title: Gene expression alterations in the cerebellum and granule neurons of Cstb(-/-) mouse are associated with early synaptic changes and inflammation.
abstract: Progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1) is an autosomal recessively inherited neurodegenerative disease, manifesting with myoclonus, seizures and ataxia, caused by mutations in the cystatin B (CSTB) gene. With the aim of understanding the molecular basis of pathogenetic events in EPM1 we characterized gene expression changes in the cerebella of pre-symptomatic postnatal day 7 (P7) and symptomatic P30 cystatin B -deficient (Cstb(-/-) ) mice, a model for the disease, and in cultured Cstb(-/-) cerebellar granule cells using a pathway-based approach. Differentially expressed genes in P7 cerebella were connected to synaptic function and plasticity, and in cultured cerebellar granule cells, to cell cycle, cytoskeleton, and intracellular transport. In particular, the gene expression data pinpointed alterations in GABAergic pathway. Electrophysiological recordings from Cstb(-/-) cerebellar Purkinje cells revealed a shift of the balance towards decreased inhibition, yet the amount of inhibitory interneurons was not declined in young animals. Instead, we found diminished number of GABAergic terminals and reduced ligand binding to GABAA receptors in Cstb(-/-) cerebellum. These results suggest that alterations in GABAergic signaling could result in reduced inhibition in Cstb(-/-) cerebellum leading to the hyperexcitable phenotype of Cstb(-/-) mice. At P30, the microarray data revealed a marked upregulation of immune and defense response genes, compatible with the previously reported early glial activation that precedes neuronal degeneration. This further implies the role of early-onset neuroinflammation in the pathogenesis of EPM1.
authors.affiliation: Folkhälsan Institute of Genetics, Helsinki, Finland ; Department of Medical Genetics, Haartman Institute and Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland ; Neuroscience Center, University of Helsinki, Helsinki, Finland.
authors.forename: Tarja
authors.initials: T
authors.lastname: Joensuu
authors.affiliation: Folkhälsan Institute of Genetics, Helsinki, Finland ; Department of Medical Genetics, Haartman Institute and Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland ; Neuroscience Center, University of Helsinki, Helsinki, Finland.
authors.forename: Saara
authors.initials: S
authors.lastname: Tegelberg
authors.affiliation: Folkhälsan Institute of Genetics, Helsinki, Finland.
authors.forename: Eva
authors.initials: E
authors.lastname: Reinmaa
authors.affiliation: Neuroscience Center, University of Helsinki, Helsinki, Finland ; Department of Biosciences, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland ; Department of Veterinary Biosciences, Faculty of Veterinary Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Mikael
authors.initials: M
authors.lastname: Segerstråle
authors.affiliation: Folkhälsan Institute of Genetics, Helsinki, Finland ; Department of Medical Genetics, Haartman Institute and Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland ; Neuroscience Center, University of Helsinki, Helsinki, Finland.
authors.forename: Paula
authors.initials: P
authors.lastname: Hakala
authors.affiliation: Institute of Biomedicine, Pharmacology, University of Helsinki, Helsinki, Finland.
authors.forename: Heidi
authors.initials: H
authors.lastname: Pehkonen
authors.affiliation: Institute of Biomedicine, Pharmacology, University of Helsinki, Helsinki, Finland.
authors.forename: Esa R
authors.initials: ER
authors.lastname: Korpi
authors.affiliation: Institute of Biomedicine, Biochemistry and Developmental Biology, University of Helsinki, Helsinki, Finland.
authors.forename: Jaana
authors.initials: J
authors.lastname: Tyynelä
authors.affiliation: Neuroscience Center, University of Helsinki, Helsinki, Finland ; Department of Veterinary Biosciences, Faculty of Veterinary Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Tomi
authors.initials: T
authors.lastname: Taira
authors.affiliation: Department of Biosciences, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland ; Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: Iiris
authors.initials: I
authors.lastname: Hovatta
authors.affiliation: Folkhälsan Institute of Genetics, Helsinki, Finland ; Department of Medical Genetics, Haartman Institute and Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland ; Neuroscience Center, University of Helsinki, Helsinki, Finland.
authors.forename: Outi
authors.initials: O
authors.lastname: Kopra
authors.affiliation: Folkhälsan Institute of Genetics, Helsinki, Finland ; Department of Medical Genetics, Haartman Institute and Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland ; Neuroscience Center, University of Helsinki, Helsinki, Finland.
authors.forename: Anna-Elina
authors.initials: AE
authors.lastname: Lehesjoki
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002531:Cerebellum / Q000276:immunology / Q000378:metabolism*; D055313:Cystatin B / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D059330:GABAergic Neurons / Q000378:metabolism; D005786:Gene Expression Regulation; D008024:Ligands; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020191:Myoclonic Epilepsies, Progressive / Q000235:genetics*; D009474:Neurons / Q000378:metabolism*; D011485:Protein Binding; D011689:Purkinje Cells / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism; D015203:Reproducibility of Results; D055366:Synaptic Potentials; D013997:Time Factors
chemical_list: C524992:Cstb protein, mouse; D008024:Ligands; D011963:Receptors, GABA-A; D055313:Cystatin B