Ewelina Bator1, Joachim Latusz1, Aleksandra Radaszkiewicz1, Krzysztof Wędzony1, Marzena Maćkowiak2. 1. Laboratory of Pharmacology and Brain Biostructure, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland. 2. Laboratory of Pharmacology and Brain Biostructure, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland. Electronic address: mackow@if-pan.krakow.pl.
Abstract
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.
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.
Authors: Mark J Millan; Annie Andrieux; George Bartzokis; Kristin Cadenhead; Paola Dazzan; Paolo Fusar-Poli; Jürgen Gallinat; Jay Giedd; Dennis R Grayson; Markus Heinrichs; René Kahn; Marie-Odile Krebs; Marion Leboyer; David Lewis; Oscar Marin; Philippe Marin; Andreas Meyer-Lindenberg; Patrick McGorry; Philip McGuire; Michael J Owen; Paul Patterson; Akira Sawa; Michael Spedding; Peter Uhlhaas; Flora Vaccarino; Claes Wahlestedt; Daniel Weinberger Journal: Nat Rev Drug Discov Date: 2016-03-04 Impact factor: 84.694
Authors: Manuel Gardea-Resendez; Mehmet Utku Kucuker; Caren J Blacker; Ada M-C Ho; Paul E Croarkin; Mark A Frye; Marin Veldic Journal: Front Pharmacol Date: 2020-04-22 Impact factor: 5.810