Epileptiform activity interferes with proteolytic processing of Reelin required for dentate granule cell positioning

Abstract

The extracellular matrix protein Reelin is an essential regulator of neuronal migration and lamination in the developing and mature brain. Lack of Reelin causes severe disturbances in cerebral layering, such as the reeler phenotype and granule cell dispersion in temporal lobe epilepsy. Reelin is synthesized and secreted by Cajal-Retzius cells and GABAergic interneurons, and its function depends on proteolytic cleavage after secretion. The mechanisms regulating these processes are largely unknown. Here, we used rat hippocampal slice cultures to investigate the effect of neuronal activation and hyperexcitation on Reelin synthesis, secretion, and proteolytic processing. We show that enhanced neuronal activity does not modulate Reelin synthesis or secretion. Moreover, we found that intracellular Reelin resides predominantly in the endoplasmic reticulum before it is constitutively secreted via the early secretory pathway. Epileptiform activity, however, impairs the proteolytic processing of Reelin and leads to accumulation of Reelin in the extracellular matrix. We found that both conditions, epileptiform activity and impaired proteolytic cleavage of Reelin, cause granule cell dispersion via inhibition of metalloproteinases. Taken together, our results strongly suggest that secretion of Reelin is activity-independent and that proteolytic processing of Reelin is required for the maintenance of granule cell lamination in the dentate gyrus.

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.…”

Cleavage within Reelin Repeat 3 Regulates the Duration and Range of the Signaling Activity of Reelin Protein

“…N-t cleavage is catalyzed by an unidentified metalloprotease(s) that bind(s) heparin (10). Abnormal N-t cleavage has been implicated in Alzheimer disease (41) and epilepsy (42). Recent studies from our laboratory and other laboratories indicate that a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) 4 is able to cleave Reelin at the N-t site (43,44), although its contribution to Reelin metabolism in vivo remains uncertain.…”

Cajal-Retzius cells: organizers of cortical development

“…Reelin is a relatively large, secreted glycoprotein that integrates into the extracellular matrix (see [92] for review). It is most probably released by constitutive, depolarization-independent pathways [87]. The canonical receptors for reelin are VLDLR (very low density lipoprotein receptor) and ApoER2 (apolipoprotein E receptor 2), which activate various molecular downstream targets via the adaptor protein Dab1 [36,37].…”