Impaired reelin processing and secretion by Cajal–Retzius cells contributes to granule cell dispersion in a mouse model of temporal lobe epilepsy

Abstract

Cajal-Retzius cells play a crucial role during ontogeny in regulating cortical lamination via release of reelin. In adult brain, they comprise small calretinin-positive interneurons located in the marginal zone of the cerebral cortex and in the hippocampal fissure. Alterations of reelin signaling or expression have been involved in major neurological disorders, and they underlie granule cell dispersion (GCD) in mesial temporal lobe epilepsy (TLE). Here, we investigated in a mouse model of TLE the contribution of Cajal-Retzius cells to reelin production in epileptic hippocampus and the molecular mechanisms underlying GCD. Following unilateral intrahippocampal Kainic acid injection in adult mice to induce an epileptic focus, we observed that Cajal-Retzius cells gradually became strongly immunopositive for reelin, due to intracellular accumulation. This phenotype resembled the morphology of Cajal-Retzius cells in reeler Orleans (reln (orl/orl) ) mice, which express a secretion-deficient 310-kDa reelin fragment. The possibility that GCD might result from abnormal reelin processing in Cajal-Retzius cells, leading to a lack of reelin secretion, was confirmed by KA injection in reln (orl/+) mice, which induced severe GCD. Furthermore, Western blot analysis in KA-treated wildtype mice revealed increased production of ∼300-kDa reelin fragments, confirming abnormal proteolytic processing. This effect was not seen upon treatment with Botulinum neurotoxin E (BoNT/E), which prevents GCD in KA-lesioned hippocampus by chronic blockade of synaptic transmission. Furthermore, BoNT/E blocked upregulation of TrkB in Cajal-Retzius cells, suggesting that production of truncated reelin in KA-treated hippocampus is activity-dependent and regulated by BDNF. Altogether, these data reveal that GCD results from abnormal reelin processing in Cajal-Retzius cells under the control of BDNF. Our findings highlight the critical role played by Cajal-Retzius cells for hippocampal neuronal reorganization in TLE.

RELN-expressing neuron density in layer I of the superior temporal lobe is similar in human brains with autism and in age-matched controls

“…We cannot rule out the possibility that even though the density of neurons is similar in the autistic and control cerebral cortex, individual neurons may produce or secrete lower amounts of RELN protein in the cerebral cortex of autistic subjects. The decrease of the amount of Reelin reported in autism could also result from abnormal RELN processing in RELN+ neurons leading to a lack or decreased synthesis and/or secretion of RELN, as has been shown for other conditions [29,30]. Nevertheless, Fatemi et al showed that not only the 410 kDa RELN isoform is decreased in human cortical areas associated to autism, but also the 330 kDa and 180 kDa isoforms, as well as RELN mRNA levels.…”

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:…”

“…an impairment in the proteolytic process of the protein that blocks the secretion of reelin by Cajal-Retzius cells, that could be secondary to an increased expression of TrkB, the high-affinity receptor of BDNF [27,29,[103][104][105]; an increased methylation of the reelin promoter [33,106].…”

“…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]. A recent consensus classification, validated through the neuropathology taskforce of the International League Against Epilepsy (ILAE) tried to incorporate aspects of all previous schemes [27,[29][30][31][32].…”

“…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]. A recent consensus classification, validated through the neuropathology taskforce of the International League Against Epilepsy (ILAE) tried to incorporate aspects of all previous schemes [27,[29][30][31][32]. The aim of this consensual classification is to reach a higher reproducibility between the different epilepsy surgery centers and is based on straightforward neuropathological approaches [31,[33][34][35].…”