Valproic acid (VPA) reduces sensorimotor gating deficits and HDAC2 overexpression in the MAM animal model of schizophrenia.
BACKGROUND
Evidence indicates that the disruption of epigenetic processes might play an important role in the development of schizophrenia symptoms. The present study investigated the role of histone acetylation in the development of sensorimotor gating deficits in a neurodevelopmental model of schizophrenia based on prenatal administration of methylazoxymethanol (MAM) at embryonic day 17.


METHODS
Valproic acid (VPA), an inhibitor of class I histone deacetylases, was administered (250 mg/kg, twice a day for 7 consecutive days) in early adolescence (23rd-29th day) or early adulthood (63rd-69th day) to rats. The effect of VPA treatment on the sensorimotor gating deficits induced by prenatal MAM administration was analyzed in adult rats at postnatal day 70 (P70). In addition, the effects of VPA administration (at the same doses) on MAM-induced changes in the levels of histone H3 acetylation at lysine 9 (H3K9ac) and histone deacetylase 2 (HDAC2) in the medial prefrontal cortex (mPFC) were determined at P70 using Western blot.


RESULTS
VPA administration in either adolescence or early adulthood prevented the sensorimotor gating deficits induced by MAM. However, VPA administration in early adolescence or early adulthood did not alter H3K9ac levels induced by MAM. In contrast, VPA administration in either adolescence or adulthood prevented the increase in HDAC2 level evoked by MAM.


CONCLUSIONS
Prenatal MAM administration impaired histone acetylation in the mPFC, which might be involved in the development of some of the neurobehavioral deficits (i.e., sensorimotor gating deficits) associated with schizophrenia. Blockade of HDAC2 might prevent the disruption of sensorimotor gating in adulthood.
Laboratory of Pharmacology and Brain Biostructure, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland.
Ewelina
E
Bator
Laboratory of Pharmacology and Brain Biostructure, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland.
Joachim
J
Latusz
Laboratory of Pharmacology and Brain Biostructure, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland.
Aleksandra
A
Radaszkiewicz
Laboratory of Pharmacology and Brain Biostructure, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland.
Krzysztof
K
Wędzony
Laboratory of Pharmacology and Brain Biostructure, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland. Electronic address: mackow@if-pan.krakow.pl.
Marzena
M
Maćkowiak
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D056464:Histone Deacetylase 2 / Q000096:biosynthesis*; D006657:Histones / Q000378:metabolism; D008297:Male; D008746:Methylazoxymethanol Acetate / Q000031:analogs & derivatives; D017397:Prefrontal Cortex / Q000378:metabolism; D051381:Rats; D012559:Schizophrenia / Q000139:chemically induced / Q000201:enzymology / Q000503:physiopathology*; D055139:Sensory Gating / Q000187:drug effects* / Q000502:physiology; D014635:Valproic Acid / Q000494:pharmacology*
D006657:Histones; D008746:Methylazoxymethanol Acetate; D014635:Valproic Acid; C533426:Hdac2 protein, rat; D056464:Histone Deacetylase 2; C030667:methylazoxymethanol
Epigenetics; Medial prefrontal cortex; Sensorimotor gating; Valproic acid