Progressive Brain Damage, Synaptic Reorganization and NMDA Activation in a Model of Epileptogenic Cortical Dysplasia

Abstract

Whether severe epilepsy could be a progressive disorder remains as yet unresolved. We previously demonstrated in a rat model of acquired focal cortical dysplasia, the methylazoxymethanol/pilocarpine - MAM/pilocarpine - rats, that the occurrence of status epilepticus (SE) and subsequent seizures fostered a pathologic process capable of modifying the morphology of cortical pyramidal neurons and NMDA receptor expression/localization. We have here extended our analysis by evaluating neocortical and hippocampal changes in MAM/pilocarpine rats at different epilepsy stages, from few days after onset up to six months of chronic epilepsy. Our findings indicate that the process triggered by SE and subsequent seizures in the malformed brain i) is steadily progressive, deeply altering neocortical and hippocampal morphology, with atrophy of neocortex and CA regions and progressive increase of granule cell layer dispersion; ii) changes dramatically the fine morphology of neurons in neocortex and hippocampus, by increasing cell size and decreasing both dendrite arborization and spine density; iii) induces reorganization of glutamatergic and GABAergic networks in both neocortex and hippocampus, favoring excitatory vs inhibitory input; iv) activates NMDA regulatory subunits. Taken together, our data indicate that, at least in experimental models of brain malformations, severe seizure activity, i.e., SE plus recurrent seizures, may lead to a widespread, steadily progressive architectural, neuronal and synaptic reorganization in the brain. They also suggest the mechanistic relevance of glutamate/NMDA hyper-activation in the seizure-related brain pathologic plasticity.

Continuous neurodegeneration and death pathway activation in neurons and glia in an experimental model of severe chronic epilepsy

“…3D3 , D 4 , arrows). As reported in our recent paper(Colciaghi et al, 2014) at chronic epilepsy stages we consistently found a progressive reduction of hippocampal volume (compareFig. 3A 1-4 with Fig.…”

“…15 reported in epileptic MP rats (Colciaghi et al, 2014). However, the activation of the c-Jun pathway is not necessarily related to ongoing cell death.…”

“…In addition, the lack of FJ staining of the thalamic reticular nucleus was surprising, since cortical and hippocampal GABAergic inputs were more selectively reduced than glutamatergic ones in MP rats at chronic stages vs controls (Colciaghi et al, 2014). However, the Rt-mediated inhibitory drive on the other thalamic nuclei (Pantoja-Jimenez et al, 2014) was likely not sufficient to prevent excitotoxic neurodegeneration, given the early FJ labeling in all thalamus and the presence of vast necrotic areas at chronic epilepsy time-points (Kubova et al, 2001).…”

Stem Cell Transplantation Reverses Chemotherapy-Induced Cognitive Dysfunction

“…Interestingly, CYP treatment induced a significant swelling of the cell body in neurons of the DG and CA1 compared to the other cohorts. Past work (38) has documented hypertrophy of the soma associated with other neuropathological conditions, and current findings suggest that chemotherapy elicits a similar response. In each of the foregoing instances, stem cell grafting promoted the recovery of overall spine density and each of the CYP-depleted spine morphologies.…”

Association of Progressive Cerebellar Atrophy With Long-term Outcome in Patients With Anti-N-Methyl-d-Aspartate Receptor Encephalitis

“…Potential risk factors include systemic complications (heart failure 20 and septic shock 21 ), malnutrition, 22,23 status epilepticus, 24,25 prolonged use of corticosteroids, 26 long-term exposure to various antiepileptic agents, 27,28 and propofol infusion syndrome. 29 Our patients with DCA developed more serious complications and required ventilatory support more frequently than did those without DCA.…”