Bibiána Török 1,2 , Anna Fodor 1, Kornél Demeter 1, Ildikó Eszik 3, Viktor Szegedi 3, Dóra Zelena 1
1 Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary
2 Semmelweis University, János Szentágothai School of PhD Studies
3 Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary
Previous studies have shown schizophrenia-like behaviors in vasopressin-deficient Brattleboro rats, and other studies have suggested that epigenetic changes may also be involved in the development of schizophrenia.
Therefore our aim was to find out whether epigenetic changes contribute to schizophrenia-like behavior of this strain.
Behavioral and epigenetic characteristics of vasopressin-deficient rats were compared to wild type controls. Locomotion was tested by telemetry, cognitive function was studied by novel object recognition, social recognition and social avoidance test, attention was measured by pre-pulse inhibition (PPI) test. DNA methyltransferase1, DNA methyltransferase3a, as well as catechol-O-methyltransferase, glutamate decarboxylase, vesicular glutamate transporter 1, serotonin 2A, brain-derived neurotrophic factor mRNA levels in prefrontal brain region and hippocampus were studied by qRT-PCR. Working with MTA SZBK, histone3 (H3) and H4 acetylation (Ac) were investigated by western-blot. Then, specifically, H3 lysine9 (K9) acetylation was studied by immunohistochemistry in the prefrontal cortex, hippocampal regions, lateral septum and nucleus accumbens.
Impaired cognitive, social and attention behavior of vasopressin-deficient rats confirmed schizophrenia-like symptoms in our local colony. There were no major significant alterations in the studied mRNA levels. The pan-AcH3 immunoreactivity was lower in prefrontal region and elevated in the hippocampus of vasopressin-deficient animals. We found lower immunoreactivity in the dorsal peduncular prefrontal cortex and the ventral lateral septum and increased AcH3K9 immunopositive cell number in CA1 region of vasopressin-deficient animals.
In conclusion, we confirmed that Brattleboro rat is a good preclinical model of schizophrenia. The appearance of schizophrenia-like behavior was accompanied by H3 acetylation changes 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.
Doctoral School: János Szentágothai School of PhD Studies
Supervisor: Dóra Zelena
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