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.

Proteomic determination of the lysine acetylome and phosphoproteome in the rat native inner medullary collecting duct

“…Third, it is plausible that chronic exposure to dDAVP and second messengers such as cAMP are required for detectable changes in K-acetylation. For example, Brattleboro rats, which lack endogenous vasopressin, have reduced K-acetylation of histone H3 K9 in different regions of the brain compared with control rats (15). Moreover, chronic 16 and 48 h of vasopressin to L6 myogenic cells significantly increased K-acetylation (59).…”

Epigenetic Modulation of Vasopressin Expression in Health and Disease

“…Our research group demonstrated the possible role of histone modification in the development of schizophrenia-like behavior in genetically AVP deficient Brattleboro rat (without changes in the enzymes responsible for DNA methylation, DNA methyltransferase, DNMT1 and DNMT3a) [16]. In AVP deficient animals, Western-blot measurements showed lower pan-AcH3 (histone 3 acetylation) immunoreactivity in the frontal part of the brain with elevated levels in the hippocampus.…”

“…AVP determines behavioral responses to environmental stimuli and participates in the development of social interactions, aggression, reproduction, parental behavior and belonging [4,10,11]. Therefore, alterations in the AVPergic tone may be implicated in the pathology of stress-related disorders (anxiety and depression) [12], Alzheimer's disorder [13], posttraumatic stress disorder [14] as well as schizophrenia [15][16][17].…”

Application of animal experimental models in the research of schizophrenia

“…Interestingly, the study by Bhardwaj, Stojkovic, Kiessling, Srivastava, and Cermakian (2015) has found that constant lighting exerts unremitting effects on the behavior of Dtnbp1 mutant mice, leading to PPI and anxiety‐like behaviors while reintroducing the mice into the normal light–dark cycle fails to completely reverse the disordered behaviors. Lately, Demeter et al (2016) has proposed that the Brattleboro rat strain lacking arginine vasopressin (AVP) is a valuable model for studying the development of schizophrenia‐like behavior and investigating the expression of affected genes. Animal experimental models provide convenience when examining changes in genetic status and testing newly discovered antipsychotics.…”