TIMP‐1 inhibits the proteolytic processing of Reelin in experimental epilepsy

Abstract

Temporal lobe epilepsy is frequently associated with granule cell dispersion (GCD), an abnormal widening of the granule cell layer in the dentate gyrus. There is increasing evidence that a loss and the functional inactivation of the positional signal Reelin is involved in GCD formation. Reelin is synthesized and released by Cajal-Retzius cells and interneurons, and its function depends on proteolytic cleavage after secretion. Epileptic conditions impair Reelin processing by inhibition of matrix metalloprotease (MMP) activity and cause the extracellular accumulation of unprocessed Reelin. Here we investigated how epileptic conditions inhibit MMP activity. We used kainate (KA) treatment of organotypic hippocampal slice cultures as an epilepsy model and found a significant increase of tissue inhibitor of metalloproteases 1 (TIMP-1) levels and strongly enhanced TIMP-1 immunolabeling in hippocampal neurons. Functional inhibition of TIMP-1 prevented the KA-induced impairment of Reelin cleavage indicating that TIMP-1 inhibits MMP activity. Moreover, application of recombinant TIMP-1 alone was sufficient to impair Reelin processing and to induce GCD, similar to that observed after KA treatment. In summary, we present evidence that epileptic conditions inhibit MMP activity by up-regulation of endogenous TIMP-1, which in turn leads to extracellular accumulation of uncleaved and inactive Reelin and thereby to GCD.

Extracellular proteolysis of reelin by tissue plasminogen activator following synaptic potentiation

“…However, these mechanisms only serve to adjust the level of reelin signaling, as they are not sufficient to initiate the reelin signal by themselves. In support of this view, preventing extracellular proteolysis of reelin by inhibiting metalloproteinases blocks signaling in the developing cortex and disrupts corticogenesis (Lambert de Rouvroit et al, 1999; Jossin et al, 2007) and also impairs reelin processing in an epilepsy model (Tinnes et al, 2013). These findings imply that reelin is tethered to the extracellular matrix following secretion, where it remains inactive until liberated by proteolysis to initiate downstream signaling.…”

Early postnatal expression and localization of matrix metalloproteinases‐2 and ‐9 during establishment of rat hippocampal synaptic circuitry

“…Molecularly, such aberrant cellular positioning following perturbation of MMP proteolysis may reflect critical, early roles of MMPs in processing the secreted glycoprotein Reelin. Reelin is necessary for proper neuronal migration and lamination in hippocampus and other cortical structures (Tissir and Goffinet, 2003) and undergoes significant extracellular proteolytic processing by several different metalloproteinases for full bioactivity in vivo (Lambert de Rouvroit et al, 1999;Jossin et al, 2007;Tinnes et al, 2011Tinnes et al, , 2013Hisanaga et al, 2012;Krstic et al, 2012).…”

Neural ECM and epilepsy

“…However, TIMP-1 KO mice were resistant to kainate-induced excitotoxicity. Recently, Tinnes et al (2013) reported that a seizure-induced increase in TIMP-1 interfered with normal proteolytic processing of reelin in the epileptogenic hippocampus, leading to granule cell dispersion. Electroconvulsive shock upregulates the TIMP-1, TIMP-2, and TIMP-4 transcription in the hippocampus (Girgenti et al, 2011).…”