title: Possible contribution of epigenetic changes in the development of schizophrenia-like behavior in vasopressin-deficient Brattleboro rats.
abstract: Schizophrenia-like symptoms were detected in vasopressin-deficient (di/di) Brattleboro rats, and it was also suggested that schizophrenia might have an epigenetic component. We aimed to clarify if epigenetic changes contribute to schizophrenia-like behavior of this strain. Behavioral (locomotion by telemetry, cognition by novel object recognition, social recognition and social avoidance test, attention by pre-pulse inhibition) and epigenetic differences were compared between wild type and di/di animals. DNA methyltransferase1 (DNMT1), DNMT3a, as well as COMT, GAD, VGLUT1, 5HT2A, BDNF mRNA levels in prefrontal brain region and hippocampus were studied by qRT-PCR. Histone3 (H3) and H4 acetylation (Ac) were studied by western-blot followed by region specific examination of H3 lysine9 (K9) acetylation by immunohistochemistry. Impaired cognitive, social and attention behavior of di/di rats confirmed schizophrenia-like symptoms in our local colony. The pan-AcH3 immunoreactivity was lower in prefrontal region and elevated in the hippocampus of di/di animals. We found lower immunopositive cell number in the dorsal peduncular prefrontal cortex and the ventral lateral septum and increased AcH3K9 immunoreactivity in CA1 region of di/di animals. There were no major significant alterations in the studied mRNA levels. We confirmed that Brattleboro rat is a good preclinical model of schizophrenia. Its schizophrenia-like behavioral alteration was accompanied by changes in H3 acetylation in the prefrontal region and hippocampus. This may contribute to disturbances of many schizophrenia-related substances leading to development of schizophrenia-like symptoms. Our studies confirmed that not a single gene, rather fine changes in an array of molecules are responsible for the majority of schizophrenia cases.
authors.affiliation: Department of Behavioral Neurobiology, Institute of Experimental Medicine, Budapest, Hungary.
authors.forename: Kornél
authors.initials: K
authors.lastname: Demeter
authors.affiliation: Department of Behavioral Neurobiology, Institute of Experimental Medicine, Budapest, Hungary.
authors.forename: Bibiána
authors.initials: B
authors.lastname: Török
authors.affiliation: Department of Behavioral Neurobiology, Institute of Experimental Medicine, Budapest, Hungary.
authors.forename: Anna
authors.initials: A
authors.lastname: Fodor
authors.affiliation: Department of Behavioral Neurobiology, Institute of Experimental Medicine, Budapest, Hungary.
authors.forename: János
authors.initials: J
authors.lastname: Varga
authors.affiliation: Laboratory of Molecular Neuroendocrinology, Institute of Experimental Medicine, Budapest, Hungary.
authors.forename: Szilamér
authors.initials: S
authors.lastname: Ferenczi
authors.affiliation: Laboratory of Molecular Neuroendocrinology, Institute of Experimental Medicine, Budapest, Hungary.
authors.forename: Krisztina J
authors.initials: KJ
authors.lastname: Kovács
authors.affiliation: Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary.
authors.forename: Ildikó
authors.initials: I
authors.lastname: Eszik
authors.affiliation: Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary.
authors.forename: Viktor
authors.initials: V
authors.lastname: Szegedi
authors.affiliation: Department of Behavioral Neurobiology, Institute of Experimental Medicine, Budapest, Hungary. Electronic address: zelena.dora@koki.mta.hu.
authors.forename: Dóra
authors.initials: D
authors.lastname: Zelena
mesh_terms: D000107:Acetylation; D000818:Animals; D001127:Arginine Vasopressin / Q000172:deficiency* / Q000235:genetics; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D005260:Female; D006624:Hippocampus / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D009043:Motor Activity / Q000502:physiology; D009714:Nucleus Accumbens / Q000378:metabolism; D017397:Prefrontal Cortex / Q000378:metabolism*; D065808:Prepulse Inhibition / Q000502:physiology; D011910:Rats, Brattleboro; D021641:Recognition, Psychology / Q000502:physiology; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism*; D012565:Schizophrenic Psychology; D020665:Septum of Brain / Q000378:metabolism; D012919:Social Behavior
chemical_list: D006657:Histones; D001127:Arginine Vasopressin
keywords: Brattleboro; Epigenetics; Schizophrenia; Vasopressin