Dysfunction in the understanding of social signals has been reported in persons with epilepsy, which may partially explain lower levels of life satisfaction in this patient population. Extensive assessment is necessary, particularly when the mesial temporal lobe, responsible for emotion processing, is affected. The authors examined multiple levels of social perception in patients with mesial temporal lobe epilepsy (MTLE), including judgments of point-light motion displays of human communicative interactions (Communicative Interactions Database-5 Alternative Forced Choice format) and theory-of-mind processes evaluated using geometric shapes (Frith-Happé animations [FHA]). This case-control study included MTLE patients with anterior temporal lobectomies (ATL+) (N=19), MTLE patients without lobectomies (ATL-) (N=21), and healthy controls (HCs) (N=20). Both groups of MTLE patients were less efficient in recognizing goal-directed and mentalizing interactions of FHA compared with HC subjects. The ATL+ group attributed emotions to FHA less accurately than HC subjects. Both the ATL- and ATL+ groups classified individual point-light animations more often as communicative than the HC group. ATL+ patients were also less efficient in interpreting point-light animations in terms of individual actions than the HC group. The number of years of epilepsy duration was inversely correlated with recognition of FHA interactions. The mean number of seizures was inversely correlated with the interaction identification in point-light stimuli. Patients with MTLE, irrespective of surgical treatment, present impaired social perception in domains assessed with abstract moving shapes or nonabstract biological motion. This impairment may be the basis of problems faced by patients reporting difficulties in understanding the intentions and feelings of other individuals.
Enhanced levels of Matrix Metalloproteinase-9 (MMP-9) have been implicated in the pathogenesis of epilepsy in humans and rodents. Lack of Mmp-9 impoverishes, whereas excess of Mmp-9 facilitates epileptogenesis. Epigenetic mechanisms driving the epileptogenesis-related upregulation of MMP-9 expression are virtually unknown. The aim of this study was to reveal these mechanisms. We analyzed hippocampi extracted from adult and pediatric patients with temporal lobe epilepsy as well as from partially and fully pentylenetetrazole kindled rats. We used a unique approach to the analysis of the kindling model results (inclusion in the analysis of rats being during kindling, and not only a group of fully kindled animals), which allowed us to separate the molecular effects exerted by the epileptogenesis from those related to epilepsy and epileptic activity. Consequently, it allowed for a disclosure of molecular mechanisms underlying causes, and not consequences, of epilepsy. Our data show that the epileptogenesis-evoked upregulation of Mmp-9 expression is regulated by removal from Mmp-9 gene proximal promoter of the two, interweaved potent silencing mechanisms–DNA methylation and Polycomb Repressive Complex 2 (PRC2)-related repression. Demethylation depends on a gradual dissociation of the DNA methyltransferases, Dnmt3a and Dnmt3b, and on progressive association of the DNA demethylation promoting protein Gadd45β to Mmp-9 proximal gene promoter in vivo. The PRC2-related mechanism relies on dissociation of the repressive transcription factor YY1 and the dissipation of the PRC2-evoked trimethylation on Lys27 of the histone H3 from the proximal Mmp-9 promoter chromatin in vivo. Moreover, we show that the DNA hydroxymethylation, a new epigenetic DNA modification, which is localized predominantly in the gene promoters and is particularly abundant in the brain, is not involved in a regulation of MMP-9 expression during the epileptogenesis in the rat hippocampus as well as in the hippocampi of pediatric and adult epileptic patients. Additionally, we have also found that despite of its transient nature, the histone modification H3S10ph is strongly and gradually accumulated during epileptogenesis in the cell nuclei and in the proximal Mmp-9 gene promoter in the hippocampus, which suggests that H3S10ph can be involved in DNA demethylation in mammals, and not only in Neurospora. The study identifies MMP-9 as the first protein coding gene which expression is regulated by DNA methylation in human epilepsy. We present a detailed epigenetic model of the epileptogenesis-evoked upregulation of MMP-9 expression in the hippocampus. To our knowledge, it is the most complex and most detailed mechanism of epigenetic regulation of gene expression ever revealed for a particular gene in epileptogenesis. Our results also suggest for the first time that dysregulation of DNA methylation found in epilepsy is a cause rather than a consequence of this condition.
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