Postmortem brain abnormalities of the glutamate neurotransmitter system in autism

Purcell, Amy E.; Jeon, Ok Hee; Zimmerman, Andrew W.; Blue, Mary E.; Pevsner, Jonathan

doi:10.1212/wnl.57.9.1618

Cited by 463 publications

(311 citation statements)

References 41 publications

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“…increased GluR2/3 and GluR2 and decreased GluR1 subunits) in membrane homogenates of cerebral cortex [106]. Interestingly, a decreased density of AMPA glutamatergic receptors also has been described in postmortem human autistic brains [96]. These findings, coupled with that of decreased 5-HT synthesis in autism, supports a role for both serotonergic and glutamatergic systems in the pathology of this disorder.…”

Section: Introductionmentioning

confidence: 68%

Modeling early cortical serotonergic deficits in autism

Boylan

Blue

Höhmann

2007

Behavioural Brain Research

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Autism is a developmental brain disorder characterized by deficits in social interaction, language and behavior. Brain imaging studies demonstrate increased cerebral cortical volumes and micro-and macroscopic neuroanatomic changes in children with this disorder. Alterations in forebrain serotonergic function may underlie the neuroanatomic and behavioral features of autism. Serotonin is involved in neuronal growth and plasticity and these actions are likely mediated via serotonergic and glutamatergic receptors. Few animal models of autism have been described that replicate both etiology and pathophysiology. We report here on a selective serotonin (5-HT) depletion model of this disorder in neonatal mice that mimics neurochemical and structural changes in cortex and, in addition, displays a behavioral phenotype consistent with autism. Newborn male and female mice were depleted of forebrain 5-HT with injections of the serotonergic neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), into the bilateral medial forebrain bundle (mfb). Behavioral testing of these animals as adults revealed alterations in social, sensory and stereotypic behaviors. Lesioned mice showed significantly increased cortical width. Serotonin immunocytochemistry showed a dramatic long-lasting depletion of 5-HT containing fibers in cerebral cortex until postnatal day (PND) 60. Autoradiographic binding to high affinity 5-HT transporters was significantly but transiently reduced in cerebral cortex of 5,7-DHT-depleted mice. AMPA glutamate receptor binding was decreased at PND 15. We hypothesize that increased cerebral cortical volume and sensorimotor, cognitive and social deficits observed in both 5-HT-depleted animals and in individuals with autism, may be the result of deficiencies in timely axonal pruning to key cerebral cortical areas.

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Section: Introductionmentioning

confidence: 68%

Modeling early cortical serotonergic deficits in autism

Boylan

Blue

Höhmann

2007

Behavioural Brain Research

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“…However, given the importance of glutamate in brain development, learning and memory, 164 the positive linkage findings on 6q21 in two studies (Table 1) as well as post-mortem evidence of brain abnormalities of the glutamate neurotransmitter system in autism, 165 this candidate gene seems to be of relevance in the pathogenesis of AD.…”

Section: Chromosomementioning

confidence: 99%

The genetics of autistic disorders and its clinical relevance: a review of the literature

2006

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Twin and family studies in autistic disorders (AD) have elucidated a high heritability of the narrow and broad phenotype of AD. In this review on the genetics of AD, we will initially delineate the phenotype of AD and discuss aspects of differential diagnosis, which are particularly relevant with regard to the genetics of autism. Cytogenetic and molecular genetic studies will be presented in detail, and the possibly involved aetiopathological pathways will be described. Implications of the different genetic findings for genetic counselling will be mentioned.

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“…54,55 In addition, alternative practitioners have been discussing the theory that anti-oxidant pathways are insufficient in patients with autism. This relationship has been noted in the past, and evidence of a predisposition of insufficient glutathione or anti-oxidant reserves in autistic patients has been described by James et al 56,57 Chez 58 previously reported a similar insufficiency in antioxidant protection in patients diagnosed with variants of Landau-Kleffner and concurrent autistic features.…”

Section: Human Evidence Of Ongoing Atypical Inflammatory Responsementioning

confidence: 99%

“…Prior reports of elevated glutamate levels and receptors in the autistic brain have been reported. 55 Modulation of NMDA receptors by NMDA antagonists in autism has been reported with noted clinical improvements. D-cycloserine, an antibiotic that also binds NMDA receptors has been shown to improve behavioral functions in autism.…”

Section: Glutamate and Nmda Receptorsmentioning

confidence: 99%

Immune Therapy in Autism: Historical Experience and Future Directions with Immunomodulatory Therapy

Chez

Guido-Estrada

2010

Neurotherapeutics

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Summary: Autism affects 1 in 110 new births, and it has no single etiology with uniform agreement. This has a significant impact on the quality of life for individuals who have been diagnosed with autism. Although autism has a spectrum quality with a shared diagnosis, it presents a uniquely different clinical appearance in each individual. Recent research of suspected immunological factors have provided more support for a probable immunological process or for processes that may play a role in the acquisition of an autistic condition. These factors include prenatal, genetic, and postnatal findings, as well as the discovery of a dysfunctional chronic pro-inflammatory state in brain tissue and cerebrospinal fluid in subsets of autistic patients. These findings offer new theories that may lead to the development of disease modification or preventative therapeutic options in the near future. This article reviews prenatal, genetic, and observed immune aspects of the autism condition that may be risk factors in the presentation of the autistic clinical phenotype. Historical immune interventions in autism are reviewed and potential new therapies and interventions are discussed.

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Postmortem brain abnormalities of the glutamate neurotransmitter system in autism

Abstract: Subjects with autism may have specific abnormalities in the AMPA-type glutamate receptors and glutamate transporters in the cerebellum. These abnormalities may be directly involved in the pathogenesis of the disorder.

Cited by 463 publications

References 41 publications

Modeling early cortical serotonergic deficits in autism

Modeling early cortical serotonergic deficits in autism

The genetics of autistic disorders and its clinical relevance: a review of the literature

Immune Therapy in Autism: Historical Experience and Future Directions with Immunomodulatory Therapy

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