G protein-coupled receptors (GPCRs) are classically characterized as cell-surface receptors transmitting extracellular signals into cells. Here we show that central components of a GPCR signaling system comprised of the melatonin type 1 receptor (MT), its associated G protein, and β-arrestins are on and within neuronal mitochondria. We discovered that the ligand melatonin is exclusively synthesized in the mitochondrial matrix and released by the organelle activating the mitochondrial MT signal-transduction pathway inhibiting stress-mediated cytochrome release and caspase activation. These findings coupled with our observation that mitochondrial MT overexpression reduces ischemic brain injury in mice delineate a mitochondrial GPCR mechanism contributing to the neuroprotective action of melatonin. We propose a new term, "automitocrine," analogous to "autocrine" when a similar phenomenon occurs at the cellular level, to describe this unexpected intracellular organelle ligand-receptor pathway that opens a new research avenue investigating mitochondrial GPCR biology.

Objective: To evaluate how distinct presentations of anxiety symptoms and intellectual impairment influence the measurement and estimated rate of clinically significant anxiety in autism spectrum disorder (ASD). Method: The sample included 75 children (ages 9-13 years) with ASD and varied IQ and 52 typically developing (TD) controls and parents. Parents completed anxiety symptom scales and a diagnostic interview, designed to (1) differentiate anxiety and ASD and (2) examine DSMspecified and unspecified ("distinct") anxiety presentations in each child, including fears of change, special interests, idiosyncratic stimuli and social confusion rather than evaluation. Children completed standard intellectual and ASD diagnostic assessments. Results: 69% of those with ASD had clinically-significant anxiety, including 21% DSM-specified anxiety disorders, 17% distinct anxiety, and 31% both. Only 8% of TD children had clinicallysignificant anxiety, all DSM-specified. DSM-specified anxiety disorders in children with ASD and intellectual impairment (IQ<70) were predominantly specific phobias. DSM-specified anxiety other than specific phobia was significantly less common in children with, versus without, intellectual impairment; this was not the case for distinct anxiety. The sensitivities of anxiety scales were moderate to poor, particularly in cases with intellectual impairment. Conclusions: ASD is associated with more frequent and varied presentations of clinical anxiety, which may align with and differ from the specified anxiety disorders of the DSM. Standard parent report anxiety scales have reduced sensitivity to detect clinical anxiety in ASD, particularly in children with intellectual impairment. "This summer [1937] we brought him to a playground slide and on the first afternoon when the other children were sliding on it he would not get about it, and when we put him up to slide down it he seemed horrorstruck. The next morning when nobody was present, however, he walked out, climbed the ladder, and slid down and he has slid on it frequently since, but slides only when no other child is present to join him in sliding." Case 1, "Donald" "He frets when the bread is put in the oven to be made into toast, and is afraid it will get burned and be hurt. He is upset when the sun sets. He is upset because the moon does not always appear in the sky at night." Case 8, "Alfred"

Human cytomegalovirus (HCMV) infection is one of the leading prenatal causes of congenital mental retardation and deformities world-wide. Access to cultured human neuronal lineages, necessary to understand the species specific pathogenic effects of HCMV, has been limited by difficulties in sustaining primary human neuronal cultures. Human induced pluripotent stem (iPS) cells now provide an opportunity for such research. We derived iPS cells from human adult fibroblasts and induced neural lineages to investigate their susceptibility to infection with HCMV strain Ad169. Analysis of iPS cells, iPS-derived neural stem cells (NSCs), neural progenitor cells (NPCs) and neurons suggests that (i) iPS cells are not permissive to HCMV infection, i.e., they do not permit a full viral replication cycle; (ii) Neural stem cells have impaired differentiation when infected by HCMV; (iii) NPCs are fully permissive for HCMV infection; altered expression of genes related to neural metabolism or neuronal differentiation is also observed; (iv) most iPS-derived neurons are not permissive to HCMV infection; and (v) infected neurons have impaired calcium influx in response to glutamate.

Autism symptom severity change was evaluated during early childhood in 125 children diagnosed with autism spectrum disorder (ASD). Children were assessed at approximately 3 and 6 years of age for autism symptom severity, IQ and adaptive functioning. Each child was assigned a change score, representing the difference between ADOS Calibrated Severity Scores (CSS) at the two ages. A Decreased Severity Group (28.8%) decreased by 2 or more points; a Stable Severity Group (54.4%) changed by 1 point or less; and an Increased Severity Group (16.8%) increased by 2 or more points. Girls tended to decrease in severity more than boys and increase in severity less than boys. There was no clear relationship between intervention history and membership in the groups.

Gastrointestinal (GI) symptoms are frequently reported in children with autism spectrum disorder (ASD). We evaluated the frequency and severity of GI symptoms in preschool-aged children with ASD compared to participants with typical development (TD). Our goal was to ascertain whether GI symptoms are associated with differences in sex or developmental and behavioral measures. Participants were between 2 and 3.5 years of age and included 255 children with ASD (184 males/71 females) and 129 age-matched TD controls (75 males/54 females). A parent interview was used to assess GI symptoms (abdominal pain, gaseousness/bloating, diarrhea, constipation, pain on stooling, vomiting, difficulty swallowing, blood in stool or in vomit). Children with GI symptoms in each diagnostic group were compared to children without GI symptoms on measures of developmental, behavioral, and adaptive functioning. GI symptoms were reported more frequently in children with ASD compared to the TD group (47.8% vs. 17.8%, respectively). Children with ASD were also more likely to experience multiple GI symptoms (30.6% vs. 5.4%). GI symptoms were equally common in males and females across both diagnostic groups. There were no statistically significant differences in developmental or adaptive measures based on presence of GI symptoms in either ASD or TD children. Co-occurring GI symptoms were, however, associated with increased self-injurious behaviors, restricted stereotyped behaviors, aggressive behaviors, sleep problems and attention problems in both ASD and TD children. In children with ASD, a higher number of GI symptoms was associated with an increase in self-injurious behaviors, somatic complaints, reduced sleep duration, and increased parasomnias.

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Epidemiological and animal research shows that maternal immune activation increases the risk of autism spectrum disorders (ASD) in offspring. Emerging evidence suggests that maternal immune conditions may play a role in the phenotypic expression of neurodevelopmental difficulties in children with ASD and this may be moderated by offspring sex. This study aimed to investigate whether maternal immune conditions were associated with increased severity of adverse neurodevelopmental outcomes in children with ASD. Maternal immune conditions were examined as predictors of ASD severity, behavioural and emotional well-being, and cognitive functioning in a cohort of 363 children with ASD (n = 363; 252 males, 111 females; median age 3.07 [interquartile range 2.64-3.36 years]). We also explored whether these outcomes varied between male and female children. Results showed that maternal asthma was the most common immune condition reported in mothers of children with ASD. A history of maternal immune conditions (p = 0.009) was more common in male children with ASD, compared to female children. Maternal immune conditions were associated with increased behavioural and emotional problems in male and female children. By contrast, maternal immune conditions were not associated with decreased cognitive function. The findings demonstrate that MIA may influence the expression of symptoms in children with ASD and outcomes may vary between males and females.

The aims of this study were to identify a subset of children with autism spectrum disorder (ASD) and co-occurring symptoms of psychopathology, and to evaluate associations between this subgroup and biological sex and amygdala volume. Method: Participants included 420 children (ASD: 91 girls, 209 boys; typically developing controls: 57 girls, 63 boys). Latent profile analysis was used to identify ASD subgroups based on symptoms of psychopathology, adaptive functioning, cognitive development, and autism severity. Differences in the proportions of girls and boys across subgroups were evaluated. Magnetic resonance imaging scans were acquired (346 children); amygdala volumes were evaluated in relation to subgroups and problem behavior scores. Results: Three ASD subgroups were identified. One group was characterized by high levels of psychopathology and moderate impairment on other measures (High Psychopathology Moderate Impairments [HPMI], comprising 27% of the sample). The other two subgroups had lower symptoms of psychopathology but were differentiated by high and low levels of impairment on other measures. A higher proportion of girls were classified into the HPMI subgroup (40% of girls versus 22% of boys). Relative to controls, amygdala volumes were enlarged only in the HPMI subgroup. There was a positive association between right amygdala volume and internalizing behaviors in girls but not in boys with ASD. Conclusion: A higher proportion of girls with ASD faced greater challenges with psychopathology, suggesting a need for closer evaluation and potentially earlier intervention to help improve outcomes. Amygdala enlargement was associated with co-occurring symptoms of psychopathology, and sex-specific correlations with symptoms were observed.