Rethinking Intellectual Disability from Neuro- to Astro-Pathology

Neurodevelopmental disorders arise from genetic and/or from environmental factors and are characterized by different degrees of intellectual disability. The mechanisms that govern important processes sustaining learning and memory, which are severely affected in intellectual disability, have classically been thought to be exclusively under neuronal control. However, this vision has recently evolved into a more integrative conception in which astroglia, rather than just acting as metabolic supply and structural anchoring for neurons, interact at distinct levels modulating neuronal communication and possibly also cognitive processes. Recently, genetic tools have made it possible to specifically manipulate astrocyte activity unraveling novel functions that involve astrocytes in memory function in the healthy brain. However, astrocyte manipulation has also underscored potential mechanisms by which dysfunctional astrocytes could contribute to memory deficits in several neurodevelopmental disorders revealing new pathogenic mechanisms in intellectual disability. Here, we review the current knowledge about astrocyte dysfunction that might contribute to learning and memory impairment in neurodevelopmental disorders, with special focus on Fragile X syndrome and Down syndrome.

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Specific effect of the fragile-X mental retardation-1 gene (FMR1) on white matter microstructure

The British Journal of Psychiatry ◽

10.1192/bjp.bp.114.151654 ◽

2015 ◽

Vol 207 (2) ◽

pp. 143-148 ◽

Cited By ~ 11

Author(s):

Tamar Green ◽

Naama Barnea-Goraly ◽

Mira Raman ◽

Scott S. Hall ◽

Amy A. Lightbody ◽

...

Keyword(s):

Genetic Variation ◽

Intellectual Disability ◽

White Matter ◽

Neurodevelopmental Disorders ◽

Fragile X ◽

Neurodevelopmental Disorder ◽

Specific Effect ◽

Radial Diffusivity ◽

Fragile X Mental Retardation ◽

White Matter Microstructure

BackgroundFragile-X syndrome (FXS) is a neurodevelopmental disorder associated with intellectual disability and neurobiological abnormalities including white matter microstructural differences. White matter differences have been found relative to neurotypical individuals.AimsTo examine whether FXS white matter differences are related specifically to FXS or more generally to the presence of intellectual disability.MethodWe used voxel-based and tract-based analytic approaches to compare individuals with FXS (n = 40) with gender- and IQ-matched controls (n = 30).ResultsIndividuals with FXS had increased fractional anisotropy and decreased radial diffusivity values compared with IQ-matched controls in the inferior longitudinal, inferior fronto-occipital and uncinate fasciculi.ConclusionsThe genetic variation associated with FXS affects white matter microstructure independently of overall IQ. White matter differences, found in FXS relative to IQ-matched controls, are distinct from reported differences relative to neurotypical controls. This underscores the need to consider cognitive ability differences when investigating white matter microstructure in neurodevelopmental disorders.

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Vestibular contribution to memory processing

Auditory and Vestibular Research ◽

10.18502/avr.v28i2.860 ◽

2019 ◽

Author(s):

Abdollah Moossavi ◽

Meymaneh Jafari

Keyword(s):

Postural Control ◽

Cognitive Processes ◽

Vestibular System ◽

Current Knowledge ◽

Memory Function ◽

Emotional Disturbances ◽

Laboratory Findings ◽

Memory Processing ◽

Sensory Inputs ◽

Memory Representations

Background and Aim: The vestibular system contributes in the stabilization of the head and body, orientation, and gazing through the processing of sensory inputs. A wealth of evidence supports the involvement of vestibular information in higher functions, too.Methods: In this paper, we reviewed the previous studies on the effect of the vestibular system on memory as one of the cognitive functions.Results: Clinical and laboratory findings indicate the association of vestibular inputs (besides postural control and oculomotor) with a variety of higher functions, especially memory function. Because part of the memory function is determined by other cognitive processes i.e. attention capacity, emotional disturbances, and executive functions, the study of the effect of vestibular inputs on these functions provides a more accurate view of how the vestibular inputs affect memory performance.Conclusion: Although our current knowledge on vestibular-memory interaction is increasing, the exact involvement of vestibular signals in memory representations is still unclear and needs further studies to determine the theoretical basis of vestibular involvement in memory processing.

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The Implication of AMPA Receptor in Synaptic Plasticity Impairment and Intellectual Disability in Fragile X Syndrome

Physiological Research ◽

10.33549/physiolres.933473 ◽

2017 ◽

pp. 715-727 ◽

Cited By ~ 9

Author(s):

G.-R. CHENG ◽

X.-Y. LI ◽

Y.-D. XIANG ◽

D. LIU ◽

S. M. MCCLINTOCK ◽

...

Keyword(s):

Synaptic Plasticity ◽

Intellectual Disability ◽

Fragile X Syndrome ◽

Ampa Receptors ◽

Molecular Mechanisms ◽

Neuronal Development ◽

Current Knowledge ◽

Fragile X ◽

Single Gene ◽

Poor Mental Health

Fragile X syndrome (FXS) is the most frequently inherited form of intellectual disability and prevalent single-gene cause of autism. A priority of FXS research is to determine the molecular mechanisms underlying the cognitive and social functioning impairments in humans and the FXS mouse model. Glutamate ionotropic alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPARs) mediate a majority of fast excitatory neurotransmission in the central nervous system and are critically important for nearly all aspects of brain function, including neuronal development, synaptic plasticity, and learning and memory. Both preclinical and clinical studies have indicated that expression, trafficking, and functions of AMPARs are altered and result in altered synapse development and plasticity, cognitive impairment, and poor mental health in FXS. In this review, we discuss the contribution of AMPARs to disorders of FXS by highlighting recent research advances with a specific focus on change in AMPARs expression, trafficking, and dependent synaptic plasticity. Since changes in synaptic strength underlie the basis of learning, development, and disease, we suggest that the current knowledge base of AMPARs has reached a unique point to permit a comprehensive re-evaluation of their roles in FXS.

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A Comparative Study of Sociability in Angelman, Cornelia de Lange, Fragile X, Down and Rubinstein Taybi Syndromes and Autism Spectrum Disorder

American Journal on Intellectual and Developmental Disabilities ◽

10.1352/1944-7558-121.6.465 ◽

2016 ◽

Vol 121 (6) ◽

pp. 465-486 ◽

Cited By ~ 14

Author(s):

Joanna Moss ◽

Lisa Nelson ◽

Laurie Powis ◽

Jane Waite ◽

Caroline Richards ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Down Syndrome ◽

Intellectual Disability ◽

Fragile X Syndrome ◽

Neurodevelopmental Disorders ◽

Fragile X ◽

Selective Mutism ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Cornelia De Lange

Abstract Few comparative studies have evaluated the heterogeneity of sociability across a range of neurodevelopmental disorders. The Sociability Questionnaire for People with Intellectual Disability (SQID) was completed by caregivers of individuals with Cornelia de Lange (n = 98), Angelman (n = 66), Fragile X (n = 142), Down (n = 117) and Rubinstein Taybi (n = 88) syndromes and autism spectrum disorder (ASD; n = 107). Between groups and age-band (<12yrs; 12–18yrs; >18yrs) comparisons of SQID scores were conducted. Rates of behaviors indicative of selective mutism were also examined. Fragile X syndrome achieved the lowest SQID scores. Cornelia de Lange, ASD, and Fragile X groups scored significantly lower than Angelman, Down and Rubinstein Taybi groups. Selective mutism characteristics were highest in Cornelia de Lange (40%) followed by Fragile X (17.8%) and ASD (18.2%). Age-band differences were identified in Cornelia de Lange and Down syndrome.

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Astrocytes and Developmental Plasticity in Fragile X

Neural Plasticity ◽

10.1155/2012/197491 ◽

2012 ◽

Vol 2012 ◽

pp. 1-12 ◽

Cited By ~ 12

Author(s):

Connie Cheng ◽

Mary Sourial ◽

Laurie C. Doering

Keyword(s):

Neurodevelopmental Disorders ◽

Developmental Plasticity ◽

Neural Circuits ◽

Current Knowledge ◽

Fragile X ◽

Synaptic Function ◽

Disease Phenotype ◽

Postnatal Brain ◽

Knowing That ◽

And Function

A growing body of research indicates a pivotal role for astrocytes at the developing synapse. In particular, astrocytes are dynamically involved in governing synapse structure, function, and plasticity. In the postnatal brain, their appearance at synapses coincides with periods of developmental plasticity when neural circuits are refined and established. Alterations in the partnership between astrocytes and neurons have now emerged as important mechanisms that underlie neuropathology. With overall synaptic function standing as a prominent link to the expression of the disease phenotype in a number of neurodevelopmental disorders and knowing that astrocytes influence synapse development and function, this paper highlights the current knowledge of astrocyte biology with a focus on their involvement in fragile X syndrome.

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Continuous VA deficiency during postnatal development decreases rat learning and memory function via excitatory Ca2+neuron

Cell Biology International ◽

10.1042/cbi034s018a ◽

2010 ◽

Vol 34 (8) ◽

pp. S18-S18

Author(s):

Wei Jiang ◽

Enyi Wen ◽

Min Gong ◽

Yang Bi ◽

Xiaojuan Zhang ◽

...

Keyword(s):

Postnatal Development ◽

Learning And Memory ◽

Memory Function

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Hypoxia, Acidification and Inflammation: Partners in Crime in Parkinson’s Disease Pathogenesis?

Immuno ◽

10.3390/immuno1020006 ◽

2021 ◽

Vol 1 (2) ◽

pp. 78-90

Author(s):

Johannes Burtscher ◽

Grégoire P. Millet

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Neurodegenerative Diseases ◽

Current Knowledge ◽

Cell Types ◽

Brain Cell ◽

Special Focus ◽

Molecular Alterations ◽

Research Fields

Like in other neurodegenerative diseases, protein aggregation, mitochondrial dysfunction, oxidative stress and neuroinflammation are hallmarks of Parkinson’s disease (PD). Differentiating characteristics of PD include the central role of α-synuclein in the aggregation pathology, a distinct vulnerability of the striato-nigral system with the related motor symptoms, as well as specific mitochondrial deficits. Which molecular alterations cause neurodegeneration and drive PD pathogenesis is poorly understood. Here, we summarize evidence of the involvement of three interdependent factors in PD and suggest that their interplay is likely a trigger and/or aggravator of PD-related neurodegeneration: hypoxia, acidification and inflammation. We aim to integrate the existing knowledge on the well-established role of inflammation and immunity, the emerging interest in the contribution of hypoxic insults and the rather neglected effects of brain acidification in PD pathogenesis. Their tight association as an important aspect of the disease merits detailed investigation. Consequences of related injuries are discussed in the context of aging and the interaction of different brain cell types, in particular with regard to potential consequences on the vulnerability of dopaminergic neurons in the substantia nigra. A special focus is put on the identification of current knowledge gaps and we emphasize the importance of related insights from other research fields, such as cancer research and immunometabolism, for neurodegeneration research. The highlighted interplay of hypoxia, acidification and inflammation is likely also of relevance for other neurodegenerative diseases, despite disease-specific biochemical and metabolic alterations.

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Stress-Related Dysfunction of Adult Hippocampal Neurogenesis—An Attempt for Understanding Resilience?

International Journal of Molecular Sciences ◽

10.3390/ijms22147339 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7339

Author(s):

Julia Leschik ◽

Beat Lutz ◽

Antonietta Gentile

Keyword(s):

Major Depression ◽

Adult Neurogenesis ◽

Current Knowledge ◽

Functional Relation ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Special Focus ◽

Extrinsic Cues ◽

Health And Disease ◽

Newborn Neurons

Newborn neurons in the adult hippocampus are regulated by many intrinsic and extrinsic cues. It is well accepted that elevated glucocorticoid levels lead to downregulation of adult neurogenesis, which this review discusses as one reason why psychiatric diseases, such as major depression, develop after long-term stress exposure. In reverse, adult neurogenesis has been suggested to protect against stress-induced major depression, and hence, could serve as a resilience mechanism. In this review, we will summarize current knowledge about the functional relation of adult neurogenesis and stress in health and disease. A special focus will lie on the mechanisms underlying the cascades of events from prolonged high glucocorticoid concentrations to reduced numbers of newborn neurons. In addition to neurotransmitter and neurotrophic factor dysregulation, these mechanisms include immunomodulatory pathways, as well as microbiota changes influencing the gut-brain axis. Finally, we discuss recent findings delineating the role of adult neurogenesis in stress resilience.

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Remote Virtual Simulation for Incident Commanders—Cognitive Aspects

Applied Sciences ◽

10.3390/app11146434 ◽

2021 ◽

Vol 11 (14) ◽

pp. 6434

Author(s):

Cecilia Hammar Wijkmark ◽

Maria Monika Metallinou ◽

Ilona Heldal

Keyword(s):

Decision Making ◽

Problem Solving ◽

Cognitive Processes ◽

Research Methodology ◽

Current Knowledge ◽

Learning Objectives ◽

Virtual Simulation ◽

Practical Training ◽

Case Research ◽

Action Case

Due to the COVID-19 restrictions, on-site Incident Commander (IC) practical training and examinations in Sweden were canceled as of March 2020. The graduation of one IC class was, however, conducted through Remote Virtual Simulation (RVS), the first such examination to our current knowledge. This paper presents the necessary enablers for setting up RVS and its influence on cognitive aspects of assessing practical competences. Data were gathered through observations, questionnaires, and interviews from students and instructors, using action-case research methodology. The results show the potential of RVS for supporting higher cognitive processes, such as recognition, comprehension, problem solving, decision making, and allowed students to demonstrate whether they had achieved the required learning objectives. Other reported benefits were the value of not gathering people (imposed by the pandemic), experiencing new, challenging incident scenarios, increased motivation for applying RVS based training both for students and instructors, and reduced traveling (corresponding to 15,400 km for a class). While further research is needed for defining how to integrate RVS in practical training and assessment for IC education and for increased generalizability, this research pinpoints current benefits and limitations, in relation to the cognitive aspects and in comparison, to previous examination formats.

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Immunity and mental illness: findings from a Danish population-based immunogenetic study of seven psychiatric and neurodevelopmental disorders

European Journal of Human Genetics ◽

10.1038/s41431-019-0402-9 ◽

2019 ◽

Vol 27 (9) ◽

pp. 1445-1455 ◽

Cited By ~ 10

Author(s):

Ron Nudel ◽

Michael E. Benros ◽

Morten Dybdahl Krebs ◽

Rosa Lundbye Allesøe ◽

Camilla Koldbæk Lemvigh ◽

...

Keyword(s):

Intellectual Disability ◽

Protective Effect ◽

Neurodevelopmental Disorders ◽

Association Studies ◽

Human Leukocyte ◽

Population Based ◽

Autism Spectrum ◽

Small Samples ◽

Hla Association ◽

Hla Genes

AbstractHuman leukocyte antigen (HLA) genes encode proteins with important roles in the regulation of the immune system. Many studies have also implicated HLA genes in psychiatric and neurodevelopmental disorders. However, these studies usually focus on one disorder and/or on one HLA candidate gene, often with small samples. Here, we access a large dataset of 65,534 genotyped individuals consisting of controls (N = 19,645) and cases having one or more of autism spectrum disorder (N = 12,331), attention deficit hyperactivity disorder (N = 14,397), schizophrenia (N = 2401), bipolar disorder (N = 1391), depression (N = 18,511), anorexia (N = 2551) or intellectual disability (N = 3175). We imputed participants’ HLA alleles to investigate the involvement of HLA genes in these disorders using regression models. We found a pronounced protective effect of DPB1*1501 on susceptibility to autism (p = 0.0094, OR = 0.72) and intellectual disability (p = 0.00099, OR = 0.41), with an increased protective effect on a comorbid diagnosis of both disorders (p = 0.003, OR = 0.29). We also identified a risk allele for intellectual disability, B*5701 (p = 0.00016, OR = 1.33). Associations with both alleles survived FDR correction and a permutation procedure. We did not find significant evidence for replication of previously-reported associations for autism or schizophrenia. Our results support an implication of HLA genes in autism and intellectual disability, which requires replication by other studies. Our study also highlights the importance of large sample sizes in HLA association studies.

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