Initial analysis of peripheral lymphocytic extracellular signal related kinase activation in autism

Erickson, Craig A.; Ray, Balmiki; Wink, Logan; Bayon, Baindu L.; Pedapati, Ernest V.; Shaffer, Rebecca C.; Schaefer, Tori L.; Lahiri, Debomoy K.

doi:10.1016/j.jpsychires.2016.09.003

Cited by 6 publications

(3 citation statements)

References 59 publications

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“…Fourth, although we assessed biological measures that had been previously implicated in prosocial behavior, ASD, and/or ASD-related syndromes, we did not observe relationships between CSF OXT concentration or blood kinase signaling and social trait variation here. This is in contrast to prior research in humans that has linked neonatal CSF OXT concentration to later social engagement [73], and blood kinase signaling to ASD and its symptom severity [74][75][76]. However, absence of evidence implicating these biological measures in monkey social functioning is not necessarily evidence of absence.…”

Section: Limitationscontrasting

confidence: 65%

Autism-associated biomarkers: test–retest reliability and relationship to quantitative social trait variation in rhesus monkeys

Oztan

Talbot²,

Argilli

et al. 2021

Molecular Autism

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Background Rhesus monkeys (Macaca mulatta) exhibit pronounced individual differences in social traits as measured by the macaque Social Responsiveness Scale-Revised. The macaque Social Responsiveness Scale was previously adapted from the Social Responsiveness Scale, an instrument designed to assess social and autistic trait variation in humans. To better understand potential biological underpinnings of this behavioral variation, we evaluated the trait-like consistency of several biological measures previously implicated in autism (e.g., arginine vasopressin, oxytocin, and their receptors, as well as ERK1/2, PTEN, and AKT(1–3) from the RAS-MAPK and PI3K-AKT pathways). We also tested which biological measures predicted macaque Social Responsiveness Scale-Revised scores. Methods Cerebrospinal fluid and blood samples were collected from N = 76 male monkeys, which, as a sample, showed a continuous distribution on the macaque Social Responsiveness Scale-Revised. In a subset of these subjects (n = 43), samples were collected thrice over a 10-month period. The following statistical tests were used: “Case 2A” intra-class correlation coefficients of consistency, principal component analysis, and general linear modeling. Results All biological measures (except AKT) showed significant test–retest reliability within individuals across time points. We next performed principal component analysis on data from monkeys with complete biological measurement sets at the first time point (n = 57), to explore potential correlations between the reliable biological measures and their relationship to macaque Social Responsiveness Scale-Revised score; a three-component solution was found. Follow-up analyses revealed that cerebrospinal fluid arginine vasopressin concentration, but no other biological measure, robustly predicted individual differences in macaque Social Responsiveness Scale-Revised scores, such that monkeys with the lowest cerebrospinal fluid arginine vasopressin concentration exhibited the greatest social impairment. Finally, we confirmed that this result held in the larger study sample (in which cerebrospinal fluid arginine vasopressin values were available from n = 75 of the subjects). Conclusions These findings indicate that cerebrospinal fluid arginine vasopressin concentration is a stable trait-like measure and that it is linked to quantitative social trait variation in male rhesus monkeys.

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Section: Limitationscontrasting

confidence: 65%

Autism-associated biomarkers: test–retest reliability and relationship to quantitative social trait variation in rhesus monkeys

Oztan

Talbot²,

Argilli

et al. 2021

Molecular Autism

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“…A further, conceptual limitation is that our animal models (except BTBR T+tf/J mice) are based on specific etiological factors, and do not model idiopathic ASD as such. However, there are no animal models of idiopathic ASD in this sense, as even BTBR T+tf/J mice were reported to share some genetic features with clinical ASD 76 – 78 . Our hypothesis was that individuals with ASD and rodent models of ASD may share key pathophysiological mechanisms regardless of etiology 79 .…”

Section: Discussionmentioning

confidence: 99%

Glutamate and GABA in autism spectrum disorder—a translational magnetic resonance spectroscopy study in man and rodent models

et al. 2018

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Autism spectrum disorder (ASD) is a pervasive neurodevelopmental syndrome with a high human and economic burden. The pathophysiology of ASD is largely unclear, thus hampering development of pharmacological treatments for the core symptoms of the disorder. Abnormalities in glutamate and GABA signaling have been hypothesized to underlie ASD symptoms, and may form a therapeutic target, but it is not known whether these abnormalities are recapitulated in humans with ASD, as well as in rodent models of the disorder. We used translational proton magnetic resonance spectroscopy ([1H]MRS) to compare glutamate and GABA levels in adult humans with ASD and in a panel of six diverse rodent ASD models, encompassing genetic and environmental etiologies. [1H]MRS was performed in the striatum and the medial prefrontal cortex, of the humans, mice, and rats in order to allow for direct cross-species comparisons in specific cortical and subcortical brain regions implicated in ASD. In humans with ASD, glutamate concentration was reduced in the striatum and this was correlated with the severity of social symptoms. GABA levels were not altered in either brain region. The reduction in striatal glutamate was recapitulated in mice prenatally exposed to valproate, and in mice and rats carrying Nlgn3 mutations, but not in rodent ASD models with other etiologies. Our findings suggest that glutamate/GABA abnormalities in the corticostriatal circuitry may be a key pathological mechanism in ASD; and may be linked to alterations in the neuroligin–neurexin signaling complex.

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“…Indeed, ERK-related mutations and genetic variation have been found in ASD patient groups (Wen et al, 2016). Eccentric ERK activation has also been observed in peripheral lymphocytes from ASD patients (Erickson et al, 2017) and in IPSC-derived neurons from patients with 22q11.2 deletions, an intellectual disability disorder with features related to ASD (Zhao et al, 2015). In animal models, dysregulation of ERK signaling has been shown to promote the expression of ASD-like phenotypes (Faridar et al, 2014; Yufune et al, 2015).…”

Section: Potential Mechanisms Of Il-17ra Activation On Cortical Dementioning

confidence: 92%

Maternal IL-17A in autism

Wong

Hoeffer

2018

Experimental Neurology

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Although autism spectrum disorder (ASD) has a strong genetic basis, its etiology is complex, with several genetic factors likely to be involved as well as environmental factors. Immune dysregulation has gained significant attention as a causal mechanism in ASD pathogenesis. ASD has been associated with immune abnormalities in the brain and periphery, including inflammatory disorders and autoimmunity in not only the affected individuals but also their mothers. Prenatal exposure to maternal immune activation (MIA) has been implicated as an environmental risk factor for ASD. In support of this notion, animal models have shown that MIA results in offspring with behavioral, neurological, and immunological abnormalities similar to those observed in ASD. This raises the question of how MIA exposure can lead to ASD in susceptible individuals. Recent evidence points to a potential inflammation pathway linking MIA-associated ASD with the activity of T helper 17 (Th17) lymphocytes and their effector cytokine interleukin-17A (IL-17A). IL-17A has been implicated from human studies and elevated IL-17A levels in the blood have been found to correlate with phenotypic severity in a subset of ASD individuals. In MIA model mice, elevated IL-17A levels also have been observed. Additionally, antibody blockade to inhibit IL-17A signaling was found to prevent ASD-like behaviors in offspring exposed to MIA. Therefore, IL-17A dysregulation may play a causal role in the development of ASD. The source of increased IL-17A in the MIA mouse model was attributed to maternal Th17 cells because genetic removal of the transcription factor RORγt to selectively inhibit Th17 differentiation in pregnant mice was able to prevent ASD-like behaviors in the offspring. Similar to ASD individuals, the MIA-exposed offspring also displayed cortical dysplasia which could be prevented by inhibition of IL-17A signaling in pregnant mice. This finding reveals one possible cellular mechanism through which ASD-related cognitive and behavioral deficits may emerge following maternal inflammation. IL-17A can exert strong effects on cell survival and differentiation and the activity of signal transduction cascades, which can have important consequences during cortical development on neural function. This review examines IL-17A signaling pathways in the context of both immunity and neural function that may contribute to the development of ASD associated with MIA.

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Initial analysis of peripheral lymphocytic extracellular signal related kinase activation in autism

Cited by 6 publications

References 59 publications

Autism-associated biomarkers: test–retest reliability and relationship to quantitative social trait variation in rhesus monkeys

Autism-associated biomarkers: test–retest reliability and relationship to quantitative social trait variation in rhesus monkeys

Glutamate and GABA in autism spectrum disorder—a translational magnetic resonance spectroscopy study in man and rodent models

Maternal IL-17A in autism

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