Connecting Genes to Brain in the Autism Spectrum Disorders

Neurogenetics Program, Neurology Department, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1769, USA.
Archives of neurology (Impact Factor: 7.42). 04/2010; 67(4):395-9. DOI: 10.1001/archneurol.2010.47
Source: PubMed


The autism spectrum disorders (ASDs) are a complex group of neuropsychiatric conditions involving language, social communication, and mental flexibility. Here, we attempt to place recent genetic advances within a developmental and anatomical context. Recent progress in identifying ASD candidate genes supports involvement of multiple brain regions, including the frontal lobes, anterior temporal lobes, caudate, and cerebellum. Understanding genetic data within an anatomical context will be critical to explain how individual risk factors operate to shape phenotypic presentation in patients.

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    • "Computational studies have found that ASD susceptibility genes are co-expressed in human cerebellum between the neonatal period and age 6 years (Willsey et al., 2013), particularly within the granule cell layer (Menashe et al., 2013). Further, many syndromic forms of ASD involve cerebellar alterations including Phelan-McDermid Syndrome, Fragile X Syndrome (FXS), Tuberous Sclerosis (TSC), and patients with 15q11 duplication syndrome (Abrahams and Geschwind, 2010; Mosconi et al., 2011; Kloth et al., 2015). Cerebellar alterations also appear to be specifically associated with ASD features. "
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    ABSTRACT: The cerebellum has been repeatedly implicated in gene expression, rodent model and post-mortem studies of autism spectrum disorder (ASD). How cellular and molecular anomalies of the cerebellum relate to clinical manifestations of ASD remains unclear. Separate circuits of the cerebellum control different sensorimotor behaviors, such as maintaining balance, walking, making eye movements, reaching and grasping. Each of these behaviors has been found to be impaired in ASD, suggesting that multiple distinct circuits of the cerebellum may be involved in the pathogenesis of patients’ sensorimotor impairments. We will review evidence that the development of these circuits is disrupted in individuals with ASD and that their study may help elucidate the pathophysiology of sensorimotor deficits and core symptoms of the disorder. Preclinical studies of monogenetic conditions associated with ASD also have identified selective defects of the cerebellum and documented behavioral rescues when the cerebellum is targeted. Based on these findings, we propose that cerebellar circuits may prove to be promising targets for therapeutic development aimed at rescuing sensorimotor and other clinical symptoms of different forms of ASD.
    Full-text · Article · Sep 2015 · Frontiers in Neuroscience
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    • "As such , orchid individuals are subject to negative outcomes in stressful , unpredictable and negligent environments but may also have exceptionally positive outcomes , when reared in enriched , predictable , and supporting environments . Considering that numerous genetic and environmental factors have been implicated in autism , but no factor alone is causative in all cases , it is possible that the biological threshold for the development of autistic abnormalities is lowered by various combinations of genetic and epigenetic factors ( Buxbaum , 2009 ; Abrahams and Geschwind , 2010 ; Markram and Markram , 2010 ) . Careful interpretation of the rat subgroups identified here , suggests that individuals exposed to an autism risk factor , such as prenatal VPA , become more sensitive to the environment , thus making them more Orchid - like than non - exposed individuals , and develop a range of autism - like features if not reared in the optimal environment . "
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    ABSTRACT: Understanding the effects of environmental stimulation in autism can improve therapeutic interventions against debilitating sensory overload, social withdrawal, fear and anxiety. Here, we evaluate the role of environmental predictability on behavior and protein expression, and inter-individual differences, in the valproic acid (VPA) model of autism. Male rats embryonically exposed (E11.5) either to VPA, a known autism risk factor in humans, or to saline, were housed from weaning into adulthood in a standard laboratory environment, an unpredictably enriched environment, or a predictably enriched environment. Animals were tested for sociability, nociception, stereotypy, fear conditioning and anxiety, and for tissue content of glutamate signaling proteins in the primary somatosensory cortex, hippocampus and amygdala, and of corticosterone in plasma, amygdala and hippocampus. Standard group analyses on separate measures were complemented with a composite emotionality score, using Cronbach's Alpha analysis, and with multivariate profiling of individual animals, using Hierarchical Cluster Analysis. We found that predictable environmental enrichment prevented the development of hyper-emotionality in the VPA-exposed group, while unpredictable enrichment did not. Individual variation in the severity of the autistic-like symptoms (fear, anxiety, social withdrawal and sensory abnormalities) correlated with neurochemical profiles, and predicted their responsiveness to predictability in the environment. In controls, the association between socio-affective behaviors, neurochemical profiles and environmental predictability was negligible. This study suggests that rearing in a predictable environment prevents the development of hyper-emotional features in animals exposed to an autism risk factor, and demonstrates that unpredictable environments can lead to negative outcomes, even in the presence of environmental enrichment.
    Full-text · Article · Jun 2015 · Frontiers in Neuroscience
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    • "Mainly older dermatoglyphic studies are available for people with Autism Spectrum Disorders (ASD), disorders of neural development that have a complex genetic basis [30] [31]. ASD in this paper is used as an umbrella term and refers to autistic disorder, Asperger syndrome, and Pervasive Developmental Disorder Not Otherwise Specified (PDD- NOS). "
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    ABSTRACT: Dermatoglyphics, ridge constellations on the hands and feet, are permanently formed by the second trimester of pregnancy. Consequently, they are considered “fossilized” evidence of a specific prenatal period. A high frequency of dermatoglyphic anomalies, or a high rate of dermatoglyphic asymmetry (discordance), is an indication of developmental instability (prenatal disturbances) prior to 24-week gestation. Most dermatoglyphic studies in psychiatry focus on adult schizophrenia. Studies on dermatoglyphic deviances and autism are sparse, include severely disturbed and intellectually retarded patients with autism, and are carried out mainly in non-Western European populations. In this study, finger print patterns, atd-angles, and palmar flexion crease patterns (PFCs) are compared between Western European adolescent teenage males, of average intellect, with Autism Spectrum Disorders (ASD; n = 46 ) and typically developing adolescent teenage males (TD; n = 49 ). Boys with ASD had a higher rate of discordance in their finger print patterns than TD boys. Thus, the hypothesized prenatal disturbances that play a role in the etiology of schizophrenia and severe autism might not be specific to these severe psychiatric disorders but might also be involved in the etiology of varying degrees of ASD.
    Full-text · Article · Nov 2014
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