Mutation or disruption of the SH3 and ankyrin repeat domains 3 (SHANK3) gene represents a highly penetrant, monogenic risk factor for autism spectrum disorder, and is a cause of Phelan-McDermid syndrome. Recent advances in gene editing have enabled the creation of genetically engineered non-human-primate models, which might better approximate the behavioural and neural phenotypes of autism spectrum disorder than do rodent models, and may lead to more effective treatments. Here we report CRISPR-Cas9-mediated generation of germline-transmissible mutations of SHANK3 in cynomolgus macaques (Macaca fascicularis) and their F1 offspring. Genotyping of somatic cells as well as brain biopsies confirmed mutations in the SHANK3 gene and reduced levels of SHANK3 protein in these macaques. Analysis of data from functional magnetic resonance imaging revealed altered local and global connectivity patterns that were indicative of circuit abnormalities. The founder mutants exhibited sleep disturbances, motor deficits and increased repetitive behaviours, as well as social and learning impairments. Together, these results parallel some aspects of the dysfunctions in the SHANK3 gene and circuits, as well as the behavioural phenotypes, that characterize autism spectrum disorder and Phelan-McDermid syndrome.

Atypical behaviour and connectivity in SHANK3-mutant macaques.

The social impairments of autism spectrum disorder (ASD) have a major impact on quality of life, yet there are no medications that effectively treat these core social behavior deficits. Preclinical research suggests that arginine vasopressin (AVP), a neuropeptide involved in promoting mammalian social behaviors, may be a possible treatment for ASD. Using a double-blind, randomized, placebo-controlled, parallel study design, we tested the efficacy and tolerability of a 4-week intranasal AVP daily treatment in 30 children with ASD. AVP-treated participants aged 6 to 9.5 years received the maximum daily target dose of 24 International Units (IU); participants aged 9.6 to 12.9 years received the maximum daily target dose of 32 IU. Intranasal AVP treatment compared to placebo enhanced social abilities as assessed by change from baseline in this phase 2 trial’s primary outcome measure, the Social Responsiveness Scale, 2nd Edition total score (SRS-2 T score; F1,20 = 9.853; P = 0.0052; ηp2 = 33.0%; Cohen’s d = 1.40). AVP treatment also diminished anxiety symptoms and some repetitive behaviors. Most of these findings were more pronounced when we accounted for pretreatment AVP concentrations in blood. AVP was well tolerated with minimal side effects. No AVP-treated participants dropped out of the trial, and there were no differences in the rate of adverse events reported between treatment conditions. Last, no changes from baseline were observed in vital signs, electrocardiogram tracings, height and body weight, or clinical chemistry measurements after 4 weeks of AVP treatment. These preliminary findings suggest that AVP has potential for treating social impairments in children with ASD.

A randomized placebo-controlled pilot trial shows that intranasal vasopressin improves social deficits in children with autism

This focus issue of Lab Animal coincides with a tipping point in biomedical research. For the first time, the scale of the reproducibility and translatability crisis is widely understood beyond the small cadre of researchers who have been studying it and the pharmaceutical and biotech companies who have been living it. Here we argue that an emerging literature, including the papers in this focus issue, has begun to congeal around a set of recurring themes, which themselves represent a paradigm shift. This paradigm shift can be characterized at the micro level as a shift from asking "what have we controlled for in this model?" to asking "what have we chosen to ignore in this model, and at what cost?" At the macro level, it is a shift from viewing animals as tools (the furry test tube), to viewing them as patients in an equivalent human medical study. We feel that we are witnessing the birth of a new discipline, which we term Therioepistemology, or the study of how knowledge is gained from animal research. In this paper, we outline six questions that serve as a heuristic for critically evaluating animal-based biomedical research from a therioepistemological perspective. These six questions sketch out the broad reaches of this new discipline, though they may change or be added to as this field evolves. Ultimately, by formalizing therioepistemology as a discipline, we can begin to discuss best practices that will improve the reproducibility and translatability of animal-based research, with concomitant benefits in terms of human health and animal well-being.

/pdf/introducing-therioepistemology-the-study-of-how-knowledge-is-3w387lfcla.pdf

Introducing Therioepistemology: the study of how knowledge is gained from animal research

Advances in nonhuman primate models of autism: Integrating neuroscience and behavior.

Mutation is the ultimate source of all genetic novelty and the cause of heritable genetic disorders. Mutational burden has been linked to complex disease, including neurodevelopmental disorders such as schizophrenia and autism. The rate of mutation is a fundamental genomic parameter and direct estimates of this parameter have been enabled by accurate comparisons of whole-genome sequences between parents and offspring. Studies in humans have revealed that the paternal age at conception explains most of the variation in mutation rate: Each additional year of paternal age in humans leads to approximately 1.5 additional inherited mutations. Here, we present an estimate of the de novo mutation rate in the rhesus macaque (Macaca mulatta) using whole-genome sequence data from 32 individuals in four large pedigrees. We estimated an average mutation rate of 0.58 × 10-8 per base pair per generation (at an average parental age of 7.5 yr), much lower than found in direct estimates from great apes. As in humans, older macaque fathers transmit more mutations to their offspring, increasing the per generation mutation rate by 4.27 × 10-10 per base pair per year. We found that the rate of mutation accumulation after puberty is similar between macaques and humans, but that a smaller number of mutations accumulate before puberty in macaques. We additionally investigated the role of paternal age on offspring sociability, a proxy for normal neurodevelopment, by studying 203 male macaques in large social groups.

/pdf/paternal-age-in-rhesus-macaques-is-positively-associated-4cpjm0rdj7.pdf

Paternal age in rhesus macaques is positively associated with germline mutation accumulation but not with measures of offspring sociability.

Autism spectrum disorder (ASD) is characterized by social cognition impairments but its basic disease mechanisms remain poorly understood Progress has been impeded by the absence of animal models that manifest behavioral phenotypes relevant to ASD Rhesus monkeys are an ideal model organism to address this barrier to progress Like humans, rhesus monkeys are highly social, possess complex social cognition abilities, and exhibit pronounced individual differences in social functioning Moreover, we have previously shown that Low-Social (LS) vs High-Social (HS) adult male monkeys exhibit lower social motivation and poorer social skills It is not known, however, when these social deficits first emerge The goals of this study were to test whether juvenile LS and HS monkeys differed as infants in their ability to process social information, and whether infant social abilities predicted later social classification (ie, LS vs HS), in order to facilitate earlier identification of monkeys at risk for poor social outcomes Social classification was determined for N = 25 LS and N = 25 HS male monkeys that were 1–4 years of age As part of a colony-wide assessment, these monkeys had previously undergone, as infants, tests of face recognition memory and the ability to respond appropriately to conspecific social signals Monkeys later identified as LS vs HS showed impairments in recognizing familiar vs novel faces and in the species-typical adaptive ability to gaze avert to scenes of conspecific aggression Additionally, multivariate logistic regression using infant social ability measures perfectly predicted later social classification of all N = 50 monkeys These findings suggest that an early capacity to process important social information may account for differences in rhesus monkeys’ motivation and competence to establish and maintain social relationships later in life Further development of this model will facilitate identification of novel biological targets for intervention to improve social outcomes in at-risk young monkeys

/pdf/early-predictors-of-impaired-social-functioning-in-male-5gf18d4dqx.pdf

Early Predictors of Impaired Social Functioning in Male Rhesus Macaques (Macaca mulatta).

Previous research has linked perceived social isolation (loneliness) to reduced antiviral immunity, but the immunologic effects of the objective social isolation imposed by pandemic "shelter in place" (SIP) policies is unknown. We assessed the immunologic impact of SIP by relocating 21 adult male rhesus macaques from 2,000-m2 field cage communities of 70 to 132 other macaques to 2 wk of individual housing in indoor shelters. SIP was associated with 30% to 50% reductions in all circulating immune cell populations (lymphocytes, monocytes, and granulocytes), down-regulation of Type I interferon (IFN) antiviral gene expression, and a relative up-regulation of CD16- classical monocytes. These effects emerged within the first 48 h of SIP, persisted for at least 2 wk, and abated within 4 wk of return to social housing. A subsequent round of SIP in the presence of a novel juvenile macaque showed comparable reductions in circulating immune cell populations but reversal of Type I IFN reductions and classical monocyte increases observed during individual SIP. Analyses of lymph node tissues showed parallel up-regulation of Type I IFN genes and enhanced control of viral gene expression during juvenile-partnered SIP compared to isolated SIP. These results identify a significant adverse effect of SIP social isolation on antiviral immune regulation in both circulating immune cells and lymphoid tissues, and they suggest a potential behavioral strategy for ameliorating gene regulatory impacts (but not immune cell declines) by promoting prosocial engagement during SIP.

https://www.pnas.org/content/pnas/118/29/e2105803118.full.pdf

The Type I interferon antiviral gene program is impaired by lockdown and preserved by caregiving.

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Early Predictors of Impaired Social Functioning in Male Rhesus Macaques (Macaca mulatta).

The Type I interferon antiviral gene program is impaired by lockdown and preserved by caregiving.