Alterations In Social Behavior Research Articles

Cannabidiol improves maternal obesity-induced behavioral, neuroinflammatory and neurochemical dysfunctions in the juvenile offspring

Maternal obesity is associated with an increased risk of psychiatric disorders such as anxiety, depression, schizophrenia and autism spectrum disorder in the offspring. While numerous studies focus on preventive measures targeting the mothers, only a limited number provide practical approaches for addressing the damages once they are already established. We have recently demonstrated the interplay between maternal obesity and treatment with cannabidiol (CBD) on hypothalamic inflammation and metabolic disturbances, however, little is known about this relationship on behavioral manifestations and neurochemical imbalances in other brain regions. Therefore, here we tested whether CBD treatment could mitigate anxiety-like and social behavioral alterations, as well as neurochemical disruptions in both male and female offspring of obese dams. Female Wistar rats were fed a cafeteria diet for 12 weeks prior to mating, and during gestation and lactation. Offspring received CBD (50 mg/kg) from weaning for 3 weeks. Behavioral tests assessed anxiety-like manifestations and social behavior, while neuroinflammatory and neurochemical markers were evaluated in the prefrontal cortex (PFC) and hippocampus. CBD treatment attenuated maternal obesity-induced anxiety-like and social behavioral alterations, followed by rescuing effects on imbalanced neurotransmitter and endocannabinoid concentrations and altered expression of glial markers, CB1, oxytocin and dopamine receptors, with important differences between sexes. Overall, the findings of this study provide insight into the signaling pathways for the therapeutic benefits of CBD on neuroinflammation and neurochemical imbalances caused by perinatal maternal obesity in the PFC and the hippocampus, which translates into the behavioral manifestations, highlighting the sexual dimorphism encompassing both the transgenerational effect of obesity and the endocannabinoid system.

Pleiotropic contribution of rbfox1 to psychiatric and neurodevelopmental phenotypes in two zebrafish models

RBFOX1 is a highly pleiotropic gene that contributes to several psychiatric and neurodevelopmental disorders. Both rare and common variants in RBFOX1 have been associated with several psychiatric conditions, but the mechanisms underlying the pleiotropic effects of RBFOX1 are not yet understood. Here we found that, in zebrafish, rbfox1 is expressed in spinal cord, mid- and hindbrain during developmental stages. In adults, expression is restricted to specific areas of the brain, including telencephalic and diencephalic regions with an important role in receiving and processing sensory information and in directing behaviour. To investigate the contribution of rbfox1 to behaviour, we used rbfox1sa15940, a zebrafish mutant line with TL background. We found that rbfox1sa15940 mutants present hyperactivity, thigmotaxis, decreased freezing behaviour and altered social behaviour. We repeated these behavioural tests in a second rbfox1 mutant line with a different genetic background (TU), rbfox1del19, and found that rbfox1 deficiency affects behaviour similarly in this line, although there were some differences. rbfox1del19 mutants present similar thigmotaxis, but stronger alterations in social behaviour and lower levels of hyperactivity than rbfox1sa15940 fish. Taken together, these results suggest that mutations in rbfox1 lead to multiple behavioural changes in zebrafish that might be modulated by environmental, epigenetic and genetic background effects, and that resemble phenotypic alterations present in Rbfox1-deficient mice and in patients with different psychiatric conditions. Our study, thus, highlights the evolutionary conservation of rbfox1 function in behaviour and paves the way to further investigate the mechanisms underlying rbfox1 pleiotropy on the onset of neurodevelopmental and psychiatric disorders.

Selective oxytocin receptor activation prevents prefrontal circuit dysfunction and social behavioral alterations in response to chronic prefrontal cortex activation in male rats.

Social behavioral changes are a hallmark of several neurodevelopmental and neuropsychiatric conditions, nevertheless the underlying neural substrates of such dysfunction remain poorly understood. Building evidence points to the prefrontal cortex (PFC) as one of the key brain regions that orchestrates social behavior. We used this concept with the aim to develop a translational rat model of social-circuit dysfunction, the chronic PFC activation model (CPA). Chemogenetic designer receptor hM3Dq was used to induce chronic activation of the PFC over 10 days, and the behavioral and electrophysiological signatures of prolonged PFC hyperactivity were evaluated. To test the sensitivity of this model to pharmacological interventions on longer timescales, and validate its translational potential, the rats were treated with our novel highly selective oxytocin receptor (OXTR) agonist RO6958375, which is not activating the related vasopressin V1a receptor. CPA rats showed reduced sociability in the three-chamber sociability test, and a concomitant decrease in neuronal excitability and synaptic transmission within the PFC as measured by electrophysiological recordings in acute slice preparation. Sub-chronic treatment with a low dose of the novel OXTR agonist following CPA interferes with the emergence of PFC circuit dysfunction, abnormal social behavior and specific transcriptomic changes. These results demonstrate that sustained PFC hyperactivity modifies circuit characteristics and social behaviors in ways that can be modulated by selective OXTR activation and that this model may be used to understand the circuit recruitment of prosocial therapies in drug discovery.

Gonadal hormones impart male-biased behavioral vulnerabilities to immune activation via microglial mitochondrial function

There is a strong male bias in the prevalence of many neurodevelopmental disorders such as autism spectrum disorder. However, the mechanisms underlying this sex bias remain elusive. Infection during the perinatal period is associated with an increased risk of neurodevelopmental disorder development. Here, we used a mouse model of early-life immune activation that reliably induces deficits in social behaviors only in males. We demonstrate that male-biased alterations in social behavior are dependent upon microglial immune signaling and are coupled to alterations in mitochondrial morphology, gene expression, and function specifically within microglia, the innate immune cells of the brain. Additionally, we show that this behavioral and microglial mitochondrial vulnerability to early-life immune activation is programmed by the male-typical perinatal gonadal hormone surge. These findings demonstrate that social behavior in males over the lifespan are regulated by microglia-specific mechanisms that are shaped by events that occur in early development.

Mice prenatally exposed to valproic acid do not show autism-related disorders when fed with polyunsaturated fatty acid-enriched diets

Dietary supplementations with n-3 polyunsaturated fatty acid (PUFA) have been explored in autism spectrum disorder (ASD) but their efficiency and potential in ameliorating cardinal symptoms of the disease remain elusive. Here, we compared a n-3 long-chain (LC) PUFA dietary supplementation (n-3 supp) obtained from fatty fish with a n-3 PUFA precursor diet (n-3 bal) obtained from plant oils in the valproic acid (VPA, 450 mg/kg at E12.5) ASD mouse model starting from embryonic life, throughout lactation and until adulthood. Maternal and offspring behaviors were investigated as well as several VPA-induced ASD biological features: cerebellar Purkinje cell (PC) number, inflammatory markers, gut microbiota, and peripheral and brain PUFA composition. Developmental milestones were delayed in the n-3 supp group compared to the n-3 bal group in both sexes. Whatever the diet, VPA-exposed offspring did not show ASD characteristic alterations in social behavior, stereotypies, PC number, or gut microbiota dysbiosis while global activity, gait, peripheral and brain PUFA levels as well as cerebellar TNF-alpha levels were differentially altered by diet and treatment according to sex. The current study provides evidence of beneficial effects of n-3 PUFA based diets, including one without LCPUFAs, on preventing several behavioral and cellular symptoms related to ASD.

Voluntary wheel running ameliorates abnormalities in social behavior induced by social isolation: Involvement of neural and neurochemical responses

Social isolation (SI) can lead to devastating behavioral effects. Increasing evidence has demonstrated that physical activity can improve sociability and brain functions, but whether voluntary exercise can ameliorate SI-induced abnormalities in social behavior and its underlying neuronal mechanisms remains unknown. The present study found that SI during adulthood increased aggression in the resident-intruder test and motivation for social exploration in the three-chamber test. Voluntary wheel running (VWR) could reverse the alterations in social behavior induced by SI in male mice. In addition, SI increased the number of c-Fos-immunoreactive neurons and c-Fos/AVP-labeled neurons in the PVN, reduced c-Fos/TPH2-labeled neurons in the DRN. These alterations could be reversed by VWR. Together, our results reveal that voluntary exercise could ameliorate SI-induced negative effects on social behavior, possibly via alterations of neuronal activation in the brain. This finding provides a potential therapy and targets to prevent or treat the psychological diseases associated with abnormalities in social behaviors.

Curiosity in zebrafish (Danio rerio)? Behavioral responses to 30 novel objects.

Curiosity-the motivation to seek out information-has been studied widely across the animal kingdom. To investigate curiosity in zebrafish we presented 30 novel objects to groups of zebrafish housed in semi-naturalistic tanks (6 tanks; 10 fish/tank; 10-min presentations). During the first 100 s and final 100 s of each object's 10-min presentation period, we recorded each group's: (i) latency to approach the object, (ii) attraction to the object, (iii) social dynamics: agonistic behavior and group cohesion and coordination, and (iv) diving behavior, a stress response in zebrafish. Comparing these behaviors to a 100 s baseline period when no object was present, we tested for neophobia (avoidance of novelty), neophilia (overall attraction to novelty), sustained interest (prolonged attraction to at least some presentations), discriminant interest (certain objects eliciting more attention than others), habituation (loss of interest over time), and alterations to social and stress behaviors. Zebrafish groups readily approached all objects (1 s median latency), were neophilic throughout all object presentations, and showed systematic sustained interest only for some object presentations at the beginning of the study (object presentations 1-10). Over the course of the study, zebrafish also showed signs of habituation such that by the final ten object presentations (21-30), there were no signs of overall sustained interest. During the beginning of the study (object presentations 1-10), we also found evidence for specific object-driven interest, with object ID accounting for 11% of the variability in interest scores (p < 0.01), and object-driven interest corresponding to alterations in social behavior: decreased aggression (p < 0.02), increased group cohesion (p < 0.02), and increased group coordination (p < 0.05). By explicitly investigating curiosity in fish, this work reveals that under certain conditions, zebrafish voluntarily engage in cognitive stimulation opportunities. More work is needed to clarify what types of information zebrafish find most rewarding and how long-term exposure to such opportunities may affect fish welfare.

Age-dependent alterations in social behavior and brain neurotransmitter levels in mice trimmed bilateral whiskers during the neonatal period

Age-dependent alterations in social behavior and brain neurotransmitter levels in mice trimmed bilateral whiskers during the neonatal period

Acute and long-term sex-dependent effects of social instability stress on anxiety-like and social behaviours in Wistar rats

Adolescence is a critical time of social learning in which both the quantity and quality of social interactions shape adult behavior and social function. During adolescence, social instability such as disrupting or limiting social interactions can lead to negative life-long effects on mental health and well-being in humans. Animal models on social instability are critically important in understanding those underlying neurobiological mechanisms. However, studies in rats using these models have produced partly inconsistent results and can be difficult to generalize. Here we assessed in a sex and age consistent manner the long-term behavioural consequences of social instability stress (SIS - 1-hr daily isolation and change in cage mate between postnatal day (PD30–45)) in Wistar rats. Female and male rats underwent a battery of tests for anxiety-like, exploratory, and social behaviour over five days beginning either in adolescence (PD46) or in adulthood (PD70). Social instability led to reduced anxiety-like behaviour in the elevated plus maze in both sexes in adolescence and in adulthood. Social interactions were also reduced in rats that underwent SIS – an effect that was independent of sex and age when tested. SIS improved social recognition memory in both sexes whereas a sex-dependent effect was seen in the social novelty preference test where male rats that underwent SIS spent more time in social approach toward a novel peer than toward their cage mate. In comparison, control male and female groups did not differ in this test, in time spent with novel versus the cage mate. Thus, overall, social instability stress in Wistar rats altered the behavioural repertoire, with enduring alterations in social behaviour, enhanced exploratory behaviour, and reduced anxiety-like behaviour. In conclusion, the social instability stress paradigm may better be interpreted as a form of enrichment in Wistar rats than as a stressor.

SRF depletion in early life contributes to social interaction deficits in the adulthood

Alterations in social behavior are core symptoms of major developmental neuropsychiatric diseases such as autism spectrum disorders or schizophrenia. Hence, understanding their molecular and cellular underpinnings constitutes the major research task. Dysregulation of the global gene expression program in the developing brain leads to modifications in a number of neuronal connections, synaptic strength and shape, causing unbalanced neuronal plasticity, which may be important substrate in the pathogenesis of neurodevelopmental disorders, contributing to their clinical outcome. Serum response factor (SRF) is a major transcription factor in the brain. The behavioral influence of SRF deletion during neuronal differentiation and maturation has never been studied because previous attempts to knock-out the gene caused premature death. Herein, we generated mice that lacked SRF from early postnatal development to precisely investigate the role of SRF starting in the specific time window before maturation of excitatory synapses that are located on dendritic spine occurs. We show that the time-controlled loss of SRF in neurons alters specific aspects of social behaviors in SRF knock-out mice, and causes deficits in developmental spine maturation at both the structural and functional levels, including downregulated expression of the AMPARs subunits GluA1 and GluA2, and increases the percentage of filopodial/immature dendritic spines. In aggregate, our study uncovers the consequences of postnatal SRF elimination for spine maturation and social interactions revealing novel mechanisms underlying developmental neuropsychiatric diseases.

Novel probiotic treatment of autism spectrum disorder associated social behavioral symptoms in two rodent models

The prevalence of autism spectrum disorder (ASD) has rapidly increased in the past decades, and several studies report about the escalating use of antibiotics and the consequent disruption of the gastrointestinal microbiome leading to the development of neurobehavioral symptoms resembling to those of ASD. The primary purpose of this study was to investigate whether depletion of the gastrointestinal microbiome via antibiotics treatment could induce ASD-like behavioral symptoms in adulthood. To reliably evaluate that, validated valproic acid (VPA) ASD animal model was introduced. At last, we intended to demonstrate the assessed potential benefits of a probiotic mixture (PM) developed by our research team. Male Wistar rats were used to create antibiotics treated; antibiotics and PM treated; PM treated, VPA treated; VPA and PM treated; and control groups. In all investigations we focused on social behavioral disturbances. Antibiotics-induced microbiome alterations during adulthood triggered severe deficits in social behavior similar to those observed in the VPA model. Furthermore, it is highlighted that our PM proved to attenuate both the antibiotics- and the VPA-generated antisocial behavioral symptoms. The present findings underline potential capacity of our PM to improve social behavioral alterations thus, indicate its promising therapeutic power to attenuate the social-affective disturbances of ASD.

Stressor-Induced Reduction in Cognitive Behavior is Associated with Impaired Colonic Mucus Layer Integrity and is Dependent Upon the LPS-Binding Protein Receptor CD14.

PurposeCommensal microbes are impacted by stressor exposure and are known contributors to cognitive and social behaviors, but the pathways through which gut microbes influence stressor-induced behavioral changes are mostly unknown. A murine social stressor was used to determine whether host–microbe interactions are necessary for stressor-induced inflammation, including neuroinflammation, that leads to reduced cognitive and social behavior.MethodsC57BL/6 male mice were exposed to a paired fighting social stressor over a 1 hr period for 6 consecutive days. Y-maze and social interaction behaviors were tested following the last day of the stressor. Serum cytokines and lipopolysaccharide binding protein (LBP) were measured and the number and morphology of hippocampal microglia determined via immunohistochemistry. Intestinal mucous thickness and antimicrobial peptide expression were determined via fluorescent staining and real-time PCR (respectively) and microbial community composition was assessed using 16S rRNA gene amplicon sequencing. To determine whether the microbiota or the LBP receptor (CD14) are necessary for stressor-induced behavioral changes, experiments were performed in mice treated with a broad-spectrum antibiotic cocktail or in CD14−/− mice.ResultsThe stressor reduced Y-maze spontaneous alternations, which was accompanied by increased microglia in the hippocampus, increased circulating cytokines (eg, IL-6, TNF-α) and LBP, and reduced intestinal mucus thickness while increasing antimicrobial peptides and cytokines. These stressor-induced changes were largely prevented in mice given broad-spectrum antibiotics and in CD14−/− mice. In contrast, social stressor-induced alterations of social behavior were not microbe-dependent.ConclusionStressor-induced cognitive deficits involve enhanced bacterial interaction with the intestine, leading to low-grade, CD14-dependent, inflammation.

Experiential modulation of social dominance in a SYNGAP1 rat model of Autism Spectrum Disorders.

Advances in the understanding of developmental brain disorders such as autism spectrum disorders (ASDs) are being achieved through human neurogenetics such as, for example, identifying de novo mutations in SYNGAP1 as one relatively common cause of ASD. A recently developed rat line lacking the calcium/lipid binding (C2) and GTPase activation protein (GAP) domain may further help uncover the neurobiological basis of deficits in children with ASD. This study focused on social dominance in the tube test using Syngap+/Δ-GAP (rats heterozygous for the C2/GAP domain deletion) as alterations in social behaviour are a key facet of the human phenotype. Male animals of this line living together formed a stable intra-cage hierarchy, but they were submissive when living with wild-type (WT) cage-mates, thereby modelling the social withdrawal seen in ASD. The study includes a detailed analysis of specific behaviours expressed in social interactions by WT and mutant animals, including the observation that when the Syngap+/Δ-GAP mutants that had been living together had separate dominance encounters with WT animals from other cages, the two higher ranking Syngap+/Δ-GAP rats remained dominant whereas the two lower ranking mutants were still submissive. Although only observed in a small subset of animals, these findings support earlier observations with a rat model of Fragile X, indicating that their experience of winning or losing dominance encounters has a lasting influence on subsequent encounters with others. Our results highlight and model that even with single-gene mutations, dominance phenotypes reflect an interaction between genotypic and environmental factors.

Advancing Autism Research From Mice to Marmosets: Behavioral Development of Offspring Following Prenatal Maternal Immune Activation.

Understanding the mechanism(s) by which maternal immune activation (MIA) during gestation may disrupt neurodevelopment and increase the susceptibility for disorders such as autism spectrum disorder (ASD) or schizophrenia is a critical step in the development of better treatments and preventive measures. A large body of literature has investigated the pathophysiology of MIA in rodents. However, a translatability gap plagues pre-clinical research of complex behavioral/developmental diseases and those diseases requiring clinical diagnosis, such as ASD. While ideal for their genetic flexibility, vast reagent toolkit, and practicality, rodent models often lack important elements of ethological validity. Hence, our study aimed to develop and characterize the prenatal MIA model in marmosets. Here, we adapted the well-characterized murine maternal immune activation model. Pregnant dams were administered 5 mg/kg poly-L-lysine stabilized polyinosinic-polycytidylic acid (Poly ICLC) subcutaneously three times during gestation (gestational day 63, 65, and 67). Dams were allowed to deliver naturally with no further experimental treatments. After parturition, offspring were screened for general health and vigor, and individual assessment of communication development and social behavior was measured during neonatal or adolescent periods. Similar to rodent models, offspring subjected to MIA exhibited a disruption in patterns of communication during early development. Assessment of social behavior in a marmoset-modified 3-chamber test at 3 and 9 months of age revealed alterations in social behavior that, in some instances, was sex-dependent. Together, our data indicate that marmosets are an excellent non-human primate model for investigating the neurodevelopmental and behavioral consequences of exposure to prenatal challenges, like MIA. Additional studies are necessary to more completely characterize the effect of prenatal inflammation on marmoset development and explore therapeutic intervention strategies that may be applicable in a clinical setting.

Social Behavior and Ultrasonic Vocalizations in a Genetic Rat Model Haploinsufficient for the Cross-Disorder Risk Gene Cacna1c.

The top-ranked cross-disorder risk gene CACNA1C is strongly associated with multiple neuropsychiatric dysfunctions. In a recent series of studies, we applied a genomically informed approach and contributed extensively to the behavioral characterization of a genetic rat model haploinsufficient for the cross-disorder risk gene Cacna1c. Because deficits in processing social signals are associated with reduced social functioning as commonly seen in neuropsychiatric disorders, we focused on socio-affective communication through 22-kHz and 50-kHz ultrasonic vocalizations (USV). Specifically, we applied a reciprocal approach for studying socio-affective communication in sender and receiver by including rough-and-tumble play and playback of 22-kHz and 50-kHz USV. Here, we review the findings obtained in this recent series of studies and link them to the key features of 50-kHz USV emission during rough-and-tumble play and social approach behavior evoked by playback of 22-kHz and 50-kHz USV. We conclude that Cacna1c haploinsufficiency in rats leads to robust deficits in socio-affective communication through 22-kHz and 50-kHz USV and associated alterations in social behavior, such as rough-and-tumble play behavior.

Involvement of the dopamine system in the effect of chronic social isolation during adolescence on social behaviors in male C57 mice

In the early stage of life, experiencing social isolation can generate long-lasting deleterious effects on behaviors and brain development. However, the effects of chronic social isolation during adolescence on social behaviors and its underlying neurobiological mechanisms remain unclear. The present study found that four weeks of social isolation during adolescence impaired social recognition ability in the three-chamber test and five-trial social recognition test, and increased aggressive-like behaviors, but reduced environmental exploration, as showed in the social interaction test. Chronic social isolation decreased levels of dopamine D2 receptor in the shell of the nucleus accumbens (NAcc) and medial prefrontal cortex. It also reduced TH in the NAcc. Using in vivo fiber photometry, it was also found that isolated mice displayed a reduction in NAcc shell activity upon exploring unfamiliar social stimuli. An injection of a 100 ng dose of the D2R agonist quinpirole into the shell of the NAcc reversed behavioral abnormalities induced by chronic social isolation. These data suggest that the dopamine system is involved in alterations in social behaviors induced by chronic social isolation. This finding sheds light on the mechanism underlying abnormalities in social behavior induced by adolescent chronic social isolation and provides a promising target to treat mental diseases relevant to social isolation.

Could Gait Biomechanics Become a Marker of Atypical Neuronal Circuitry in Human Development?-The Example of Autism Spectrum Disorder.

This perspective paper presents converging recent knowledge in neurosciences (motor neurophysiology, neuroimaging and neuro cognition) and biomechanics to outline the relationships between maturing neuronal network, behavior, and gait in human development. Autism Spectrum Disorder (ASD) represents a particularly relevant neurodevelopmental disorder (NDD) to study these convergences, as an early life condition presenting with sensorimotor and social behavioral alterations. ASD diagnosis relies solely on behavioral criteria. The absence of biological marker in ASD is a main challenge, and hampers correlations between behavioral development and standardized data such as brain structure alterations, brain connectivity, or genetic profile. Gait, as a way to study motor system development, represents a well-studied, early life ability that can be characterized through standardized biomechanical analysis. Therefore, developmental gait biomechanics might appear as a possible motor phenotype and biomarker, solid enough to be correlated to neuronal network maturation, in normal and atypical developmental trajectories—like in ASD.

Ketamine anesthesia enhances fear memory consolidation via noradrenergic activation in the basolateral amygdala

Trauma patients treated with ketamine during emergency care present aggravated early post- traumatic stress reaction which is highly predictive of post-traumatic stress disorder (PTSD) development and severity. The use of ketamine in the acute trauma phase may directly or indirectly interfere with neural processes of memory consolidation of the traumatic event, thus leading to the formation of maladaptive memories, a hallmark symptom of PTSD. We have recently shown that ketamine anesthesia, immediately after a traumatic event, enhances memory consolidation and leads to long-lasting alterations of social behavior in rats. Based on the evidence that ketamine induces a robust central and peripheral adrenergic/noradrenergic potentiation and that activation of this system is essential for the formation of memory for stressful events, we explored the possibility that the strong sympathomimetic action of ketamine might underlie its memory enhancing effects. We found that rats given immediate, but not delayed, post-training ketamine anesthesia (125 mg/kg) presented enhanced 48-h memory retention in an inhibitory avoidance task and that these effects were blocked by adrenal medullectomy, lesions of the locus coeruleus, systemic or intra-basolateral amygdala ß-adrenergic receptor antagonism. Thus, the memory enhancing effects of ketamine anesthesia are time-dependent and mediated by a combined peripheral-central sympathomimetic action. We elucidated a mechanism by which ketamine exacerbates acute post-traumatic reaction, possibly leading to development of PTSD symptomatology later in life. These findings will help guide for a better management of sedation/anesthesia in emergency care to promote the prophylaxis and reduce the risk of developing trauma-related disorders in trauma victims.

Differentially altered social dominance- and cooperative-like behaviors in Shank2- and Shank3-mutant mice

BackgroundRecent progress in genomics has contributed to the identification of a large number of autism spectrum disorder (ASD) risk genes, many of which encode synaptic proteins. Our understanding of ASDs has advanced rapidly, partly owing to the development of numerous animal models. Extensive characterizations using a variety of behavioral batteries that analyze social behaviors have shown that a subset of engineered mice that model mutations in genes encoding Shanks, a family of excitatory postsynaptic scaffolding proteins, exhibit autism-like behaviors. Although these behavioral assays have been useful in identifying deficits in simple social behaviors, alterations in complex social behaviors remain largely untested.MethodsTwo syndromic ASD mouse models—Shank2 constitutive knockout [KO] mice and Shank3 constitutive KO mice—were examined for alterations in social dominance and social cooperative behaviors using tube tests and automated cooperation tests. Upon naïve and salient behavioral experience, expression levels of c-Fos were analyzed as a proxy for neural activity across diverse brain areas, including the medial prefrontal cortex (mPFC) and a number of subcortical structures.FindingsAs previously reported, Shank2 KO mice showed deficits in sociability, with intact social recognition memory, whereas Shank3 KO mice displayed no overt phenotypes. Strikingly, the two Shank KO mouse models exhibited diametrically opposed alterations in social dominance and cooperative behaviors. After a specific social behavioral experience, Shank mutant mice exhibited distinct changes in number of c-Fos+ neurons in the number of cortical and subcortical brain regions.ConclusionsOur results underscore the heterogeneity of social behavioral alterations in different ASD mouse models and highlight the utility of testing complex social behaviors in validating neurodevelopmental and neuropsychiatric disorder models. In addition, neural activities at distinct brain regions are likely collectively involved in eliciting complex social behaviors, which are differentially altered in ASD mouse models.

Intronic Variant in CNTNAP2 Gene in a Boy With Remarkable Conduct Disorder, Minor Facial Features, Mild Intellectual Disability, and Seizures.

Introduction: Mutations in the contactin-associated protein-like 2 (CNTNAP2) gene (MIM#604569) encoding for CASPR2, a cell adhesion protein of the neurexin family, are known to be associated with autism, intellectual disability, and other neuropsychiatric disorders. A set of intronic deletions of CNTNAP2 gene has also been suggested to have a causative role in individuals with a wide phenotypic spectrum, including Pitt-Hopkins syndrome, cortical dysplasia–focal epilepsy syndrome, Tourette syndrome, language dysfunction, and abnormal behavioral manifestations.Case presentation: A 10-years-old boy was referred to the hospital with mild intellectual disability and language impairment. Moreover, the child exhibited minor facial features, epileptic seizures, and notable behavioral abnormalities including impulsivity, aggressivity, and hyperactivity suggestive of the diagnosis of disruptive, impulse-control and conduct disorder (CD). Array comparative genomic hybridization (CGH) revealed a copy number variant (CNV) deletion in the first intron of CNTNAP2 gene inherited from a healthy father.Conclusions: A comprehensive description of the phenotypic features of the child is provided, revealing a distinct and remarkable alteration of social behavior not previously reported in individuals affected by disorders related to CNTNAP2 gene disruptions. A possible causative link between the deletion of a non-coding regulatory region and the symptoms presented by the boy has been advanced.