Clinical and Macroscopic Correlates of Minicolumnar Pathology in Autism

Casanova, Manuel F.; Buxhoeveden, Daniel P.; Brown, Caroline

doi:10.1177/088307380201700908

Cited by 178 publications

(147 citation statements)

References 52 publications

(1 reference statement)

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“…Casanova et al [21,22] showed that in postmortem brain tissues from individuals with autism, the frontal and temporal cortical minicolumns were smaller, more numerous and less compact than those of non-autistic subjects. Alterations in the size and cellular distribution within cortical minicolumns in autism may reflect disturbances in the processing of thalamic inputs to cortex.…”

Section: Discussionmentioning

confidence: 99%

“…-stereotypical behaviors, impaired verbal and nonverbal communication and blunted social interaction) are accompanied by structural and functional changes in cortex, cerebellum and amygdala [3,4,7,8,[19][20][21][22]37,38,49,55,67,101,125]. Structural and functional changes apparent in early childhood suggest that autism is a disorder of brain development [4,19,20,[37][38][39]111].…”

Section: Introductionmentioning

confidence: 99%

“…Postmortem microscopic evaluation of brain tissue from adults with autism demonstrates abnormalities in cerebral cortical development that include increased cortical thickness and neuronal density, neuronal disorganization related to abnormal migration, poorly differentiated gray-white matter boundaries and an increased number of white matter neurons [4]. In addition, frontal and temporal cortical minicolumns are smaller and more numerous and less compact than those of control subjects [21,22]. Alterations in the size and cellular distribution within cortical minicolumns in autism may reflect disturbances in the processing of thalamic inputs to cortex.…”

Section: Introductionmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Modeling early cortical serotonergic deficits in autism

Boylan

Blue

Höhmann

2007

Behavioural Brain Research

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“…Thus, we argue that MSDs are more closely related to the number of underlying neural units defining the morphology of the cortical surface. For example, many regions with significantly reduced MSDs (e.g., BA 3-4, 9, and 21-22) overlap with those that have previously been reported to have an increased minicolumn density in ASD, and decreased peripheral neurophil space (PNS) (48,49). Thus, our findings suggest that differences in MSDs may be closely related to the density of cortical minicolumns, and that minicolumns may be more unevenly distributed (and so more dense) in some regions relative to others.…”

Section: Discussionmentioning

confidence: 99%

Intrinsic gray-matter connectivity of the brain in adults with autism spectrum disorder

Ecker

Ronan

Feng

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

100

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Autism spectrum disorders (ASD) are a group of neurodevelopmental conditions that are accompanied by atypical brain connectivity. So far, in vivo evidence for atypical structural brain connectivity in ASD has mainly been based on neuroimaging studies of cortical white matter. However, genetic studies suggest that abnormal connectivity in ASD may also affect neural connections within the cortical gray matter. Such intrinsic gray-matter connections are inherently more difficult to describe in vivo but may be inferred from a variety of surface-based geometric features that can be measured using magnetic resonance imaging. Here, we present a neuroimaging study that examines the intrinsic cortico-cortical connectivity of the brain in ASD using measures of "cortical separation distances" to assess the global and local intrinsic "wiring costs" of the cortex (i.e., estimated length of horizontal connections required to wire the cortex within the cortical sheet). In a sample of 68 adults with ASD and matched controls, we observed significantly reduced intrinsic wiring costs of cortex in ASD, both globally and locally. Differences in global and local wiring cost were predominantly observed in fronto-temporal regions and also significantly predicted the severity of social and repetitive symptoms (respectively). Our study confirms that atypical cortico-cortical "connectivity" in ASD is not restricted to the development of white-matter connections but may also affect the intrinsic gray-matter architecture (and connectivity) within the cortical sheet. Thus, the atypical connectivity of the brain in ASD is complex, affecting both gray and white matter, and forms part of the core neural substrates underlying autistic symptoms.brain structure | gyrification | morphometry A utism spectrum disorders (ASDs) are a group of neurodevelopmental conditions characterized by impaired social communication, social reciprocity, and repetitive/stereotypic behavior (1). There is consensus that ASD is accompanied by developmental differences in brain anatomy and connectivity (2). However, the specific neurobiological substrate of ASD remains elusive.Neuroimaging evidence suggests that ASD is accompanied by anatomical differences in several large-scale neurocognitive networks (3), which typically include the cerebellum (4), the amygdalahippocampal complex (5), fronto-temporal regions (6), and the caudate nuclei (7). These gross-anatomical abnormalities are likely to reflect differences in the cytoarchitectonic make-up of individual brain regions in ASD, as can be observed in postmortem studies. For instance, individuals with ASD may have a reduced size, but increased number, of minicolumns (8), which could underpin differences in cortical surface area (9, 10). Also, individuals with ASD may have an excess number of neurons in some brain regions (11), which in turn may affect measures of cortical thickness (9, 12). Therefore, different morphometric features of the cortical surface provide proxy measures of various aspects of local gray-matter arc...

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“…Some of these include neocortical malformations such as irregular laminar patterns, thickened cortices, abnormally oriented pyramidal cells, and an increase in the number of layer one neurons [7]. In specific cortical areas, Casonanova et al [17] have reported the presence of smaller, more compact, and more numerous minicolumns. Regions in the forebrain that show reduced neuronal size and increased cell packing density include the hippocampus, subiculum, entorhinal cortex, mammilary bodies, anterior cingulated gyrus, septum and amygdala ( [38] and see [12,27,47] for recent reviews on autism neuropathology).…”

Section: Introductionmentioning

confidence: 99%

The mouse Engrailed genes: A window into autism

Kuemerle

Gulden

Cherosky

et al. 2007

Behavioural Brain Research

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The complex behavioral symptoms and neuroanatomical abnormalities observed in autistic individuals strongly suggest a multi-factorial basis for this perplexing disease. Although not the perfect model, we believe the Engrailed genes provide an invaluable "window" into the elusive etiology of Autism Spectrum Disorder. The Engrailed-2 gene has been associated with autism in genetic linkage studies. The En2 knock-out mouse harbors cerebellar abnormalities that are similar to those found in autistic individuals and, as we report here, has a distinct anterior shift in the position of the amygdala in the cerebral cortex. Our initial analysis of background effects in the En1 mouse knock-out provides insight as to possible molecular mechanisms and gender differences associated with autism. These findings further the connection between Engrailed and autism and provide new avenues to explore in the ongoing study of the biological basis of this multifaceted disease.

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Clinical and Macroscopic Correlates of Minicolumnar Pathology in Autism

Cited by 178 publications

References 52 publications

Modeling early cortical serotonergic deficits in autism

Modeling early cortical serotonergic deficits in autism

Intrinsic gray-matter connectivity of the brain in adults with autism spectrum disorder

The mouse Engrailed genes: A window into autism

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