Increased Dopamine Type 2 Gene Expression in the Dorsal Striatum in Individuals With Autism Spectrum Disorder Suggests Alterations in Indirect Pathway Signaling and Circuitry

Brandenburg, Cheryl; Soghomonian, Jean‐Jacques; Zhang, Kunzhong; Sulkaj, Ina; Randolph, Brianna; Kachadoorian, Marissa; Blatt, Gene J.

doi:10.3389/fncel.2020.577858

Cited by 30 publications

(26 citation statements)

References 70 publications

(89 reference statements)

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“…Increased D2 MSN signaling could explain impaired reward processing in these animals. Recent human studies with small sample sizes support this hypothesis, by showing increased D2 receptor mRNA expression in striatal medium spiny neurons (MSNs) in ASD relative to controls ( Brandenburg et al, 2020 ), but no change in striatal DA D1 receptor occupancies in ASD ( Kubota et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

The functional neural architecture of dysfunctional reward processing in autism

Janouschek

Chase

Sharkey

et al. 2021

NeuroImage: Clinical

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Section: Discussionmentioning

confidence: 99%

The functional neural architecture of dysfunctional reward processing in autism

Janouschek

Chase

Sharkey

et al. 2021

NeuroImage: Clinical

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“…While these studies illustrate how a higher DRD1/DRD2 activation ratio could lead to stereotyped behaviors, they do not account for the social deficits reported by Lee et al [45]. Moreover, a recent study found that individuals with ASD exhibit actually increased DRD2 gene expression in the DS [50], so further studies are warranted in order to elucidate the complex interplay of dopamine receptors in this critical brain region.…”

Section: The Nigrostriatal Pathwaymentioning

confidence: 95%

The Dopamine Hypothesis of Autism Spectrum Disorder Revisited: Current Status and Future Prospects

Pavǎl¹,

Miclutia

2021

Dev Neurosci

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Autism spectrum disorder (ASD) comprises a group of neurodevelopmental disorders characterized by social deficits and stereotyped behaviors. Despite intensive research, its etiopathogenesis remains largely unclear. Although studies consistently reported dopaminergic anomalies, a coherent dopaminergic model of ASD was lacking until recently. In 2017, we provided a theoretical framework for a “dopamine hypothesis of ASD” which proposed that autistic behavior arises from a dysfunctional midbrain dopaminergic system. Namely, we hypothesized that malfunction of 2 critical circuits originating in the midbrain, that is, the mesocorticolimbic and nigrostriatal pathways, generates the core behavioral features of ASD. Moreover, we provided key predictions of our model along with testing means. Since then, a notable number of studies referenced our work and numerous others provided support for our model. To account for these developments, we review all these recent data and discuss their implications. Furthermore, in the light of these new insights, we further refine and reconceptualize our model, debating on the possibility that various etiologies of ASD converge upon a dysfunctional midbrain dopaminergic system. In addition, we discuss future prospects, providing new means of testing our hypothesis, as well as its limitations. Along these lines, we aimed to provide a model which, if confirmed, could provide a better understanding of the etiopathogenesis of ASD along with new therapeutic strategies.

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“…6. These results indicate alterations in the indirect pathway of the basal ganglia, with possible implications for the E/I balance in the direct/indirect feedback pathways through thalamic and motor cortical areas [54]. Our study is the rst study that displays Nurr1 involved in the pathogenesis of ASD, indicating that the upregulation of Nurr1 expression in the striatum from VPA mice is the cause of the altered dendritic spine density of mature forms and may contribute to the autistic behavior.…”

Section: Discussionmentioning

confidence: 60%

Transcriptomic Analysis in the Striatum Reveals an Involvement of Nurr1 in Social Behavior of Prenatally Valproic Acid-Exposed Mice

Kim¹,

Yang²,

Kim³

et al. 2021

Preprint

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BackgroundThe striatum of the basal ganglia is the major subcortical component of the mammalian forebrain. Magnetic resonance imaging (MRI) studies have implicated surface deformation of the striatum in the brains of patients with autism spectrum disorders (ASD) and their correlation with behavioral phenotypes. MethodsUsing RNA sequencing (RNA-Seq), we analyzed transcriptome alteration in striatal tissues from 10-week-old prenatally valproic acid (VPA)-exposed BALB/c male mice. To investigate the relationship of Nurr1 with synaptic and social deficit, we activated the expression level of nuclear receptor related 1 protein (Nurr1) by i.p. injection of amodiaquine (AQ) for 2 weeks. Furthermore, we employed lentiviral system to inhibit the Nurr1 expression and provide evidence for the role of Nurr1 in social behavior. ResultsTranscriptomic analysis showed higher levels of genes related to synaptic function of neurons in striatal tissues from the prenatally VPA-exposed mice. Among those genes, Nurr1 expression was significantly upregulated. The treatment with AQ, which has been known to be a ligand for Nurr1, to saline-exposed mice mimicked social deficits and synaptic abnormality observed in prenatally VPA-exposed mice. Moreover, viral inhibition of Nurr1 markedly improved social deficits in prenatally VPA-exposed mice. LimitationsThis study did not identify the mechanism of how Nurr1 activation regulates striatum-related circuit. Identification of the mechanism will provide explanation for behavioral impairments in prenatally VPA-exposed mice.ConclusionsTaken together, these results suggest that the increase in Nurr1 expression in the striatum is a mechanism related to the changes in synaptic deficits and behavioral phenotypes of VPA-induced ASD mouse model.

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Increased Dopamine Type 2 Gene Expression in the Dorsal Striatum in Individuals With Autism Spectrum Disorder Suggests Alterations in Indirect Pathway Signaling and Circuitry

Cited by 30 publications

References 70 publications

The functional neural architecture of dysfunctional reward processing in autism

The functional neural architecture of dysfunctional reward processing in autism

The Dopamine Hypothesis of Autism Spectrum Disorder Revisited: Current Status and Future Prospects

Transcriptomic Analysis in the Striatum Reveals an Involvement of Nurr1 in Social Behavior of Prenatally Valproic Acid-Exposed Mice

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