The Implications of Brain Connectivity in the Neuropsychology of Autism

Maximo, Jose O.; Cadena, Elyse J.; Kana, Rajesh K.

doi:10.1007/s11065-014-9250-0

Cited by 235 publications

(168 citation statements)

References 165 publications

(223 reference statements)

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“…Holmes the inclusion/exclusion criteria related to ID, the regions, and even the frequencies reported vary by publication. Overall, EEG-derived coherence literature generally mirrors that obtained using MRI, in that the results are widely varied and provide evidence for both over-and underconnectivity in ASD (Luckhardt et al 2014;Maximo et al 2014).…”

Section: Aberrant Connectivity In Autismmentioning

confidence: 69%

Epilepsy and Autism

Buckley

Holmes

2016

Cold Spring Harb Perspect Med

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Epilepsy and autistic spectrum disorder frequently coexist in the same individual. Electroencephalogram (EEG) epileptiform activity is also present at a substantially higher rate in children with autism than normally developing children. As with epilepsy, there are a multitude of genetic and environmental factors that can result in autistic spectrum disorder. There is growing consensus from both animal and clinical studies that autism is a disorder of aberrant connectivity. As measured with functional magnetic resonance imaging (MRI) and EEG, the brain in autistic spectrum disorder may be under-or overconnected or have a mixture of over-and underconnectivity. In the case of comorbid epilepsy and autism, an imbalance of the excitatory/inhibitory (E/I) ratio in selected regions of the brain may drive overconnectivity. Understanding the mechanism by which altered connectivity in individuals with comorbid epilepsy and autistic spectrum disorder results in the behaviors specific to the autistic spectrum disorder remains a challenge.

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Section: Aberrant Connectivity In Autismmentioning

confidence: 69%

Epilepsy and Autism

Buckley

Holmes

2016

Cold Spring Harb Perspect Med

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“…Multilevel interaction between PTEN and the molecular machinery of synaptic communication represent a direct link to a hallmark feature of ASD neuropathology, described at the level of neuroimaging, as well as transcriptomic studies [69,78]. The first report placing Pten at the synapse came in 2004, when Peradones et al [79] described PTEN localization in dendrites and their spines during developmental periods of synaptic stabilization.…”

Section: Pten Loss In Mice Leads To Cytoarchitecture and Synaptic Altmentioning

confidence: 99%

“…Alterations in each of these processes are linked to ASD pathogenesis, suggesting that PTEN-regulated pathways may be point of convergence in the broad etiologies of the disorder [78]. Several reports indicate that PTEN inhibition of PI3K is essential for LTD, with conflicting reports on its requirement in LTP [42,63].…”

Section: Pten Loss In Mice Leads To Cytoarchitecture and Synaptic Altmentioning

confidence: 99%

Balancing Proliferation and Connectivity in PTEN-associated Autism Spectrum Disorder

2015

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Germline mutations in PTEN, which encodes a widely expressed phosphatase, was mapped to 10q23 and identified as the susceptibility gene for Cowden syndrome, characterized by macrocephaly and high risks of breast, thyroid, and other cancers. The phenotypic spectrum of PTEN mutations expanded to include autism with macrocephaly only 10 years ago. Neurological studies of patients with PTENassociated autism spectrum disorder (ASD) show increases in cortical white matter and a distinctive cognitive profile, including delayed language development with poor working memory and processing speed. Once a germline PTEN mutation is found, and a diagnosis of phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome made, the clinical outlook broadens to include higher lifetime risks for multiple cancers, beginning in childhood with thyroid cancer. First described as a tumor suppressor, PTEN is a major negative regulator of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (mTOR) signaling pathway-controlling growth, protein synthesis, and proliferation. This canonical function combines with less well-understood mechanisms to influence synaptic plasticity and neuronal cytoarchitecture. Several excellent mouse models of Pten loss or dysfunction link these neural functions to autism-like behavioral abnormalities, such as altered sociability, repetitive behaviors, and phenotypes like anxiety that are often associated with ASD in humans. These models also show the promise of mTOR inhibitors as therapeutic agents capable of reversing phenotypes ranging from overgrowth to low social behavior. Based on these findings, therapeutic options for patients with PTEN hamartoma tumor syndrome and ASD are coming into view, even as new discoveries in PTEN biology add complexity to our understanding of this master regulator.

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“…Answering these questions is difficult because the disorder is multifactorial in nature with multiple genetic variants and environmental factors contributing to the core symptoms (10)(11)(12)(13). To face this challenge, extensive efforts have been made to identify the targeting and functional convergence of the autism-risk genes, such as those involved in translation regulation (14)(15)(16) and long-range connectivity among different brain regions (17)(18)(19). These targets and functions provide a better biological basis for elucidating the causal paths between risk genes and the disorders of autism.…”

mentioning

confidence: 99%

Inability to activate Rac1-dependent forgetting contributes to behavioral inflexibility in mutants of multiple autism-risk genes

Dong

Wang

et al. 2016

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

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The etiology of autism is so complicated because it involves the effects of variants of several hundred risk genes along with the contribution of environmental factors. Therefore, it has been challenging to identify the causal paths that lead to the core autistic symptoms such as social deficit, repetitive behaviors, and behavioral inflexibility. As an alternative approach, extensive efforts have been devoted to identifying the convergence of the targets and functions of the autism-risk genes to facilitate mapping out causal paths. In this study, we used a reversal-learning task to measure behavioral flexibility in Drosophila and determined the effects of loss-of-function mutations in multiple autism-risk gene homologs in flies. Mutations of five autism-risk genes with diversified molecular functions all led to a similar phenotype of behavioral inflexibility indicated by impaired reversal-learning. These reversal-learning defects resulted from the inability to forget or rather, specifically, to activate Rac1 (Ras-related C3 botulinum toxin substrate 1)-dependent forgetting. Thus, behavior-evoked activation of Rac1-dependent forgetting has a converging function for autism-risk genes.A utism spectrum disorders are common polygenic neurodevelopmental disorders diagnosed by a cluster of core clinical syndromes characterized by impaired social interaction, communication deficits, and behavioral inflexibility (1-3). A large number of autism-risk genes have been identified through different genetic approaches (4-8). These candidate genes play highly diversified roles in synaptic organization, transmission, intracellular signaling pathways, and protein expression regulation, among others (9). How do variants of these risk genes lead to the core symptoms of autism? Are there causal paths that can determine the onset of autism? Answering these questions is difficult because the disorder is multifactorial in nature with multiple genetic variants and environmental factors contributing to the core symptoms (10-13). To face this challenge, extensive efforts have been made to identify the targeting and functional convergence of the autism-risk genes, such as those involved in translation regulation (14-16) and long-range connectivity among different brain regions (17)(18)(19). These targets and functions provide a better biological basis for elucidating the causal paths between risk genes and the disorders of autism.The aim of the this study was to determine whether Rac1 (Rasrelated C3 botulinum toxin substrate 1)-dependent forgetting is a functional converging point for autism-risk genes. This idea was inspired by two clues. First, inhibition of Rac1 activity in Drosophila leads to the failure to activate Rac1-dependent forgetting, resulting in behavioral inflexibility as assayed through a reversal-learning task (20). Behavioral inflexibility has been observed frequently in the clinical studies of autism patients (21,22), and children with autism are reported to have impaired reversal-learning, although they can learn new beh...

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The Implications of Brain Connectivity in the Neuropsychology of Autism

Cited by 235 publications

References 165 publications

Epilepsy and Autism

Epilepsy and Autism

Balancing Proliferation and Connectivity in PTEN-associated Autism Spectrum Disorder

Inability to activate Rac1-dependent forgetting contributes to behavioral inflexibility in mutants of multiple autism-risk genes

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