Reduced prefrontal dopaminergic activity in valproic acid-treated mouse autism model

Hara, Yuta; Takuma, Kazuhiro; Takano, Erika; Katashiba, Keisuke; Taruta, Atsuki; Higashino, Kosuke; Hashimoto, Hitoshi; Ago, Yukio; Matsuda, Takehisa

doi:10.1016/j.bbr.2015.04.022

Cited by 41 publications

(23 citation statements)

References 35 publications

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“…A major finding of the current study is the recovery of striosomal organization and improvement of USVs with chronic treatments of risperidone, a dopamine D2 receptor antagonist (48). VPA has been shown to enhance dopamine D2 receptor signaling in primary striatal culture (60); however, prenatal VPA treatment results in dopamine hypofunction of the prefrontal cortex, although striatal dopamine function is not affected (61). It is not yet known whether the rescue effects of risperidone are mediated by changes in dopamine neurotransmission or other mechanisms.…”

Section: Risperidone Mitigates Anatomic Abnormality and The Usv Phenomentioning

confidence: 99%

Valproic acid induces aberrant development of striatal compartments and corticostriatal pathways in a mouse model of autism spectrum disorder

Kuo¹,

Liu²

2017

FASEB j.

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The striatum comprises two neurochemical compartments: striosomes and the matrix. Striosomal and matrix compartments receive inputs from limbic system-related and sensorimotor cortices, respectively. Here, we investigate the impact on the corticostriosomal pathway in the valproic acid (VPA)-induced autism spectrum disorder mouse model. VPA administration during the neurogenesis time windows of striosomes, but not the matrix, resulted in aberrant compartmentation [, maternal VPA injections at embryonic day (E)12.75 decreased μ-opioid receptor-positive striosomes, but increased calbindin-positive matrix in the rostral striatum]. VPA treatment also impaired the aggregation of cells pulse labeled with 5-bromo-2'-deoxyuridine at E12.75 into striosomal cell clusters, which suggests defective segregation of striosomal cells from matrix cells. This possibility was supported by our findings that VPA treatment altered the expression of ephrinA5 and EphA4, two molecules that are related to compartmental segregation. In the VPA neocortex, Foxp2-positive neurons were decreased in layer VI, but increased in layer V, which projects to the striosomal compartment. We also investigated VPA effects on the corticostriosomal pathway. VPA treatment decreased the putative corticostriosomal synapses of striosomal neurons and induced an aberrant pattern of isolation stress-induced ultrasonic vocalizations. Of interest, risperidone treatments conjointly improved ultrasonic vocalizations and restored the striosomal compartment in VPA pups. Collectively, dysfunctional corticostriatal pathways, particularly the aberrant striosomal compartment, may be involved in autism spectrum disorder pathophysiology.-Kuo, H.-Y., Liu, F.-C. Valproic acid induces aberrant development of striatal compartments and corticostriatal pathways in a mouse model of autism spectrum disorder.

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Section: Risperidone Mitigates Anatomic Abnormality and The Usv Phenomentioning

confidence: 99%

Valproic acid induces aberrant development of striatal compartments and corticostriatal pathways in a mouse model of autism spectrum disorder

Kuo¹,

Liu²

2017

FASEB j.

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“…Genetic studies suggest that the dopamine system is involved in the etiology of ASD [Hamilton et al, ; Hettinger, Liu, Schwartz, Michaelis, & Holden, ; Nguyen et al, ; Qian, Chen, Forssberg, & Diaz Heijtz, ; Reiersen & Todorov, ; Staal, de Krom, & de Jonge, ]. We recently found that prenatal VPA causes hypofunction of the prefrontal dopaminergic system in a sex‐dependent manner in mice [Hara et al, ]. This suggests that reduced prefrontal dopaminergic activity is associated with behavioral abnormalities in VPA‐treated mice.…”

Section: Introductionmentioning

confidence: 99%

Improvement by methylphenidate and atomoxetine of social interaction deficits and recognition memory impairment in a mouse model of valproic acid‐induced autism

et al. 2015

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Rodents exposed prenatally to valproic acid (VPA) show autism-related behavioral abnormalities. We recently found that prenatal VPA exposure causes a reduction of dopaminergic activity in the prefrontal cortex of male, but not female, mice. This suggests that reduced prefrontal dopaminergic activity is associated with behavioral abnormalities in VPA-treated mice. In the present study, we examined whether the attention deficit/hyperactivity disorder drugs methylphenidate and atomoxetine (which increase dopamine release in the prefrontal cortex, but not striatum, in mice) could alleviate the behavioral abnormalities and changes in dendritic spine morphology induced by prenatal VPA exposure. We found that methylphenidate and atomoxetine increased prefrontal dopamine and noradrenaline release in VPA-treated mice. Acute treatment with methylphenidate or atomoxetine did not alleviate the social interaction deficits or recognition memory impairment in VPA-treated mice, while chronic treatment for 2 weeks did. Methylphenidate or atomoxetine for 2 weeks also improved the prenatal VPA-induced decrease in dendritic spine density in the prefrontal cortex. The effects of these drugs on behaviors and dendritic spine morphology were antagonized by concomitant treatment with the dopamine-D1 receptor antagonist SCH39166 or the dopamine-D2 receptor antagonist raclopride, but not by the α2 -adrenoceptor antagonist idazoxan. These findings suggest that chronic treatment with methylphenidate or atomoxetine improves abnormal behaviors and diminishes the reduction in spine density in VPA-treated mice via a prefrontal dopaminergic system-dependent mechanism. Autism Res 2016, 9: 926-939. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.

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“…The animals had ad libitum access to food and water, and were handled in accordance with the guidelines established by the Animal Care and Use Committee of the Graduate Schools of Pharmaceutical Sciences and Dentistry, Osaka University, the Guiding Principles for the Care and Use of Laboratory Animals approved by the Japanese Pharmacological Society, and the US National Institutes of Health Guide for the Care and Use of Laboratory Animals. The vaginal smear test was performed according to a previously published method [27, 28]. When a vaginal smear indicated proestrus or early estrus, male and female mice were mated overnight, and the next day was considered gestation day 0.…”

Section: Methodsmentioning

confidence: 99%

“…The pregnant mice were intraperitoneally injected with either 500 mg/kg VPA (Sigma-Aldrich, St. Louis, MO, USA) or saline on E12.5 [4–6, 27, 28]. VPA was dissolved in 0.9% NaCl solution (Otsuka Pharma.…”

Section: Methodsmentioning

confidence: 99%

Prenatal exposure to valproic acid increases miR-132 levels in the mouse embryonic brain

et al. 2017

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BackgroundMicroRNAs, small non-coding RNAs, are highly expressed in the mammalian brain, and the dysregulation of microRNA levels may be involved in neurodevelopmental disorders such as autism spectrum disorder (ASD). In the present study, we examined whether prenatal valproic acid (VPA) exposure affects levels of microRNAs, especially the brain specific and enriched microRNAs, in the mouse embryonic brain.ResultsPrenatal exposure to VPA at E12.5 immediately increased miR-132 levels, but not miR-9 or miR-124 levels, in the male embryonic brain. Prenatal exposure to VPA at E12.5 also increased miR-132 levels in the female embryonic brain. We further found that the prenatal exposure to VPA at E12.5 increased mRNA levels of Arc, c-Fos and brain-derived neurotrophic factor in both male and female embryonic brains, prior to miR-132 expression. In contrast, prenatal exposure to VPA at E14.5 did not affect miR-132 levels in either male or female embryonic brain. The prenatal VPA exposure at E12.5 also decreased mRNA levels of methyl-CpG-binding protein 2 and Rho GTPase-activating protein p250GAP, both of which are molecular targets of miR-132. Furthermore, RNA sequence analysis revealed that prenatal VPA exposure caused changes in several microRNA levels other than miR-132 in the embryonic whole brain.ConclusionsThese findings suggest that the alterations in neuronal activity-dependent microRNAs levels, including an increased level of miR-132, in the embryonic period, at least in part, underlie the ASD-like behaviors and cortical pathology produced by prenatal VPA exposure.

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Reduced prefrontal dopaminergic activity in valproic acid-treated mouse autism model

Cited by 41 publications

References 35 publications

Valproic acid induces aberrant development of striatal compartments and corticostriatal pathways in a mouse model of autism spectrum disorder

Valproic acid induces aberrant development of striatal compartments and corticostriatal pathways in a mouse model of autism spectrum disorder

Improvement by methylphenidate and atomoxetine of social interaction deficits and recognition memory impairment in a mouse model of valproic acid‐induced autism

Prenatal exposure to valproic acid increases miR-132 levels in the mouse embryonic brain

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