Inhibition of histone deacetylase in utero causes sociability deficits in postnatal mice

Moldrich, Randal X.; Leanage, Gayeshika; She, David T.; Dolan-Evans, Elliot; Nelson, Michael; Reza, Nargis; Reutens, David C.

doi:10.1016/j.bbr.2013.09.049

Cited by 92 publications

(88 citation statements)

References 56 publications

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“…Consequently, HDAC inhibition may induce abnormal gene expression during embryogenesis, causing behavioral impairments at later time points (Phiel et al, 2001). Notably, a recent rodent study demonstrated that inhibition of HDAC in utero is sufficient to cause autism-like phenotypes including sociability deficits in exposed offspring (Moldrich et al, 2013). …”

Section: Discussionmentioning

confidence: 99%

Abnormal emotional learning in a rat model of autism exposed to valproic acid in utero

Banerjee

Sauls

Morales

et al. 2014

Front. Behav. Neurosci.

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Autism Spectrum Disorders (ASD) are complex neurodevelopmental disorders characterized by repetitive behavior and impaired social communication and interactions. Apart from these core symptoms, a significant number of ASD individuals display higher levels of anxiety and some ASD individuals exhibit impaired emotional learning. We therefore sought to further examine anxiety and emotional learning in an environmentally induced animal model of ASD that utilizes the administration of the known teratogen, valproic acid (VPA) during gestation. Specifically we exposed dams to one of two different doses of VPA (500 and 600 mg/kg) or vehicle on day 12.5 of gestation and examined the resultant progeny. Our data indicate that animals exposed to VPA in utero exhibit enhanced anxiety in the open field test and normal object recognition memory compared to control animals. Animals exposed to 500 mg/kg of VPA displayed normal acquisition of auditory fear conditioning, and exhibited reduced extinction of fear memory and normal litter survival rates as compared to control animals. We observed that animals exposed to 600 mg/kg of VPA exhibited a significant reduction in the acquisition of fear conditioning, a significant reduction in social interaction and a significant reduction in litter survival rates as compared to control animals. VPA (600 mg/kg) exposed animals exhibited similar shock sensitivity and hearing as compared to control animals indicating the fear conditioning deficit observed in these animals was not likely due to sensory deficits, but rather due to deficits in learning or memory retrieval. In conclusion, considering that progeny from dams exposed to rather similar doses of VPA exhibit striking differences in emotional learning, the VPA model may serve as a useful tool to explore the molecular and cellular mechanisms that contribute to not only ASD, but also emotional learning.

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Section: Discussionmentioning

confidence: 99%

Abnormal emotional learning in a rat model of autism exposed to valproic acid in utero

Banerjee

Sauls

Morales

et al. 2014

Front. Behav. Neurosci.

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“…In order to assess the effect of genetic background on the results of prenatal exposure to valproate in the current study, we compared C57BL/6 and BALB/c strains of mice. Both strains were previously reported to exhibit prenatal-valproate-exposure-related behavioral impairments (Wagner et al, 2006; Fucic et al, 2010; Gandal et al, 2010; Roullet et al, 2010; Moldrich et al, 2013). Moreover, they are known for their diverse, innate tendency to exhibit stereotypic behaviors (Moy et al, 2008), their diverse sociability (Chen et al, 2009) and social motivation (Kennedy et al, 2012).…”

Section: Introductionmentioning

confidence: 92%

“…In utero VPA treatment constitutes a model with construct and face validity for autism (Roullet et al, 2013). The valproate mouse model, well-characterized in ‘conventional’ behavioral procedures, allowed for comparison between the known phenotypic trait differences and the results obtained in the designed automated tests (Wagner et al, 2006; Yochum et al, 2008; Moldrich et al, 2013; Roullet et al, 2013). In order to assess the effect of genetic background on the results of prenatal exposure to valproate in the current study, we compared C57BL/6 and BALB/c strains of mice.…”

Section: Introductionmentioning

confidence: 99%

A novel automated behavioral test battery assessing cognitive rigidity in two genetic mouse models of autism

Puścian

Łęski

Górkiewicz

et al. 2014

Front. Behav. Neurosci.

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Repetitive behaviors are a key feature of many pervasive developmental disorders, such as autism. As a heterogeneous group of symptoms, repetitive behaviors are conceptualized into two main subgroups: sensory/motor (lower-order) and cognitive rigidity (higher-order). Although lower-order repetitive behaviors are measured in mouse models in several paradigms, so far there have been no high-throughput tests directly measuring cognitive rigidity. We describe a novel approach for monitoring repetitive behaviors during reversal learning in mice in the automated IntelliCage system. During the reward-motivated place preference reversal learning, designed to assess cognitive abilities of mice, visits to the previously rewarded places were recorded to measure cognitive flexibility. Thereafter, emotional flexibility was assessed by measuring conditioned fear extinction. Additionally, to look for neuronal correlates of cognitive impairments, we measured CA3-CA1 hippocampal long term potentiation (LTP). To standardize the designed tests we used C57BL/6 and BALB/c mice, representing two genetic backgrounds, for induction of autism by prenatal exposure to the sodium valproate. We found impairments of place learning related to perseveration and no LTP impairments in C57BL/6 valproate-treated mice. In contrast, BALB/c valproate-treated mice displayed severe deficits of place learning not associated with perseverative behaviors and accompanied by hippocampal LTP impairments. Alterations of cognitive flexibility observed in C57BL/6 valproate-treated mice were related to neither restricted exploration pattern nor to emotional flexibility. Altogether, we showed that the designed tests of cognitive performance and perseverative behaviors are efficient and highly replicable. Moreover, the results suggest that genetic background is crucial for the behavioral effects of prenatal valproate treatment.

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“…Similar abnormal social behaviors are observed when mice are treated with the HDAC inhibitor TSA in utero (Moldrich et al, 2013). This suggests that HDACs play an important role in brain development mechanisms that lead to autism.…”

Section: Autism Spectrum Disordersmentioning

confidence: 58%

“…In utero exposure to the HDAC inhibitor valproic acid (VPA) has been linked to autism spectrum disorder in humans and has been shown to trigger social cognition deficits in rodents (Cohen et al, 2013;Moldrich et al, 2013). Similar abnormal social behaviors are observed when mice are treated with the HDAC inhibitor TSA in utero (Moldrich et al, 2013).…”

Section: Autism Spectrum Disordersmentioning

confidence: 91%

Histone deacetylases (HDACs) and brain function

2015

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Modulation of gene expression is a constant and necessary event for mammalian brain function. An important way of regulating gene expression is through the remodeling of chromatin, the complex of DNA, and histone proteins around which DNA wraps. The "histone code hypothesis" places histone post-translational modifications as a significant part of chromatin remodeling to regulate transcriptional activity. Acetylation of histones by histone acetyl transferases and deacetylation by histone deacetylases (HDACs) at lysine residues are the most studied histone post-translational modifications in cognition and neuropsychiatric diseases. Here, we review the literature regarding the role of HDACs in brain function. Among the roles of HDACs in the brain, studies show that they participate in glial lineage development, learning and memory, neuropsychiatric diseases, and even rare neurologic diseases. Most HDACs can be targeted with small molecules. However, additional brain-penetrant specific inhibitors with high central nervous system exposure are needed to determine the cause-and-effect relationship between individual HDACs and brain-associated diseases.

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Inhibition of histone deacetylase in utero causes sociability deficits in postnatal mice

Cited by 92 publications

References 56 publications

Abnormal emotional learning in a rat model of autism exposed to valproic acid in utero

Abnormal emotional learning in a rat model of autism exposed to valproic acid in utero

A novel automated behavioral test battery assessing cognitive rigidity in two genetic mouse models of autism

Histone deacetylases (HDACs) and brain function

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