Retracted: Association of upregulated Ras/Raf/ERK1/2 signaling with autism

Zou, Hua; Yu, Ying; Sheikh, Ashfaq M.; Malik, Mazhar N.; Yang, Kun; Wen, Gen; Chadman, Kathryn K.; Brown, W. Ted; Li, X.

doi:10.1111/j.1601-183x.2011.00702.x

Cited by 34 publications

(31 citation statements)

References 56 publications

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“…Zou et al . demonstrated that RAS/RAF/ERK1/2 signaling was upregulated in the brains of the BTBR mouse model of autism [63]. Recently, the upregulation of this pathway (and of ERK5) has been shown to occur in the brains of autistic subjects [64].…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic analysis of genetically defined autism candidate genes reveals common mechanisms of action

Lanz¹,

Guilmette²,

Gosink³

et al. 2013

Molecular Autism

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BackgroundAustism spectrum disorder (ASD) is a heterogeneous behavioral disorder or condition characterized by severe impairment of social engagement and the presence of repetitive activities. The molecular etiology of ASD is still largely unknown despite a strong genetic component. Part of the difficulty in turning genetics into disease mechanisms and potentially new therapeutics is the sheer number and diversity of the genes that have been associated with ASD and ASD symptoms. The goal of this work is to use shRNA-generated models of genetic defects proposed as causative for ASD to identify the common pathways that might explain how they produce a core clinical disability.MethodsTranscript levels of Mecp2, Mef2a, Mef2d, Fmr1, Nlgn1, Nlgn3, Pten, and Shank3 were knocked-down in mouse primary neuron cultures using shRNA constructs. Whole genome expression analysis was conducted for each of the knockdown cultures as well as a mock-transduced culture and a culture exposed to a lentivirus expressing an anti-luciferase shRNA. Gene set enrichment and a causal reasoning engine was employed to identify pathway level perturbations generated by the transcript knockdown.ResultsQuantification of the shRNA targets confirmed the successful knockdown at the transcript and protein levels of at least 75% for each of the genes. After subtracting out potential artifacts caused by viral infection, gene set enrichment and causal reasoning engine analysis showed that a significant number of gene expression changes mapped to pathways associated with neurogenesis, long-term potentiation, and synaptic activity.ConclusionsThis work demonstrates that despite the complex genetic nature of ASD, there are common molecular mechanisms that connect many of the best established autism candidate genes. By identifying the key regulatory checkpoints in the interlinking transcriptional networks underlying autism, we are better able to discover the ideal points of intervention that provide the broadest efficacy across the diverse population of autism patients.

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Section: Discussionmentioning

confidence: 99%

Transcriptomic analysis of genetically defined autism candidate genes reveals common mechanisms of action

Lanz¹,

Guilmette²,

Gosink³

et al. 2013

Molecular Autism

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“…A recent study demonstrated elevated ERK1/2 phosphorylation in whole frontal cortical homogenates of BTBR mice (Zou et al, 2011). Many studies, including our own, have shown that synaptic ERK1/ 2 phosphorylation is constitutively elevated in Fmr1 KOs (Hou et al, 2006;Michalon et al, 2012;Seese et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

“…We focused on ERK1/2 because (i) mutations in this kinase are associated with autism (Samuels et al, 2009), (ii) ERK1/2 levels are reportedly abnormal in BTBRs and other strains with autism-like phenotypes (Hou et al, 2006;Seese et al, 2012;Zou et al, 2011) and (iii) ERK1/2 activity is necessary for and activated by learning and memory (Thomas and Huganir, 2004). To test if ERK1/2 levels were abnormal at BTBR synapses, we employed fluorescence deconvolution tomography to quantify postsynaptic immunolabeling in CA1b fields containing B40 000 postsynaptic densities (PSDs) (Seese et al, 2013).…”

Section: Density Of Phospho-erk1/2 Is Abnormally Low In Btbr Synapsesmentioning

confidence: 99%

“…We used the hippocampus-dependent object location memory (OLM) task to compare memory in BTBRs and C57BL/6 mice, and fluorescence deconvolution tomography to determine whether strain effects on cognitive performance are associated with abnormalities in synaptic signaling of extracellular signal-regulated kinase (ERK) 1/2, a protein critical for long-term memory (Thomas and Huganir, 2004) and disturbed in forms of autism and its models (Hou et al, 2006;Michalon et al, 2012;Samuels et al, 2009;Seese et al, 2012;Zou et al, 2011). The results show that poor learning performance is associated with disturbances in ERK1/2 signaling in BTBRs and that both measures are amenable to normalization with pharmacological treatments.…”

Section: Introductionmentioning

confidence: 99%

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Long-Term Memory Deficits are Associated with Elevated Synaptic ERK1/2 Activation and Reversed by mGluR5 Antagonism in an Animal Model of Autism

Seese

Maske

Lynch

et al. 2014

Neuropsychopharmacol

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A significant proportion of patients with autism exhibit some degree of intellectual disability. The BTBR T þ Itpr3 tf /J mouse strain exhibits behaviors that align with the major diagnostic criteria of autism. To further evaluate the BTBR strain's cognitive impairments, we quantified hippocampus-dependent object location memory (OLM) and found that one-third of the BTBR mice exhibited robust memory, whereas the remainder did not. Fluorescence deconvolution tomography was used to test whether synaptic levels of activated extracellular signal-regulated kinase 1/2 (ERK1/2), a protein that contributes importantly to plasticity, correlate with OLM scores in individual mice. In hippocampal field CA1, the BTBRs had fewer post-synaptic densities associated with high levels of phosphorylated (p-) ERK1/2 as compared with C57BL/6 mice. Although counts of p-ERK1/2 immunoreactive synapses did not correlate with OLM performance, the intensity of synaptic p-ERK1/2 immunolabeling was negatively correlated with OLM scores across BTBRs. Metabotropic glutamate receptor (mGluR) 5 signaling activates ERK1/2. Therefore, we tested whether treatment with the mGluR5 antagonist MPEP normalizes synaptic and learning measures in BTBR mice: MPEP facilitated OLM and decreased synaptic p-ERK1/2 immunolabeling intensity without affecting numbers of p-ERK1/2 þ synapses. In contrast, semi-chronic ampakine treatment, which facilitates memory in other models of cognitive impairment, had no effect on OLM in BTBRs. These results suggest that intellectual disabilities associated with different neurodevelopmental disorders on the autism spectrum require distinct therapeutic strategies based on underlying synaptic pathology.

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“…Interestingly, several syndromic forms of ASDs due to the effects of single major genes (e.g., tuberous sclerosis complex and fragile X syndrome) are associated with overactivation of mTOR signaling (Ehninger and Silva, 2011; Sahin, 2012; Sharma et al, 2010). Importantly, the BTBR mouse strain has upregu-lated Ras/Raf/ERK1/2 signaling, which governs activity of mTORC1 (Yang et al, 2011; Zou et al, 2011). Specifically, relative to the B6 comparator strain, BTBR mice showed increased expression of immunoreactive Ras protein in frontal cortex and cerebellum (Zou et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

d-Cycloserine improves sociability in the BTBR T+ Itpr3tf/J mouse model of autism spectrum disorders with altered Ras/Raf/ERK1/2 signaling

Burket¹,

Benson²,

Tang³

et al. 2013

Brain Research Bulletin

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The genetically inbred BTBR T+ Itpr3tf/J (BTBR) mouse is a proposed model of autism spectrum disorders (ASDs). Similar to several syndromic forms of ASDs, mTOR activity may be enhanced in this mouse strain as a result of increased Ras signaling. Recently, d-cycloserine, a partial glycineB site agonist that targets the NMDA receptor, was shown to improve the sociability of the Balb/c mouse strain, another proposed genetically inbred model of ASDs. NMDA receptor activation is an important regulator of mTOR signaling activity. Given the ability of d-cycloserine to improve the sociability of the Balb/c mouse strain and the regulatory role of the NMDA receptor in mTOR signaling, we wondered if d-cycloserine would improve the impaired sociability of the BTBR mouse strain. d-Cycloserine (320 mg/kg, ip) improved measures of sociability in a standard sociability paradigm and spontaneous grooming that emerged during social interaction with an ICR stimulus mouse in the BTBR strain; however, similar effects were observed in the Swiss Webster comparator strain, raising questions about their strain-selectivity. Importantly, the profile of d-cycloserine's effects on both measures of sociability and stereotypies is consistent with that of a desired medication for ASDs; specifically, a desired medication would not improve sociability at the expense of worsening stereotypic behaviors or vice versa.

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Retracted: Association of upregulated Ras/Raf/ERK1/2 signaling with autism

Cited by 34 publications

References 56 publications

Transcriptomic analysis of genetically defined autism candidate genes reveals common mechanisms of action

Transcriptomic analysis of genetically defined autism candidate genes reveals common mechanisms of action

Long-Term Memory Deficits are Associated with Elevated Synaptic ERK1/2 Activation and Reversed by mGluR5 Antagonism in an Animal Model of Autism

d-Cycloserine improves sociability in the BTBR T+ Itpr3tf/J mouse model of autism spectrum disorders with altered Ras/Raf/ERK1/2 signaling

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