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The GluD1 gene is associated with susceptibility for schizophrenia, autism, depression, and bipolar disorder. However, the function of GluD1 and how it is involved in these conditions remain elusive. In this study, we generated a Grid1 gene-knockout (GluD1-KO) mouse line with a pure C57BL/6N genetic background and performed several behavioral analyses. Compared to a control group, GluD1-KO mice showed no significant anxiety-related behavioral differences, evaluated using behavior in an open field, elevated plus maze, a light-dark transition test, the resident-intruder test of aggression and sensorimotor gating evaluated by the prepulse inhibition test. However, GluD1-KO mice showed (1) higher locomotor activity in the open field, (2) decreased sociability and social novelty preference in the three-chambered social interaction test, (3) impaired memory in contextual, but not cued fear conditioning tests, and (4) enhanced depressive-like behavior in a forced swim test. Pharmacological studies revealed that enhanced depressive-like behavior in GluD1-KO mice was restored by the serotonin reuptake inhibitors imipramine and fluoxetine, but not the norepinephrine transporter inhibitor desipramine. In addition, biochemical analysis revealed no significant difference in protein expression levels, such as other glutamate receptors in the synaptosome and postsynaptic densities prepared from the frontal cortex and the hippocampus. These results suggest that GluD1 plays critical roles in fear memory, sociability, and depressive-like behavior.

Autism spectrum disorders (ASD) are defined by behavioral deficits in social interaction and communication, repetitive stereotyped behaviors, and restricted interests/cognitive rigidity. Recent studies in humans and animal-models suggest that dysfunction of the cholinergic system may underlie autism-related behavioral symptoms. Here we tested the hypothesis that augmentation of acetylcholine (ACh) in the synaptic cleft by inhibiting acetylcholinesterase may ameliorate autistic phenotypes. We first administered the acetylcholinesterase inhibitor (AChEI) Donepezil systemically by intraperitoneal (i.p.) injections. Second, the drug was injected directly into the rodent homolog of the caudate nucleus, the dorsomedial striatum (DMS), of the inbred mouse strain BTBR T+tf/J (BTBR), a commonly-used model presenting all core autism-related phenotypes and expressing low brain ACh levels. We found that i.p. injection of AChEI to BTBR mice significantly relieved autism-relevant phenotypes, including decreasing cognitive rigidity, improving social preference, and enhancing social interaction, in a dose-dependent manner. Microinjection of the drug directly into the DMS, but not into the ventromedial striatum, led to significant amelioration of the cognitive-rigidity and social-deficiency phenotypes. Taken together, these findings provide evidence of the key role of the cholinergic system and the DMS in the etiology of ASD, and suggest that elevated cognitive flexibility may result in enhanced social attention. The potential therapeutic effect of AChEIs in ASD patients is discussed.

Haploinsufficiency of the SHANK3 gene is causally linked to autism spectrum disorder (ASD), and ASD-associated genes are also enriched for chromatin remodelers. Here we found that brief treatment with romidepsin, a highly potent class I histone deacetylase (HDAC) inhibitor, alleviated social deficits in Shank3-deficient mice, which persisted for ~3 weeks. HDAC2 transcription was upregulated in these mice, and knockdown of HDAC2 in prefrontal cortex also rescued their social deficits. Nuclear localization of β-catenin, a Shank3-binding protein that regulates cell adhesion and transcription, was increased in Shank3-deficient mice, which induced HDAC2 upregulation and social deficits. At the downstream molecular level, romidepsin treatment elevated the expression and histone acetylation of Grin2a and actin-regulatory genes and restored NMDA-receptor function and actin filaments in Shank3-deficient mice. Taken together, these findings highlight an epigenetic mechanism underlying social deficits linked to Shank3 deficiency, which may suggest potential therapeutic strategies for ASD patients bearing SHANK3 mutations.

Early callous-unemotional behaviours identify children at risk for antisocial behaviour. Recent work suggests that the high heritability of callous-unemotional behaviours is qualified by interactions with positive parenting. To examine whether heritable temperament dimensions of fearlessness and low affiliative behaviour are associated with early callous-unemotional behaviours and whether parenting moderates these associations. Using an adoption sample (n = 561), we examined pathways from biological mother self-reported fearlessness and affiliative behaviour to child callous-unemotional behaviours via observed child fearlessness and affiliative behaviour, and whether adoptive parent observed positive parenting moderated pathways. Biological mother fearlessness predicted child callous-unemotional behaviours via earlier child fearlessness. Biological mother low affiliative behaviour predicted child callous-unemotional behaviours, although not via child affiliative behaviours. Adoptive mother positive parenting moderated the fearlessness to callous-unemotional behaviour pathway. Heritable fearlessness and low interpersonal affiliation traits contribute to the development of callous-unemotional behaviours. Positive parenting can buffer these risky pathways.

Research suggests that direct exposure (personal victimization) and indirect exposure (witnessing or hearing about the victimization of a family member, friend, or neighbor) to violence are correlated. However, questions remain about the co-occurrence of these phenomena within individuals. We used data on 1915 youths (with an average age of 12 years at baseline) from the Project on Human Development in Chicago Neighborhoods to examine this issue. Results indicated that youths who tended to be personally victimized were also likely to witness violence; conversely, youths who disproportionately witnessed violence were relatively unlikely to experience personal victimization. In addition, direct and indirect exposures to violence were associated with subsequent adverse outcomes in similar ways. The key distinguishing factor was, rather, the cumulative level of violence (both direct and indirect) to which youths were exposed.

The role of melatonin has been extensively investigated in pathophysiological conditions, including autism spectrum disorder (ASD). Reduced melatonin secretion has been reported in ASD and led to many clinical trials using immediate-release and prolonged-release oral formulations of melatonin. However, melatonin’s effects in ASD and the choice of formulation type require further study. Therapeutic benefits of melatonin on sleep disorders in ASD were observed, notably on sleep latency and sleep quality. Importantly, melatonin may also have a role in improving autistic behavioral impairments. The objective of this article is to review factors influencing treatment response and possible side effects following melatonin administration. It appears that the effects of exposure to exogenous melatonin are dependent on age, sex, route and time of administration, formulation type, dose, and association with several substances (such as tobacco or contraceptive pills). In addition, no major melatonin-related adverse effect was described in typical development and ASD. In conclusion, melatonin represents currently a well-validated and tolerated treatment for sleep disorders in children and adolescents with ASD. A more thorough consideration of factors influencing melatonin pharmacokinetics could illuminate the best use of melatonin in this population. Future studies are required in ASD to explore further dose-effect relationships of melatonin on sleep problems and autistic behavioral impairments.

Autism spectrum disorder is defined by two core symptoms: a deficit in social communication and the presence of repetitive behaviors and/or restricted interests. Currently, there is no US Food and Drug Administration-approved drug for these core symptoms. This article reviews the biological origins of the social function deficit associated with autism spectrum disorder and the drug therapies with the potential to treat this deficit. A review of the history of autism demonstrates that a deficit in social interaction has been the defining feature of the concept of autism from its conception. Abnormalities identified in early social skill development and an overview of the pathophysiology abnormalities associated with autism spectrum disorder are discussed as are the abnormalities in brain circuits associated with the social function deficit. Previous and ongoing clinical trials examining agents that have the potential to improve social deficits associated with autism spectrum disorder are discussed in detail. This discussion reveals that agents such as oxytocin and propranolol are particularly promising and undergoing active investigation, while other agents such as vasopressin agonists and antagonists are being activity investigated but have limited published evidence at this time. In addition, agents such as bumetanide and manipulation of the enteric microbiome using microbiota transfer therapy appear to have promising effects on core autism spectrum disorder symptoms including social function. Other pertinent issues associated with developing treatments in autism spectrum disorder, such as disease heterogeneity, high placebo response rates, trial design, and the most appropriate way of assessing effects on social skills (outcome measures), are also discussed.

When learning to use a novel tool, autistic children build a stronger link between their movements and proprioceptive feedback than typically developing children. Their greater reliance on proprioception correlates with the severity of social and impairment deficits. Children with autism spectrum disorder (ASD) have deficits in motor control, imitation and social function. Does a dysfunction in the neural basis of representing internal models of action contribute to these problems? We measured patterns of generalization as children learned to control a novel tool and found that the autistic brain built a stronger than normal association between self-generated motor commands and proprioceptive feedback; furthermore, the greater the reliance on proprioception, the greater the child's impairments in social function and imitation.

In this review, a conceptualization of oppositional defiant (ODD) and conduct disorder (CD) is presented according to which social learning processes in these disorders are affected by neurocognitive dysfunctions. Neurobiological studies in ODD and CD suggest that the ability to make associations between behaviors and negative and positive consequences is compromised in children and adolescents with these disorders due to reduced sensitivity to punishment and to reward. As a result, both learning of appropriate behavior and learning to refrain from inappropriate behavior may be affected. Likewise, problem solving is impaired due to deficiencies in inhibition, attention, cognitive flexibility, and decision making. Consequently, children and adolescents with ODD and CD may have difficulty learning to optimize their behavior in changeable environments. This conceptualization of ODD and CD is relevant for the improvement of the effect of psychological treatments. Behavioral and cognitive-behavioral interventions that have been shown to be modestly effective in ODD and CD are based on social learning. Limited effectiveness of these interventions may be caused by difficulties in social learning in children and adolescents with ODD and CD. However, although these impairments have been observed at a group level, the deficits in reward processing, punishment processing, and cognitive control mentioned above may not be present to the same extent in each individual with ODD and CD. Therefore, the neurocognitive characteristics in children and adolescents with ODD and CD should be assessed individually. Thus, instead of delivering interventions in a standardized way, these programs may benefit from an individualized approach that depends on the weaknesses and strengths of the neurocognitive characteristics of the child and the adolescent.

The aim of this study was to assess the prevalence of chronic multisite pain with high disability in relation to emotional or behavioral problems and resilience factors in adolescence. A second aim was to investigate if resilience factors could attenuate the associations between psychiatric symptoms and chronic multisite pain. The study was based on a large cross-sectional study carried out in Norway between 2006 and 2008 and included 7,070 adolescents aged 13–19 years. Chronic multisite pain was defined as pain at least once a week during the last 3 months, scoring high on a disability index, and occurring in three or more locations. Chronic multisite pain was prevalent among adolescents with high scores (>85 %) for anxiety/depression, social anxiety, conduct or attention problems (22.8–31.0 % for girls, 8.8–19.0 % for boys). Several coexistent psychiatric symptoms increased the prevalence of chronic multisite pain for both girls and boys. Resilience factors, including high self-esteem, seldom feeling lonely, and high scores for family cohesion or social competence, were associated with a lower prevalence and markedly attenuated the association between psychiatric symptoms and chronic multisite pain. Psychiatrists should be careful to assess and treat comorbid chronic pain in adolescents with emotional or behavioral problems.