DRD1 and DRD2 Receptor Polymorphisms: Genetic Neuromodulation of the Dopaminergic System as a Risk Factor for ASD, ADHD and ASD/ADHD Overlap

Mariggiò, Maria Addolorata; Palumbi, Roberto; Vinella, Angela; Laterza, Riccardo; Petruzzelli, Maria Giuseppina; Peschechera, Antonia; Gabellone, Alessandra; Gentile, Ottavio; Vincenti, Alessandra; Margari, Lucia

doi:10.3389/fnins.2021.705890

Cited by 23 publications

(15 citation statements)

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“…DRD2 Taq1A (rs1800497) ( Neville et al, 2004 ; Pan et al, 2015 ) has been reported to relate to DRD2 expression levels ( Laakso et al, 2005 ). DRD2-12 ( rs7131465 ) is related to a higher risk for ADHD and autism spectrum disorder overlap ( Mariggiò et al, 2021 ). The intronic DRD2 SNPs (rs1079727, rs1079595, and rs1124491), and SNP in the 3’-UTR (rs1800497) have been linked with ADHD in males ( Nyman et al, 2007 ).…”

Section: Resultsmentioning

confidence: 99%

Attention-deficit/hyperactive disorder updates

Kessi

Duan

Xiong

et al. 2022

Front. Mol. Neurosci.

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BackgroundAttention-deficit/hyperactive disorder (ADHD) is a neurodevelopmental disorder that commonly occurs in children with a prevalence ranging from 3.4 to 7.2%. It profoundly affects academic achievement, well-being, and social interactions. As a result, this disorder is of high cost to both individuals and society. Despite the availability of knowledge regarding the mechanisms of ADHD, the pathogenesis is not clear, hence, the existence of many challenges especially in making correct early diagnosis and provision of accurate management.ObjectivesWe aimed to review the pathogenic pathways of ADHD in children. The major focus was to provide an update on the reported etiologies in humans, animal models, modulators, therapies, mechanisms, epigenetic changes, and the interaction between genetic and environmental factors.MethodsReferences for this review were identified through a systematic search in PubMed by using special keywords for all years until January 2022.ResultsSeveral genes have been reported to associate with ADHD: DRD1, DRD2, DRD4, DAT1, TPH2, HTR1A, HTR1B, SLC6A4, HTR2A, DBH, NET1, ADRA2A, ADRA2C, CHRNA4, CHRNA7, GAD1, GRM1, GRM5, GRM7, GRM8, TARBP1, ADGRL3, FGF1, MAOA, BDNF, SNAP25, STX1A, ATXN7, and SORCS2. Some of these genes have evidence both from human beings and animal models, while others have evidence in either humans or animal models only. Notably, most of these animal models are knockout and do not generate the genetic alteration of the patients. Besides, some of the gene polymorphisms reported differ according to the ethnic groups. The majority of the available animal models are related to the dopaminergic pathway. Epigenetic changes including SUMOylation, methylation, and acetylation have been reported in genes related to the dopaminergic pathway.ConclusionThe dopaminergic pathway remains to be crucial in the pathogenesis of ADHD. It can be affected by environmental factors and other pathways. Nevertheless, it is still unclear how environmental factors relate to all neurotransmitter pathways; thus, more studies are needed. Although several genes have been related to ADHD, there are few animal model studies on the majority of the genes, and they do not generate the genetic alteration of the patients. More animal models and epigenetic studies are required.

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Section: Resultsmentioning

confidence: 99%

Attention-deficit/hyperactive disorder updates

Kessi

Duan

Xiong

et al. 2022

Front. Mol. Neurosci.

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“…Based on this, one may assume that the increase in neurons with D2R in the VTA of Clstn2-KO mice reported herein may be associated with an increased locomo tor activity of these animals. It is also interesting to note that human studies have shown that nucleotide polymorphism in the D2R gene can be considered as a potential risk factor for the development of not only ASD, but also attention deficit hyperactivity disorder (Mariggio et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Alterations in the social-conditioned place preference and density of dopaminergic neurons in the ventral tegmental area in Clsnt2-KO mice

et al. 2023

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The incidence of autistic spectrum disorders (ASD) constantly increases in the world. Studying the mechanisms underlying ASD as well as searching for new therapeutic targets are crucial tasks. Many researchers agree that autism is a neurodevelopmental disorder. Clstn2-KO mouse strain with a knockout of calsyntenin 2 gene (Clstn2) is model for investigating ASD. This study aims to evaluate the social-conditioned place preference as well as density of dopaminergic (DA) neurons in the ventral tegmental area (VTA), which belongs to the brain reward system, in the males of the Clstn2-KO strain using wild type C57BL/6J males as controls. Social-conditioned place preference test evaluates a reward-dependent component of social behavior. The results of this test revealed differences between the Clstn2-KO and the control males, as the former did not value socializing with the familiar partner, spending equal time in the isolationand socializing-associated compartments. The Clstn2-KO group entered both compartments more frequently, but spent less time in the socializingassociated compartment compared to the controls. By contrast, the control males of the C57BL/6J strain spent more time in socializing-associated compartment and less time in the compartment that was associated with loneness. At the same time, an increased number of DA and possibly GABA neurons labeled with antibodies against the type 2 dopamine receptor as well as against tyrosine hydroxylase were detected in the VTA of the Clstn2-KO mice. Thus, a change in social-conditioned place preference in Clstn2-KO mice as well as a higher number of neurons expressing type 2 dopamine receptors and tyrosine hydroxylase in the VTA, the key structure of the mesolimbic dopaminergic pathway, were observed.

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“…Table 2) , including the negative regulation of neuron differentiation (GO:0045665, hit 45 in observed failed lines) or the regulation of neuron apoptotic process (GO:0043523, hit 82 in predicted failed lines). The most mutated genes (log 2 FC>1.5) contributing to the enrichment of those biological processes in failed lines are well-known disease associations: NSUN5 in William Beuren Syndrome 21 , FOXG1 in FOXG1-syndrome 22 , DRD1 in Autism Disorder 23 or ASCL1 in neuropsychiatric disorders 24 . In other cases, those genes are key regulators of neuron differentiation like NRBP2 for neural progenitor cell (NPC) survival 25 , DMRTA2 for NPC maintenance 26 , S100A8 involved in microglial inflammation 27 or SOX14, essential for the initiation of neuron differentiation 28 .…”

Section: The Genome-wide Burden Of Acquired Mutations Does Not Explai...mentioning

confidence: 99%

Effects of somatic mutations on cellular differentiation in iPSC models of neurodevelopment

Puigdevall

Jerber

Danecek

et al. 2022

Preprint

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The use of induced pluripotent stem cells (iPSC) as models for development and human disease has enabled the study of otherwise inaccessible tissues. A remaining challenge in developing reliable models is our limited understanding of the factors driving irregular in vitro differentiation of iPSCs, particularly the impact of acquired somatic mutations. We leveraged data from a pooled dopaminergic neuron differentiation experiment of 238 iPSC lines profiled with single-cell and whole-exome sequencing to study how somatic mutations affect differentiation outcomes. Differentiation was tracked at three time points corresponding to neural progenitors, early neurons and mature neurons. We found that deleterious somatic mutations in key developmental genes, notably the BCOR gene, are strongly associated with failure in dopaminergic neuron differentiation, with lines carrying such mutations also showing larger proliferation rate in culture. We further identified broad differences in cell type composition between failed and successfully differentiating lines, as well as significant changes in gene expression contributing to the inhibition of neurogenesis, a functional process also targeted by deleterious mutations in failed lines. Our work highlights the need to routinely measure the burden of deleterious mutations in iPSC lines and calls for caution in interpreting differentiation-related phenotypes in disease-modelling experiments.

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DRD1 and DRD2 Receptor Polymorphisms: Genetic Neuromodulation of the Dopaminergic System as a Risk Factor for ASD, ADHD and ASD/ADHD Overlap

Cited by 23 publications

References 53 publications

Attention-deficit/hyperactive disorder updates

Attention-deficit/hyperactive disorder updates

Alterations in the social-conditioned place preference and density of dopaminergic neurons in the ventral tegmental area in Clsnt2-KO mice

Effects of somatic mutations on cellular differentiation in iPSC models of neurodevelopment

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