Key role for gene dosage and synaptic homeostasis in autism spectrum disorders

Toro, Roberto; Konyukh, Marina; Delorme, Richard; Leblond, Claire S.; Chaste, Pauline; Fauchereau, Fabien; Coleman, Mary; Leboyer, Marion; Gillberg, Christopher; Bourgeron, Thomas

doi:10.1016/j.tig.2010.05.007

Cited by 300 publications

(330 citation statements)

References 104 publications

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“…Involved pathways revealed differences with GO analysis are largely associated with immune/inflammatory responses as well as cytokines and chemokines, possibly reflecting fundamental differences in the 2 study groups. It should be noted that recent genetic studies have been accumulating evidence that ASD is a behavioral syndrome encompassing markedly heterogeneous populations (Bale et al, 2010;Rudan, 2010;Toro et al, 2010). Our findings also support results of previous genetic studies.…”

Section: Discussionsupporting

confidence: 91%

Impaired Oral Tolerance in ASD Children with Food Protein Induced Enterocolitis Syndrome (FPIES) – Altered Innate and Adaptive Immune Responses in ASD Children Recovered from FPIES in Comparison with non-ASD/FPIES and ASD/non-FPIES Children

Jyonouchi¹,

Geng²,

Kattouf³

et al. 2011

Autism - A Neurodevelopmental Journey From Genes to Behaviour

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Section: Discussionsupporting

confidence: 91%

Impaired Oral Tolerance in ASD Children with Food Protein Induced Enterocolitis Syndrome (FPIES) – Altered Innate and Adaptive Immune Responses in ASD Children Recovered from FPIES in Comparison with non-ASD/FPIES and ASD/non-FPIES Children

Jyonouchi¹,

Geng²,

Kattouf³

et al. 2011

Autism - A Neurodevelopmental Journey From Genes to Behaviour

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“…In mice with the human R415C mutation in Nlgn3, which affects synaptic adhesion, numbers of parvalbuminpositive inhibitory interneurons are again decreased [31], with an associated increase in levels of vesicular transporters for GABA, frequency of spontaneous inhibitory currents, and amplitude of evoked inhibitory currents [36,42]. As noted above, the nonlinearity of inhibitory function may help to explain why both increases and decreases in inhibitory function can alter homeostasis [43], and lead to similar-appearing effects at the network and behavioral levels.…”

Section: Inhibition At the Molecular And Cellular Levelmentioning

confidence: 95%

Inhibition-Based Biomarkers for Autism Spectrum Disorder

Levin

Nelson

2015

Neurotherapeutics

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Autism spectrum disorder (ASD) is a behaviorally defined and heterogeneous disorder. Biomarkers for ASD offer the opportunity to improve prediction, diagnosis, stratification by severity and subtype, monitoring over time and in response to interventions, and overall understanding of the underlying biology of this disorder. A variety of potential biomarkers, from the level of genes and proteins to network-level interactions, is currently being examined. Many of these biomarkers relate to inhibition, which is of particular interest because in many cases ASD is thought to be a disorder of imbalance between excitation and inhibition. Abnormalities in inhibition at the cellular level lead to emergent properties in networks of neurons. These properties take into account a more complete genetic and cellular background than findings at the level of individual genes or cells, and are able to be measured in live humans, offering additional potential as diagnostic biomarkers and predictors of behaviors. In this review we provide examples of how altered inhibition may inform the search for ASD biomarkers at multiple levels, from genes to cells to networks.

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“…The decreased synapse number and PSD size in Prickle2 −/− neurons led us to test synaptic transmission, which is abnormal in many ASD mouse models (2,6,21,(45)(46)(47)(48)(49)(50). We assessed spontaneous miniature synaptic currents in hippocampal slices from Prickle2 −/− and Prickle2 +/+ mice.…”

Section: Prickle2 Disruption Alters the Post-synaptic Density (Psd) Amentioning

confidence: 99%

Erratum: Disruption of the non-canonical Wnt gene PRICKLE2 leads to autism-like behaviors with evidence for hippocampal synaptic dysfunction

Sowers¹,

Loo²,

Wu³

et al. 2013

Mol Psychiatry

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Author Contributions: LPS contributed to all experiments, planning, and writing of the paper. LL performed all in vitro electrophysiology. YW performed in vivo electrophysiology. LL, LPS and DPM analyzed all the electrophysiology data. EC performed mouse behavioral experiments. YMU and JU performed a part of primary hippocampal neuron cultures. SW performed western blot experiments. JRM, HEL, LP, TW, XY and KM aided in the collection and sequencing of human DNA. PF, NU and SW conducted production and breeding of mice of different genotypes used in this study. AJS assisted in all immunocytochemistry experiments and analysis. GBR, DPM, and JM provided reagents, supervised experiments and analysis, and aided in manuscript writing. JAW provided all behavioral equipment. JAW and DPM provided scientific input to the study design. BWD provided statistical analysis for whole exome sequencing data. All authors contributed to the writing of this manuscript. AGB supervised all aspects of the project design, execution and writing of the paper. The datasets used for the analysis described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000298.v1.p1, under dbGAP Research Project #4357 (Variation in PRICKLE2 and related Genes in Autism) to AGB. The data set(s) were deposited by the ARRA Autism Sequencing Collaborative, an ARRA funded research initiative. AbstractAutism spectrum disorders (ASDs) have been suggested to arise from abnormalities in the canonical and non-canonical Wnt signaling pathways. However, a direct connection between a human variant in a Wnt pathway gene and ASD-relevant brain pathology has not been established. Prickle2 (Pk2) is a post-synaptic non-canonical Wnt signaling protein shown to interact with post synaptic density 95 (PSD-95). Here we show that mice with disruption in Prickle2 display behavioral abnormalities including altered social interaction, learning abnormalities, and behavioral inflexibility. Prickle2 disruption in mouse hippocampal neurons led to reductions in dendrite branching, synapse number, and post-synaptic density size. Consistent with these findings, Prickle2 null neurons show decreased frequency and size of spontaneous miniature synaptic currents. These behavioral and physiological abnormalities in Prickle2 disrupted mice are consistent with ASD-like phenotypes present in other mouse models of ASDs. In 384 individuals with autism, we identified two with distinct, heterozygous, rare, non-synonymous PRICKLE2 variants (p.E8Q and p.V153I) that were shared by their affected siblings and inherited paternally. Unlike wild-type PRICKLE2, the PRICKLE2 variants found in ASD patients exhibit deficits in morphological and electrophysiological assays. These data suggest that these PRICKLE2 variants cause a critical loss of PRICKLE2 function. The data presented here provide new insight into the biological roles of Prickle2, its behavioral importance, and suggest disruptions in non-canonical Wnt genes such as PRICKLE2 may contribu...

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Key role for gene dosage and synaptic homeostasis in autism spectrum disorders

Cited by 300 publications

References 104 publications

Impaired Oral Tolerance in ASD Children with Food Protein Induced Enterocolitis Syndrome (FPIES) – Altered Innate and Adaptive Immune Responses in ASD Children Recovered from FPIES in Comparison with non-ASD/FPIES and ASD/non-FPIES Children

Impaired Oral Tolerance in ASD Children with Food Protein Induced Enterocolitis Syndrome (FPIES) – Altered Innate and Adaptive Immune Responses in ASD Children Recovered from FPIES in Comparison with non-ASD/FPIES and ASD/non-FPIES Children

Inhibition-Based Biomarkers for Autism Spectrum Disorder

Erratum: Disruption of the non-canonical Wnt gene PRICKLE2 leads to autism-like behaviors with evidence for hippocampal synaptic dysfunction

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