton which takes part in the maintenance of cytoplasmic morphology, functional and structural changes to the cytoskeleton can affect cortical neurons because of the procession of hydrocephalus, moreover, the axonal lesion in the periventricular white matter presented with the most incomplete recovery after shunt placement could attribute to the impaired cognitive function who have received shunt placement and have obviously restructured cerebral mantles. [ 19 ]…”

“…[17] Patients with pathological focal lesion and cortical dysplasia had lower seizure threshold. [18] Hydrocephalus can cause neuronal damage in the cortex by disturbing activity of the dopaminergic and noradrenergic neuronal system as well as to synaptogenesis, in advanced hydrocephalus, morphological deformation of cortical neurons are accompanied by variation in neurofilament immunoreactivity, since the neurofilament is the key component of the neuronal cytoskeleton which takes part in the maintenance of cytoplasmic morphology, functional and structural changes to the cytoskeleton can affect cortical neurons because of the procession of hydrocephalus, moreover, the axonal lesion in the periventricular white matter presented with the most incomplete recovery after shunt placement could attribute to the impaired cognitive function who have received shunt placement and have obviously restructured cerebral mantles. [19] Shunt-related seizure is reported in nearly 48% of the patients and are suggested to be connected with the insertion of the VPS, seizure can be observed after VPS in children who have not presented any sign of hemorrhage or infection as underlying causes, the occurrence of shunt-related seizure might be explained by the reparation of the brain tissue and the injury to the brain parenchyma through ventricular catheter or the immunologic reaction to the catheter itself.…”

Neural Regulation of Cancer: Cancer‐Induced Remodeling of the Central Nervous System

“…[20] The cellular and molecular events associated with epilepsy-induced structural synaptic alterations further contribute to remodeling of neural circuits that could either reestablish normal neuronal functions or aggravate the pathological processes associated with epilepsy. [20,21] Importantly, evidence from animal models of epilepsy, demonstrating the ability of newborn neurons to mature and integrate into nearby neural circuitries implies the strong propensity of changes in the structural connectome to impact functional outcomes and recovery in epilepsy patients. [22] Among several CNS imaging techniques employed, fMRI has emerged as a widely used tool to investigate the long-range neuronal network remodeling occurring in both injured and unaffected hemispheres during seizures and postrecovery.…”