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Autism spectrum disorder is a construct used to describe individuals with a specific combination of impairments in social communication and repetitive behaviours, highly restricted interests and/or sensory behaviours beginning early in life. The worldwide prevalence of autism is just under 1%, but estimates are higher in high-income countries. Although gross brain pathology is not characteristic of autism, subtle anatomical and functional differences have been observed in post-mortem, neuroimaging and electrophysiological studies. Initially, it was hoped that accurate measurement of behavioural phenotypes would lead to specific genetic subtypes, but genetic findings have mainly applied to heterogeneous groups that are not specific to autism. Psychosocial interventions in children can improve specific behaviours, such as joint attention, language and social engagement, that may affect further development and could reduce symptom severity. However, further research is necessary to identify the long-term needs of people with autism, and treatments and the mechanisms behind them that could result in improved independence and quality of life over time. Families are often the major source of support for people with autism throughout much of life and need to be considered, along with the perspectives of autistic individuals, in both research and practice. Autism spectrum disorder — or autism — is a neurodevelopmental disorder that typically manifests in young children. This Primer by Lord and colleagues reviews the epidemiology, mechanisms, clinical detection and treatment of autism.

Autism Spectrum Disorder (ASD) is a common neurodevelopmental disorder affecting approximately 1% of children. ASD is defined by core symptoms in two domains: negative symptoms of impairment in social and communication function, and positive symptoms of restricted and repetitive behaviors. Available treatments are inadequate for treating both core symptoms and associated conditions. Twin studies indicate that ASD susceptibility has a large heritable component. Genetic studies have identified promising leads, with converging insights emerging from single-gene disorders that bear ASD features, with particular interest in mammalian target of rapamycin (mTOR)-linked synaptic plasticity mechanisms. Mouse models of these disorders are revealing not only opportunities to model behavioral perturbations across species, but also evidence of postnatal rescue of brain and behavioral phenotypes. An intense search for ASD biomarkers has consistently pointed to elevated platelet serotonin (5-HT) levels and a surge in brain growth in the first 2 years of life. Following a review of the diversity of ASD phenotypes and its genetic origins and biomarkers, we discuss opportunities for translation of these findings into novel ASD treatments, focusing on mTor- and 5-HT-signaling pathways, and their possible intersection. Paralleling the progress made in understanding the root causes of rare genetic syndromes that affect cognitive development, we anticipate progress in models systems using bona fide ASD-associated molecular changes that have the potential to accelerate the development of ASD diagnostics and therapeutics.

Neuropsychiatric disorders vary substantially in age of onset but are best understood within the context of neurodevelopment. Here, we review opportunities for intervention at critical points in developmental trajectories. We begin by discussing potential opportunities to prevent neuropsychiatric disorders. Once symptoms begin to emerge, a number of interventions have been studied either before a diagnosis can be made or shortly after diagnosis. Although some of these interventions are helpful, few are based upon an understanding of pathophysiology, and most ameliorate rather than resolve symptoms. As such, in the next portion of the review, we turn our discussion to genetic syndromes that are rare phenocopies of common diagnoses such as autism spectrum disorder or schizophrenia. Cellular or animal models of these syndromes point to specific regulatory or signaling pathways. As examples, findings from the mouse models of Fragile X and Rett syndromes point to potential treatments now being tested in randomized clinical trials. Paralleling oncology, we can hope that our treatments will move from nonspecific, like chemotherapies thrown at a wide range of tumor types, to specific, like the protein kinase inhibitors that target molecularly defined tumors. Some of these targeted treatments later show benefit for a broader, yet specific, array of cancers. We can hope that medications developed within rare neurodevelopmental syndromes will similarly help subgroups of patients with disruptions in overlapping signaling pathways. The insights gleaned from treatment development in rare phenocopy syndromes may also teach us how to test treatments based upon emerging common genetic or environmental risk factors.

RationaleTransgenic mouse lines expressing Cre-recombinase under the regulation of either dopamine transporter (DAT) or tyrosine hydroxylase (TH) promoters are commonly used to study the dopamine (DA) system. While use of the TH promoter appears to have less liability to changes in native gene expression, transgene insertion in the DAT locus results in reduced DAT expression and function. This confound is sometimes overlooked in genetically targeted behavioral experiments.ObjectivesWe sought to evaluate the suitability of DAT-Ires-Cre and TH-Cre transgenic lines for behavioral pharmacology experiments with DA agonists. We hypothesized that DAT-Ires-Cre expression would impact DAT-mediated behaviors, but no impact of TH-Cre expression would be observed.MethodsDAT-Ires-Cre and TH-Cre mice bred on mixed 129S6/C57BL/6 and pure C57BL/6 backgrounds were evaluated for novelty-induced, baseline, and amphetamine (AMPH)–induced locomotion, and for AMPH and D1 agonist (SKF-38393)–induced preservative behaviors.ResultsDAT-Ires-Cre mice on both mixed 129S6/C57BL/6 and pure C57BL/6 backgrounds displayed increased novelty-induced activity and decreased AMPH-induced locomotion, with mixed results for AMPH-induced stereotypy. TH-Cre mice on both backgrounds showed typical baseline activity and AMPH-induced stereotypy, with a difference in AMPH-induced locomotion observed only on the mixed background. Both transgenic lines displayed unaltered SKF-38393-induced grooming behavior.ConclusionsOur findings indicate that the DAT-Ires-Cre transgenic line may lead to confounds for experiments that are dependent on DAT expression. The TH-Cre transgenic line studied here may be a more useful option, depending on background strain, because of its lack of baseline and drug-induced phenotypes. These data highlight the importance of appropriate controls in studies employing transgenic mice.

Electroencephalogram-recorded epileptiform activity is common in children with autism spectrum disorder (ASD), even without clinical seizures. A systematic literature search identified 7 randomized, placebo-controlled trials of antiepileptic drugs (AEDs) in ASD (total n = 171), including three of valproate, and one each of lamotrigine, levetiracetam, and topiramate. Meta-analysis revealed no significant difference between medication and placebo in four studies targeting irritability/agitation and three studies investigating global improvement, although limitations include lack of power and different medications with diverse actions. Across all seven studies, there was no significant difference in discontinuation rate between two groups. AEDs do not appear to have a large effect size to treat behavioral symptoms in ASD, but further research is needed, particularly in the subgroup of patients with epileptiform abnormalities.

In the classical model of the basal ganglia, direct pathway striatal projection neurons (dSPNs) send projections to the substantia nigra (SNr) and entopeduncular nucleus to regulate motor function. Recent studies have re-established that dSPNs also possess axon collaterals within the globus pallidus (GPe) (bridging collaterals), yet the significance of these collaterals for behavior is unknown. Here we use in vivo optical and chemogenetic tools combined with deep learning approaches in mice to dissect the roles of dSPN GPe collaterals in motor function. We find that dSPNs projecting to the SNr send synchronous motor-related information to the GPe via axon collaterals. Inhibition of native activity in dSPN GPe terminals impairs motor activity and function via regulation of Npas1 neurons. We propose a model by which dSPN GPe axon collaterals (striatopallidal Go pathway) act in concert with the canonical terminals in the SNr to support motor control by inhibiting Npas1 neurons. The basal ganglia direct and indirect pathways are classically described as anatomically segregated and functionally opposing. Here the authors describe a non-canonical direct pathway made of axon collaterals to the globus pallidus that promotes motor action.

RationaleElevated whole-blood serotonin (5-HT) is a robust biomarker in ~ 30% of patients with autism spectrum disorders, in which repetitive behavior is a core symptom. Furthermore, elevated whole-blood 5-HT has also been described in patients with pediatric obsessive-compulsive disorder. The 5-HT1B receptor is associated with repetitive behaviors seen in both disorders. Chronic blockade of serotonin transporter (SERT) reduces 5-HT1B receptor levels in the orbitofrontal cortex (OFC) and attenuates the sensorimotor deficits and hyperactivity seen with the 5-HT1B agonist RU24969. We hypothesized that enhanced SERT function would increase 5-HT1B receptor levels in OFC and enhance sensorimotor deficits and hyperactivity induced by RU24969.ObjectivesWe examined the impact of the SERT Ala56 mutation, which leads to enhanced SERT function, on 5-HT1B receptor binding and 5-HT1B-mediated sensorimotor deficits.MethodsSpecific binding to 5-HT1B receptors was measured in OFC and striatum of naïve SERT Ala56 or wild-type mice. The impact of the 5-HT1A/1B receptor agonist RU24969 on prepulse inhibition (PPI) of startle, hyperactivity, and expression of cFos was examined.ResultsWhile enhanced SERT function increased 5-HT1B receptor levels in OFC of Ala56 mice, RU24969-induced PPI deficits and hyperlocomotion were not different between genotypes. Baseline levels of cFos expression were not different between groups. RU24969 increased cFos expression in OFC of wild-types and decreased cFos in the striatum.ConclusionsWhile reducing 5-HT1B receptors may attenuate sensorimotor gating deficits, increased 5-HT1B levels in SERT Ala56 mice do not necessarily exacerbate these deficits, potentially due to compensations during neural circuit development in this model system.

STX209 (arbaclofen), a selective GABA-B agonist, is hypothesized to modulate the balance of excitatory to inhibitory neurotransmission, and has shown preliminary evidence of benefit in fragile X syndrome. We evaluated its safety, tolerability, and efficacy in non-syndromic autism spectrum disorders, in an 8-week open-label trial enrolling 32 children and adolescents with either Autistic Disorder or Pervasive Developmental Disorder—Not Otherwise Specified, and a score ≥17 on the Aberrant Behavior Checklist (ABC)—Irritability subscale. STX209 was generally well-tolerated. The most common adverse events were agitation and irritability, which typically resolved without dose changes, and were often felt to represent spontaneous variation in underlying symptoms. Improvements were observed on several outcome measures in this exploratory trial, including the ABC-Irritability (the primary endpoint) and the Lethargy/Social Withdrawal subscales, the Social Responsiveness Scale, the CY-BOCS-PDD, and clinical global impression scales. Placebo-controlled study of STX209 is warranted.