Epilepsy-Induced Motility of Differentiated Neurons

Abstract

Neuronal ectopia, such as granule cell dispersion (GCD) in temporal lobe epilepsy (TLE), has been assumed to result from a migration defect during development. Indeed, recent studies reported that aberrant migration of neonatal-generated dentate granule cells (GCs) increased the risk to develop epilepsy later in life. On the contrary, in the present study, we show that fully differentiated GCs become motile following the induction of epileptiform activity, resulting in GCD. Hippocampal slice cultures from transgenic mice expressing green fluorescent protein in differentiated, but not in newly generated GCs, were incubated with the glutamate receptor agonist kainate (KA), which induced GC burst activity and GCD. Using real-time microscopy, we observed that KA-exposed, differentiated GCs translocated their cell bodies and changed their dendritic organization. As found in human TLE, KA application was associated with decreased expression of the extracellular matrix protein Reelin, particularly in hilar interneurons. Together these findings suggest that KA-induced motility of differentiated GCs contributes to the development of GCD and establish slice cultures as a model to study neuronal changes induced by epileptiform activity.

Reelin protects against amyloid β toxicity in vivo

“…Supplementation with Reelin can prevent granule cell dispersion following kainic acid injection (54). We found that complete loss of Reelin in adult mice resulted in no dispersion of the granule cell layer, suggesting that additional signaling cascades are activated in response to enhanced glutamate release in MTLE and experimental kainate application, respectively, eventually leading to increased granule cell motility and dispersion (55). …”

Hippocampal granule cell pathology in epilepsy — A possible structural basis for comorbidities of epilepsy?

“…8). Pronounced migration of newborn granule cells into the molecular layer following Disc1 KO or KD suggest a similar phenomenon could be occurring in these animals [136–138]. Finally, reduced Disc1 expression is correlated with expansion of the granule cell layer in the kindling model of epilepsy [139, 140], supporting the hypothesis that changes in Disc1 expression may mediate some of the granule cell abnormalities observed in epilepsy.…”

Revisiting hippocampal sclerosis in mesial temporal lobe epilepsy according to the “two-hit” hypothesis

“…In human patients with MTLE, a negative correlation was found between granule cell dispersion and the expression of reelin RNA [8,10,12,14,86,100]. In animal models, this hypothesis was confirmed in both ex vivo slice culture infused with kainate [20,99] and the KA-MTLE mouse model [14,24,26,27,101,102]. Two different mechanisms were suggested to explain the decrease in reelin expression:…”

“…Moreover, the application of kainate in slice culture induced a cell bodies translocation of fully mature granule cells and changed their dendritic organization [20,85]. The fact that in the Reeler mouse mutant where the protein reelin is lacking [99][100][101]111], GCD is observed, suggested that this protein plays a key role in the control of granule cell migration during brain development [100,112].…”

“…Many classifications of HS have been proposed based on the distribution and extent of neuronal loss and gliosis in different hippocampal subfields [8][9][10][11][12][13][14][15][16][17][18][19]. The most recent classification allowed correlations between clinical histories, post-surgical outcomes and neuropathological findings [19][20][21][22][23]. For example, an early (<3 years old) initial precipitating event is associated with a type 1a or 1b HS (i.e., classical or total HS) and a better post-surgical outcome [14,19,[24][25][26][27][28].…”