The core symptoms of autism are deficits in social interaction and language, and the presence of repetitive/stereotyped behaviors. We demonstrate that behaviors related to these symptoms are present in a mouse model of an environmental risk factor for autism, maternal infection. We stimulate the maternal immune system by injecting the viral mimic poly(I:C) during pregnancy, and analyze the social and communicative behaviors of the offspring. In one test, young pups respond to a brief separation from the mother with ultrasonic vocalizations (USVs). We find that, compared to pups born to saline-injected mothers, pups born to maternal immune activation (MIA) mothers produce a lower rate of USVs in the isolation test starting at day 8. The quality of the vocalizations is also different; analysis of sound spectrograms of ten day-old pups shows that male pups from MIA mothers emit significantly fewer harmonic and more complex and short syllables. These communication differences are also apparent in adult offspring. Compared to controls, adult MIA males emit significantly fewer USVs in response to social encounters with females or males, and display reduced scent marking in response to female urine. Regarding a second autism symptom, MIA males display decreased sociability. In a third test of characteristic autism behaviors, MIA offspring exhibit increased repetitive/stereotyped behavior in both marble burying and self-grooming tests. In sum, these results indicate that MIA yields male offspring with deficient social and communicative behavior, as well as high levels of repetitive behaviors, all of which are hallmarks of autism.

Significance Here, we model a positive symptom of schizophrenia, hallucination-like activity, in a mouse model of an environmental risk factor of schizophrenia, maternal immune activation (MIA). MIA offspring display an enhanced susceptibility to the hallucinogen 2,5-dimethoxy-4-iodoamphetamine (DOI) and demonstrate elevated DOI-induced brain activity as measured by induction of immediate early genes and manganese-enhanced MRI. High sensitivity to DOI in MIA offspring can be explained by an increased level of serotonin receptor 2A (5-HT2AR) that mediates the effect of DOI on the prefrontal cortex. Chronic treatment with the 5-HT2AR antagonist ketanserin reduces DOI-induction of head twitching in MIA offspring. Our data demonstrate that DOI-induced hallucination-like activity can be modeled in the MIA mouse model and suggest 5-HT2AR as a potential therapeutic target for schizophrenia.

In epithelial collective migration, leader and follower cells migrate while maintaining cell–cell adhesion and tissue polarity. We have identified a conserved protein and interactors required for maintaining cell adhesion during a simple collective migration in the developing C. elegans male gonad. LINKIN is a previously uncharacterized, transmembrane protein conserved throughout Metazoa. We identified seven atypical FG–GAP domains in the extracellular domain, which potentially folds into a β-propeller structure resembling the α-integrin ligand-binding domain. C. elegans LNKN-1 localizes to the plasma membrane of all gonadal cells, with apical and lateral bias. We identified the LINKIN interactors RUVBL1, RUVBL2, and α-tubulin by using SILAC mass spectrometry on human HEK 293T cells and testing candidates for lnkn-1-like function in C. elegans male gonad. We propose that LINKIN promotes adhesion between neighboring cells through its extracellular domain and regulates microtubule dynamics through RUVBL proteins at its intracellular domain.DOI: http://dx.doi.org/10.7554/eLife.04449.001

Background: Gentamicin therapy in neonates is optimized through achieving specific peak and trough concentrations. The objective of this study was to compare the ability a Bayesian clinical decision support system (CDSS) with standard of care (SOC) in determining personalized gentamicin therapies for neonates, at regimen initiation and in response to measured drug concentrations. Methods: This retrospective review and simulation compared target attainment among 4 arms: historical dosing according to SOC, via nomogram for initial dosing (SOC-initial) and via clinician judgment in response to measured concentrations (SOC-adjusted), and simulated dosing using the CDSS, incorporating a neonatal pharmacokinetic model for initial dosing (CDSS-initial) and incorporating maximum a posteriori-Bayesian analysis in response to measured concentrations (CDSS-adjusted). “True” patient pharmacokinetic parameters and peak and trough concentration predictions were calculated via the CDSS using the entirety of the patient dosing and concentration history. The primary outcome was pharmacokinetic target attainment of desired gentamicin peak and trough concentrations. Results: The study included 564 gentamicin concentrations among 339 patients. Mean demographics were 35 weeks gestational age (52% premature births) and 2.44 kg dosing weight. Mean PK parameters were 0.0533 L/h/kg clearance, 0.458 L/kg volume of distribution, and 8.66 hours half-life. Peak concentrations in the desired range were achieved in 96% of significantly more often in the CDSS-initial regimens and 94% of CDSS-adjusted regimens versus 86% of SOC-initial regimens and 66% of SOC-adjusted regimens. No difference was found in trough target attainment among study groups. Conclusions: In simulation, a Bayesian CDSS showed superiority to SOC in achieving gentamicin pharmacokinetic exposure targets in neonates. Use of a CDSS may improve the safety and efficacy of gentamicin therapy for neonates.