Common EIF4E variants modulate risk for autism spectrum disorders in the high-functioning range

Waltes, Regina; Gfesser, Johannes; Haslinger, Denise; Schneider-Momm, Katja; Biscaldi, Monica; Voran, Anette; Freitag, Christine M.; Chiocchetti, Andreas G.

doi:10.1007/s00702-014-1230-2

Cited by 19 publications

(12 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Since 4EBP1 can be regulated by multiple pathways [79], and given the compartment-specific alterations in dendritic structure as discussed above, it is likely that other mechanisms, such as the mTOR pathway, also play a role in the changes of dendritic structure observed in this study. Notably, dysregulation of eIF4E has been implicated in the pathophysiology of ASD [80–82], supporting a potentially important role of this pathway in the disorder.…”

Section: Discussionmentioning

confidence: 99%

Dendritic overgrowth and elevated ERK signaling during neonatal development in a mouse model of autism

et al. 2017

View full text Add to dashboard Cite

Autism spectrum disorder (hereafter referred to as “ASD”) is a heterogeneous neurodevelopmental condition characterized by impaired social communication and interactions, and restricted, repetitive activities or interests. Alterations in network connectivity and memory function are frequently observed in autism patients, often involving the hippocampus. However, specific changes during early brain development leading to disrupted functioning remain largely unclear. Here, we investigated the development of dendritic arbor of hippocampal CA1 pyramidal neurons in the BTBR T+tf/J (BTBR) mouse model of autism. BTBR mice display the defining behavioural features of autism, and also exhibit impaired learning and memory. We found that compared to control C57BL/6J (B6) animals, the lengths of both apical and basal dendrites were significantly greater in neonatal BTBR animals. Further, basal dendrites in the BTBR mice had higher branching complexity. In contrast, cross-sectional area of the soma was unchanged. In addition, we observed a similar density of CA1 pyramidal neurons and thickness of the neuronal layer between the two strains. Thus, there was a specific, compartmentalized overgrowth of dendrites during early development in the BTBR animals. Biochemical analysis further showed that the extracellular signal-regulated kinases (ERK) pathway was up-regulated in the hippocampus of neonatal BTBR animals. Since dendritic structure is critical for information integration and relay, our data suggest that altered development of dendrites could potentially contribute to impaired hippocampal function and behavior observed in the BTBR model, and that this might be related to increased activation of the ERK pathway.

show abstract

Section: Discussionmentioning

confidence: 99%

Dendritic overgrowth and elevated ERK signaling during neonatal development in a mouse model of autism

et al. 2017

View full text Add to dashboard Cite

show abstract

“…ASD is present in ∼60% of males and ∼20% of females with FXS (Betancur 2011 Waltes et al 2014). Notably, ASD is diagnosed in approximately 50% of AS patients, implicating loss of Ube3a in ASD etiology.…”

Section: Autism Spectrum Disordersmentioning

confidence: 98%

Glutamate Synapses in Human Cognitive Disorders

Volk

Chiu

Sharma

et al. 2015

Annu. Rev. Neurosci.

224

179

View full text Add to dashboard Cite

Accumulating data, including those from large genetic association studies, indicate that alterations in glutamatergic synapse structure and function represent a common underlying pathology in many symptomatically distinct cognitive disorders. In this review, we discuss evidence from human genetic studies and data from animal models supporting a role for aberrant glutamatergic synapse function in the etiology of intellectual disability (ID), autism spectrum disorder (ASD), and schizophrenia (SCZ), neurodevelopmental disorders that comprise a significant proportion of human cognitive disease and exact a substantial financial and social burden. The varied manifestations of impaired perceptual processing, executive function, social interaction, communication, and/or intellectual ability in ID, ASD, and SCZ appear to emerge from altered neural microstructure, function, and/or wiring rather than gross changes in neuron number or morphology. Here, we review evidence that these disorders may share a common underlying neuropathy: altered excitatory synapse function. We focus on the most promising candidate genes affecting glutamatergic synapse function, highlighting the likely disease-relevant functional consequences of each. We first present a brief overview of glutamatergic synapses and then explore the genetic and phenotypic evidence for altered glutamate signaling in ID, ASD, and SCZ.

show abstract

“…Genetic variants in chromosome 4q, which contains the EIF4E locus, have been described in patients with ASD (43, 44). Notably, in ASD subjects several of these common genetic variants in the EIF4E gene are associated with a clinical phenotype characterized by repetitive and stereotyped behaviors, but not intellectual disability (45). A de novo chromosomal translocation involving the promoter region of the EIF4E gene in a boy with classic non-syndromic ASD has been described (46).…”

Section: Genes Encoding For Proteins That Regulate Translationmentioning

confidence: 99%

Reciprocal signaling between translational control pathways and synaptic proteins in autism spectrum disorders

Santini

Klann

2014

Sci. Signal.

View full text Add to dashboard Cite

Autism spectrum disorder (ASD) is a heterogeneous group of heritable neurodevelopmental disorders whose symptoms, which include deficits in social interaction skills, impaired communication ability, and ritualistic-like repetitive behaviors, appear in early childhood and continue throughout life. Genetic studies have revealed at least two clusters of genes frequently associated with ASD and intellectual disability: genes encoding for proteins involved in translational control and proteins involved in synaptic function. We hypothesize that mutations occurring in these two clusters of genes interfere with interconnected downstream signaling pathways to cause ASD symptomatology. In this review, we focus on the monogenic forms of ASD caused by mutations in genes encoding for proteins that regulate translation and synaptic proteins. Specifically, we describe the function of these proteins, the intracellular signaling regulated by them, and the current mouse models utilized to characterize synaptic and behavioral features of these mutations. Finally, we summarize recent studies that have established a connection between these two signaling pathways in models of ASD and propose that dysregulation of one pathway has a detrimental impact of the other.

show abstract

Common EIF4E variants modulate risk for autism spectrum disorders in the high-functioning range

Cited by 19 publications

References 50 publications

Dendritic overgrowth and elevated ERK signaling during neonatal development in a mouse model of autism

Dendritic overgrowth and elevated ERK signaling during neonatal development in a mouse model of autism

Glutamate Synapses in Human Cognitive Disorders

Reciprocal signaling between translational control pathways and synaptic proteins in autism spectrum disorders

Contact Info

Product

Resources

About