Mesial temporal lobe epilepsy (MTLE) is a chronic neurological disorder characterized by the occurrence of seizures, and histopathological abnormalities in the mesial temporal lobe structures, mainly hippocampal sclerosis (HS). We used a multi-omics approach to determine the profile of transcript and protein expression in the dorsal and ventral hippocampal dentate gyrus (DG) and Cornu Ammonis 3 (CA3) in an animal model of MTLE induced by pilocarpine. We performed label-free proteomics and RNAseq from laser-microdissected tissue isolated from pilocarpine-induced Wistar rats. We divided the DG and CA3 into dorsal and ventral areas and analyzed them separately. We performed a data integration analysis and evaluated enriched signaling pathways, as well as the integrated networks generated based on the gene ontology processes. Our results indicate differences in the transcriptomic and proteomic profiles among the DG and the CA3 subfields of the hippocampus. Moreover, our data suggest that epileptogenesis is enhanced in the CA3 region when compared to the DG, with most abnormalities in transcript and protein levels occurring in the CA3. Furthermore, our results show that the epileptogenesis in the pilocarpine model involves predominantly abnormal regulation of excitatory neuronal mechanisms mediated by N-methyl D-aspartate (NMDA) receptors, changes in the serotonin signaling, and neuronal activity controlled by calcium/calmodulin-dependent protein Amanda M. Canto and Alexandre H. B. Matos should be considered joint first author.
cendes 8,9 & iscia Lopes-cendes 1,9* Mesial temporal lobe epilepsy (MTLE) is a chronic neurological disorder affecting almost 40% of adult patients with epilepsy. Hippocampal sclerosis (HS) is a common histopathological abnormality found in patients with MTLE. HS is characterised by extensive neuronal loss in different hippocampus subregions. In this study, we used laser microdissection-based microproteomics to determine the protein abundances in different regions and layers of the hippocampus dentate gyrus (DG) in an electric stimulation rodent model which displays classical HS damage similar to that found in patients with MTLE. Our results indicate that there are differences in the proteomic profiles of different layers (granule cell and molecular), as well as different regions, of the DG (ventral and dorsal). We have identified new signalling pathways and proteins present in specific layers and regions of the DG, such as PARK7, RACK1, and connexin 31/gap junction. We also found two major signalling pathways that are common to all layers and regions: inflammation and energy metabolism. Finally, our results highlight the utility of high-throughput microproteomics and spatial-limited isolation of tissues in the study of complex disorders to fully appreciate the large biological heterogeneity present in different cell populations within the central nervous system. Currently, it is well recognised that proteins and their biological roles are multifaceted and complex since all biological mechanisms rely on correct protein function. However, a major part of protein cellular machinery remains unknown, especially in disease-related processes. Therefore, studying proteins, specifically their presence and abundance, is relevant when addressing complex mechanisms leading to disease 1. Laser microdissection-based microproteomics allows for the study of the proteome of enriched specific cell types of interest obtained from a small amount of tissue (100 μg or less) 1-3. Epilepsy is a chronic neurological disorder affecting around 2% of the world population 27/02/2020 18:22:00. It presents a wide variety of clinic manifestations, aetiologies, severities, and prognoses. However, the occurrence of an epileptic seizure, caused by abnormal neuronal discharges, is the common feature of all types of epilepsy 4. Mesial temporal lobe epilepsy (MTLE) is the most frequent form in adults, present in 40% of patients with epilepsy, many of whom do not respond to clinical treatment 5-8 .
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