Low medial prefrontal dopaminergic activity in autistic children

Ernst, Monique; Zametkin, AJ; Matochik, JA; Pascualvaca, Daisy M.; Rm, Cohen

doi:10.1016/s0140-6736(05)63326-0

Cited by 194 publications

(111 citation statements)

References 4 publications

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“…Furthermore, the role of Engrailed in the patterning of dopaminergic neurons is also compatible with some findings implicating a dopaminergic defect in autism [Ernst et al, 1997].…”

Section: Engrailed and Differentiation Of Dopaminergic Neuronssupporting

confidence: 84%

Toward a developmental neurobiology of autism

Polleux

Lauder

2004

Ment. Retard. Dev. Disabil. Res. Rev.

183

130

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Autism is a complex, behaviorally defined, developmental brain disorder with an estimated prevalence of 1 in 1,000. It is now clear that autism is not a disease, but a syndrome with a strong genetic component. The etiology of autism is poorly defined both at the cellular and the molecular levels. Based on the fact that seizure activity is frequently associated with autism and that abnormal evoked potentials have been observed in autistic individuals in response to tasks that require attention, several investigators have recently proposed that autism might be caused by an imbalance between excitation and inhibition in key neural systems including the cortex. Despite considerable ongoing effort toward the identification of chromosome regions affected in autism and the characterization of many potential gene candidates, only a few genes have been reproducibly shown to display specific mutations that segregate with autism, likely because of the complex polygenic nature of this syndrome. Among those, several candidate genes have been shown to control the early patterning and/or the late synaptic maturation of specific neuronal subpopulations controlling the balance between excitation and inhibition in the developing cortex and cerebellum. In the present article, we review our current understanding of the developmental mechanisms patterning the balance between excitation and inhibition in the context of the neurobiology of autism.

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“…Furthermore, the role of Engrailed in the patterning of dopaminergic neurons is also compatible with some findings implicating a dopaminergic defect in autism [Ernst et al, 1997].…”

Section: Engrailed and Differentiation Of Dopaminergic Neuronssupporting

confidence: 84%

Toward a developmental neurobiology of autism

Polleux

Lauder

2004

Ment. Retard. Dev. Disabil. Res. Rev.

183

130

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“…[166][167][168][169][170] Dopamine-blocking agents, such as Haldol, are the oldest and most effective drugs for treating the core symptoms of autism, although their potentially irreversible motor and other side effects drastically limit their use. 158 There is evidence of abnormal dopaminergic activity in the low medial prefrontal cortex of children with autism, 171 as well as elevated levels of catecholamines in the blood, urine, and cerebrospinal fluid of some children with autism. 172,173 Genetic studies have examined the dopamine receptors D2, D3, and D5; the tyrosine hydroxylase gene; and the dopamine ␤ hydroxylase gene (among others) but with few results.…”

Section: Hypothesis Driven Studies: the Search For Candidate Genesmentioning

confidence: 99%

The Genetics of Autism

2004

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ABSTRACT. Autism is a complex, behaviorally defined, static disorder of the immature brain that is of great concern to the practicing pediatrician because of an astonishing 556% reported increase in pediatric prevalence between 1991 and 1997, to a prevalence higher than that of spina bifida, cancer, or Down syndrome. This jump is probably attributable to heightened awareness and changing diagnostic criteria rather than to new environmental influences. Autism is not a disease but a syndrome with multiple nongenetic and genetic causes. By autism (the autistic spectrum disorders [ASDs]), we mean the wide spectrum of developmental disorders characterized by impairments in 3 behavioral domains: 1) social interaction; 2) language, communication, and imaginative play; and 3) range of interests and activities. Epidemiologic studies indicate that environmental factors such as toxic exposures, teratogens, perinatal insults, and prenatal infections such as rubella and cytomegalovirus account for few cases. These studies fail to confirm that immunizations with the measles-mumps-rubella vaccine are responsible for the surge in autism. Epilepsy, the medical condition most highly associated with autism, has equally complex genetic/nongenetic (but mostly unknown) causes. Autism is frequent in tuberous sclerosis complex and fragile X syndrome, but these 2 disorders account for but a small minority of cases. Currently, diagnosable medical conditions, cytogenetic abnormalities, and single-gene defects (eg, tuberous sclerosis complex, fragile X syndrome, and other rare diseases) together account for <10% of cases. There is convincing evidence that "idiopathic" autism is a heritable disorder. Epidemiologic studies report an ASD prevalence of ϳ3 to 6/1000, with a male to female ratio of 3:1. This skewed ratio remains unexplained: despite the contribution of a few well characterized X-linked disorders, male-to-male transmission in a number of families rules out X-linkage as the prevailing mode of inheritance. The recurrence rate in siblings of affected children is ϳ2% to 8%, much higher than the prevalence rate in the general population but much lower than in single-gene diseases. Twin studies reported 60% concordance for classic autism in monozygotic (MZ) twins versus 0 in dizygotic (DZ) twins, the higher MZ concordance attesting to genetic inheritance as the predominant causative agent. Reevaluation for a broader autistic phenotype that included communication and social disorders increased concordance remarkably from 60% to 92% in MZ twins and from 0% to 10% in DZ pairs. This suggests that interactions between multiple genes cause "idiopathic" autism but that epigenetic factors and exposure to environmental modifiers may contribute to variable expression of autism-related traits. The identity and number of genes involved remain unknown. The wide phenotypic variability of the ASDs likely reflects the interaction of multiple genes within an individual's genome and the existence of distinct genes and gene combinations among those affec...

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“…There are few studies of striatal DA binding in ASD, and to date there has been no consistent evidence of striatal DAT-binding differences in ASD [584,585], although a recent study with a relatively large sample found evidence of higher DAT binding in the orbitofrontal cortex in ASD [586]. Ernst and colleagues [587] found reduced ventromedial prefrontal cortex DA metabolism in children with ASDs, whereas Nieminen-von Wendt and colleagues [588] found no such evidence. A small pilot study of 13 children with ASDs who received a 6-month course of fluoxetine treatment showed that good clinical responders had a significant decrease in striatal DAT binding [589], suggesting that studies of modulation of striatal DAT binding may be relevant to understand potential mechanisms of action of treatments for ASD, even when such treatments do not primarily affect DA systems.…”

Section: Reviewmentioning

confidence: 99%

Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings

Dichter

Damiano

Allen

2012

J Neurodevelop Disord

245

205

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This review summarizes evidence of dysregulated reward circuitry function in a range of neurodevelopmental and psychiatric disorders and genetic syndromes. First, the contribution of identifying a core mechanistic process across disparate disorders to disease classification is discussed, followed by a review of the neurobiology of reward circuitry. We next consider preclinical animal models and clinical evidence of reward-pathway dysfunction in a range of disorders, including psychiatric disorders (i.e., substance-use disorders, affective disorders, eating disorders, and obsessive compulsive disorders), neurodevelopmental disorders (i.e., schizophrenia, attention-deficit/hyperactivity disorder, autism spectrum disorders, Tourette’s syndrome, conduct disorder/oppositional defiant disorder), and genetic syndromes (i.e., Fragile X syndrome, Prader–Willi syndrome, Williams syndrome, Angelman syndrome, and Rett syndrome). We also provide brief overviews of effective psychopharmacologic agents that have an effect on the dopamine system in these disorders. This review concludes with methodological considerations for future research designed to more clearly probe reward-circuitry dysfunction, with the ultimate goal of improved intervention strategies.

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Low medial prefrontal dopaminergic activity in autistic children

Cited by 194 publications

References 4 publications

Toward a developmental neurobiology of autism

Toward a developmental neurobiology of autism

The Genetics of Autism

Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings

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