Genetic studies in ASD have mostly focused on the proband, with no clear understanding of parental genetic contributions to fetal neurodevelopment. Among parental etiological factors, perinatal maternal inflammation secondary to autoimmunity, infections, and toxins is associated with ASD. However, the inherent impact of maternal genetics on in-utero inflammation and fetal neurodevelopment in the absence of strong external inflammatory exposures is not known. We used the PtenWT/m3m4 mouse model for ASD to demonstrate the impact of maternal genetics on the penetrance of ASD-like phenotypes in the offspring. PtenWT/m3m4 (Momm3m4) or PtenWT/WT (MomWT) females, their offspring, and placental interface were analyzed for inflammatory markers, gene expression, and cellular phenotypes at E17.5. Postnatal behavior was tested by comparing pups from Momm3m4 vs. MomWT. Mothers of the PtenWT/m3m4 genotype (Momm3m4) showed inadequate induction of IL-10 mediated immunosuppression during pregnancy. Low IL-10 in the mother was directly correlated with decreased complement expression in the fetal liver. Fetuses from Momm3m4 had increased breakdown of the blood–brain–barrier, neuronal loss, and lack of glial cell maturation during in-utero stages. This impact of maternal genotype translated to a postnatal increase in the risk of newborn mortality, visible macrocephaly and ASD-like repetitive and social behaviors. Depending on maternal genotype, non-predisposed (wildtype) offspring showed ASD-like phenotypes, and phenotypic penetrance was decreased in predisposed pups from MomWT. Our study introduces the concept that maternal genetics alone, without any added external inflammatory insults, can modulate fetal neurodevelopment and ASD-related phenotypes in the offspring via alteration of IL-10 mediated materno-fetal immunosuppression.
Background PTEN is a well-established risk gene for autism spectrum disorder (ASD). Yet, little is known about how PTEN mutations and associated molecular processes influence neurobehavioral function in mutation carriers with (PTEN-ASD) and without ASD (PTEN no-ASD). The primary aim of the present study was to examine group differences in peripheral blood-derived PTEN pathway protein levels between PTEN-ASD, PTEN no-ASD, and idiopathic macrocephalic ASD patients (macro-ASD). Secondarily, associations between protein levels and neurobehavioral functions were examined in the full cohort. Methods Patients were recruited at four tertiary medical centers. Peripheral blood-derived protein levels from canonical PTEN pathways (PI3K/AKT and MAPK/ERK) were analyzed using Western blot analyses blinded to genotype and ASD status. Neurobehavioral measures included standardized assessments of global cognitive ability and multiple neurobehavioral domains. Analysis of variance models examined group differences in demographic, neurobehavioral, and protein measures. Bivariate correlations, structural models, and statistical learning procedures estimated associations between molecular and neurobehavioral variables. To complement patient data, Western blots for downstream proteins were generated to evaluate canonical PTEN pathways in the PTEN-m3m4 mouse model. Results Participants included 61 patients (25 PTEN-ASD, 16 PTEN no-ASD, and 20 macro-ASD). Decreased PTEN and S6 were observed in both PTEN mutation groups. Reductions in MnSOD and increases in P-S6 were observed in ASD groups. Elevated neural P-AKT/AKT and P-S6/S6 from PTEN murine models parallel our patient observations. Patient PTEN and AKT levels were independently associated with global cognitive ability, and p27 expression was associated with frontal sub-cortical functions. As a group, molecular measures added significant predictive value to several neurobehavioral domains over and above PTEN mutation status. Limitations Sample sizes were small, precluding within-group analyses. Protein and neurobehavioral data were limited to a single evaluation. A small number of patients were excluded with invalid protein data, and cognitively impaired patients had missing data on some assessments. Conclusions Several canonical PTEN pathway molecules appear to influence the presence of ASD and modify neurobehavioral function in PTEN mutation patients. Protein assays of the PTEN pathway may be useful for predicting neurobehavioral outcomes in PTEN patients. Future longitudinal analyses are needed to replicate these findings and evaluate within-group relationships between protein and neurobehavioral measures. Trial registration ClinicalTrials.gov Identifier NCT02461446
The magnitude effect, where larger outcomes are discounted proportionally less than smaller outcomes, is a well‐established phenomenon in delay discounting by human participants. To this point in the literature magnitude effects have not been reliably evidenced in nonhuman animals. , however, used a concurrent‐chains arrangement with pigeon and found evidence for a magnitude effect. Grace et al. suggested that in many delay discounting experimental arrangements with nonhuman animals (e.g., adjusting amount, adjusting delay) the organism is not given the opportunity to directly compare outcomes of different sizes. They suggest that because of the lack of direct comparison it is difficult for the organism to determine the relative size of each outcome, which in turn mutes the effect of the amount differences between outcomes. As a test of this “comparison hypothesis,” the present experiment was conducted to assess whether the magnitude effect would be evidenced in pigeon when using an adjusting amount procedure where outcomes of different amounts were presented proximally. In the present arrangement, pigeons were presented two choice panels in an operant chamber where each panel was associated with an independent adjusting amount delay discounting task, but with differing outcome amounts (i.e., a 32‐food pellet panel and an 8‐food pellet panel). In this arrangement the choice panels alternated in their availability within a session from trial block to trial block. The present findings indicate no reliable effect of amount, even when the outcomes were proximal and thus readily comparable. This result suggests that the lack of magnitude effect is not driven by the organism's ability to compare the difference in amount between choice alternatives.
A series of procedures were conducted in an attempt to assess various forms of validity related to the use of pigeons in research on delay discounting. In separate experimental arrangements, pigeons pressed a treadle, pecked a lit key, pecked a darkened key, or pecked a lit key with a hold as the required response. First, the obtained results were consistent with what would be necessary if the construct of delay discounting were being measured, which provides evidence of face validity. Second, criterion validity was assessed by comparing individual differences in rates of discounting across procedures. Third, to assess internal validity, each pigeon repeated the Treadle, Key Peck, and Dark Key procedures. Again, at both the aggregate and individual levels, the obtained indifference points did not differ systematically between replications. Finally, to assess external validity, discounting was observed regardless of the procedure, where the patterns of data at the aggregate level, and generally at the individual level, were orderly and well described by a hyperbolic function. In addition, rates of discounting were similar when pigeons pecked a lit key, a dark key, or a key with a hold; and each of those rates of discounting tended to be steeper than when treadle pressing. Generally speaking, pigeons that discounted relatively steeply on one procedure also tended to discount relatively steeply on the other procedures. The procedures evidence some of the necessary elements involved with the use of pigeons in research on delay discounting.
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