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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 (MT₁), 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 MT₁ signal-transduction pathway inhibiting stress-mediated cytochrome c release and caspase activation. These findings coupled with our observation that mitochondrial MT₁ 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.

Previous studies have reported alterations in cortical thickness in autism. However, few have included enough autistic females to determine if there are sex specific differences in cortical structure in autism. This longitudinal study aimed to investigate autistic sex differences in cortical thickness and trajectory of cortical thinning across childhood. Participants included 290 autistic (88 females) and 139 nonautistic (60 females) individuals assessed at up to 4 timepoints spanning ~2–13 years of age (918 total MRI timepoints). Estimates of cortical thickness in early and late childhood as well as the trajectory of cortical thinning were modeled using spatiotemporal linear mixed effects models of age-by-sex-by-diagnosis. Additionally, the spatial correspondence between cortical maps of sex-by-diagnosis differences and neurotypical sex differences were evaluated. Relative to their nonautistic peers, autistic females had more extensive cortical differences than autistic males. These differences involved multiple functional networks, and were mainly characterized by thicker cortex at ~3 years of age and faster cortical thinning in autistic females. Cortical regions in which autistic alterations were different between the sexes significantly overlapped with regions that differed by sex in neurotypical development. Autistic females and males demonstrated some shared differences in cortical thickness and rate of cortical thinning across childhood relative to their nonautistic peers, however these areas were relatively small compared to the widespread differences observed across the sexes. These results support evidence of sex-specific neurobiology in autism and suggest that processes that regulate sex differentiation in the neurotypical brain contribute to sex differences in the etiology of autism.

The structure of large-scale intrinsic connectivity networks is atypical in adolescents diagnosed with autism spectrum disorder (ASD or autism). However, the degree to which alterations occur in younger children, and whether these differences vary by sex, is unknown. We utilized structural magnetic resonance imaging (MRI) data from a sex- and age- matched sample of 122 autistic and 122 typically developing (TD) children (2–4 years old) to investigate differences in underlying network structure in preschool-aged autistic children within three large scale intrinsic connectivity networks implicated in ASD: the Socioemotional Salience, Executive Control, and Default Mode Networks. Utilizing structural covariance MRI (scMRI), we report network-level differences in autistic versus TD children, and further report preliminary findings of sex-dependent differences within network topology.

One of the most universally accepted facts about autism is that it is heterogenous. Individuals diagnosed with autism spectrum disorder have a wide range of behavioral presentations and a variety of co-occurring medical and mental health conditions. The identification of more homogenous subgroups is likely to lead to a better understanding of etiologies as well as more targeted interventions and treatments. In 2006, we initiated the UC Davis MIND Institute Autism Phenome Project (APP) with the overarching goal of identifying clinically meaningful subtypes of autism. This ongoing longitudinal multidisciplinary study now includes over 400 children and involves comprehensive medical, behavioral, and neuroimaging assessments from early childhood through adolescence (2 to 19 years of age). We have employed several strategies to identify sub-populations within autistic individuals: subgrouping by neural, biological, behavioral or clinical characteristics as well as by developmental trajectories. In this Mini Review, we summarize findings to date from the APP cohort and describe progress made towards identifying meaningful subgroups of autism.

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.

Background We extended our study of trajectories of intellectual development of autistic individuals in early (mean age 3 years; T1), and middle childhood (mean age 5 years, 7 months; T2) into later middle childhood/preadolescence (mean age 11 years, 6 months; T3) in the longitudinal Autism Phenome Project cohort. Participants included 373 autistic children (115 females). Methods Multivariate latent class growth analysis was used to identify distinct IQ trajectory subgroups. Baseline and developmental course group differences and predictors of trajectory membership were assessed using linear mixed effects models for repeated measures with pairwise testing, multinomial logistic regression models, and sensitivity analyses. Results We isolated three IQ trajectory groups between T1 and T3 for autistic youth that were similar to those found in our prior work. These included a group with persistent intellectual disability (ID; 45%), a group with substantial increases in IQ (CHG; 39%), and a group with persistently average or above IQs (P‐High; 16%). By T3, the groups did not differ in ADOS‐2 calibrated severity scores (CSS), and there were no group differences between Vineland (VABS) communication scores in CHG and P‐High. T1‐T3 externalizing behaviors declined significantly for CHG, however, there were no significant T3 group differences between internalizing or externalizing symptoms. T1 correlates for CHG and P‐High versus ID group membership included higher VABS communication and lower ADOS‐2 CSS. A T1 to T2 increase in VABS communication scores and a decline in externalizing predicted CHG versus ID group membership, while T1 to T2 improvement in VABS communication and reduction in ADOS‐2 CSS predicted P‐High versus ID group membership. Conclusions Autistic youth exhibit consistent IQ developmental trajectories from early childhood through preadolescence. Factors associated with trajectory group membership may provide clues about prognosis, and the need for treatments that improve adaptive communication and externalizing symptoms. Three IQ trajectories between early childhood and preadolescence were isolated for autistic youth. One showed persistent intellectual disability (ID), one showed persistent higher intellectual ability, and one demonstrated increasing intellectual development with IQ scores rising at least 1 standard deviations. Repetitive behaviors and externalizing behaviors declined for this group with increasing IQs, who together with the persistently high group showed greater symptoms of internalizing. The group with persistent ID showed the most impaired communication and social adaptive functioning, and an NVIQ that was significantly greater than VIQ in early childhood.

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.

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.

Huntington’s Disease (HD) is a fatal, autosomal dominant, neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene. The disease is characterized by chorea, as well as psychiatric and cognitive symptoms. At present, no treatment able to modify the disease progression is available. HD is characterized by the death of medium striatal spiny neurons within the brain. Melatonin is a hormone which acts as a neuroprotectant in a variety of neurodegenerative diseases. While most endogenous melatonin is produced by the pineal gland and circulated in the bloodstream, melatonin is also present in neurons. Here I use a novel method of detecting site specific melatonin synthesis to show melatonin is synthesized in neuronal mitochondria, where melatonin receptors are also localized. Previous research shows the melatonin receptor MT1 to be the mechanism of melatonin’s neuroprotection in cell and mouse models of HD. Here I measure the expression of MT1 in the R6/2 mouse model of HD to compare with literature reported decrease in expression, and test the effects of the R6/2 phenotype on overexpression of MT1 in a transgenic MT1 mouse model (NSE-MT1). Further, I use the cross of the NSE-MT1 mouse model and R6/2 to assess the effects of overexpression of MT1 in increasing melatonin’s neuroprotective properties to ameliorate disease phenotypes including caspase activation, neuronal density, rotarod behavioral testing, and survival. Together, these data show overexpression of MT1 produces small increases in melatonin’s neuroprotective properties with regard to caspase activation, but this protective effect does not cause corresponding increases in behavioral deficits or survival. Neuroprotection by melatonin is partially mediated by the MT1- receptor in an HD mouse model, but may additionally function by alternate pathways or be modulated by regulatory mechanisms. Understanding melatonin’s role as a neuroprotectant can help with the development of melatonergic therapeutics to treat HD and other neurodegenerative diseases to significantly impact public health outcomes.

Abstract Isolated/idiopathic rapid eye movement sleep behavior disorder (iRBD) is a usually prodromal manifestation of neurodegenerative disorders with α-synuclein pathology: Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Clinical trials in the iRBD population face substantial barriers: limited access to well-characterized cohorts, inconsistent assessment protocols across centers, and the absence of validated biomarkers of disease burden. The North American Prodromal Synucleinopathy (NAPS) Consortium was established to address these challenges and facilitate clinical trials for neuroprotective therapies targeting synucleinopathy at the earliest known stages. In this multi-site, longitudinal, observational study, nine academic centers across North America will enroll and follow over 500 individuals with iRBD from existing sleep centers. Sixty control participants, matched for age, sex, and race will also be recruited. A harmonized protocol—including a standardized clinical battery assessing motor, cognitive, autonomic, psychiatric, sensory, and sleep function; structured diagnostic adjudication; biospecimen collection; and centralized analysis of both polysomnography and neuroimaging data—is outlined herein and reflects NAPS Stage 2. Each participants completes these assessments annually, and are replaced in the event of phenoconversion. By unifying assessments and expanding geographic reach, NAPS lays the groundwork for efficient, well-powered clinical trials designed to delay or prevent progression of iRBD to overt PD, DLB, or MSA—ultimately enabling earlier, more effective therapeutic intervention for neurodegenerative disease. Registered at clinicaltrials.gov (NCT05826457).