Early postnatal behavioral changes in the Mecp2‐308 truncation mouse model of Rett syndrome

In a mouse model of Rett syndrome (RTT) which expresses a truncated form of methyl‐CpG‐binding protein 2 (Mecp2) gene (Mecp2‐308), we performed a neurobehavioral evaluation across the life span, starting from soon after birth till adulthood. A focus was made on those developmental phases and behavioral domains which have not been previously investigated. The results evidenced subtle anomalies on postnatal days (pnds) 3 to 9 (so‐called presymptomatic phase) in spontaneous movements by hemizygous neonatal male mice. Specifically as early as pnd 3, mutant pups exhibited more intense curling and more side responses and on pnd 9 more pivoting and head rising behaviors than wild type (wt) littermates. A significant decrease in ultrasonic vocalization rate, also emerged in Mecp2‐308 pups. The same mice were also characterized by increased anxiety‐like behaviors (open‐field and zero‐maze tests) during the early symptomatic phase, in the absence of changes in cognitive passive‐avoidance task and rotarod performances. Upon the clearly symptomatic stage, 5‐month‐old Mecp2‐308 mice were also associated with reduced spontaneous home‐cage motor activity, motor coordination impairments (rotarod and dowel tests), and a more marked profile of d ‐amphetamine (10 mg/kg) released stereotyped behavioral syndrome than wt mice. Present results provide an interesting timeline of the progression of symptoms in the Mecp2‐308 model and emphasize the need for increased attention to the presymptomatic phase which may be especially informative in mouse models of human neurodevelopmental disorders. This analysis has provided evidence of precocious behavioral markers of RTT and has identified an early developmental window of opportunities on which potential therapies could be investigated.     

Convergent synaptic and circuit substrates underlying autism genetic risks

There has been a surge of diagnosis of autism spectrum disorders （ASD） over the past decade. While large, high powered genome screening studies of children with ASD have identified numerous genetic risk factors, research efforts to understanding how each of these risk factors contributes to the development autism has met with limited success. Revealing the mechanisms by which these genetic risk factors affect brain development and predispose a child to autism requires mechanistic understanding of the neurobiological changes underlying this devastating group of developmental disorders at multifaceted molecular, cellular and system levels. It has been increasingly clear that the normal trajectory of neurodevelopment is compromised in autism, in multiple domains as much as aberrant neuronal production, growth, functional maturation, patterned connectivity, and balanced excitation and inhibition of brain networks. Many autism risk factors identified in humans have been now reconstituted in experimental mouse models to allow mechanistic interrogation of the biological role of the risk gene. Studies utilizing these mouse models have revealed that underlying the enormous heterogeneity of perturbed cellular events, mechanisms directing synaptic and circuit assembly may provide a unifying explanation for the pathophysiological changes and behavioral endophenotypes seen in autism, although synaptic perturbations are far from being the only alterations relevant for ASD. In this review, we discuss synaptic and circuit abnormalities obtained from several prevalent mouse models, particularly those reflecting syndromic forms of ASD that are caused by single gene perturbations. These compiled results reveal that ASD risk genes contribute to proper signaling of the developing gene networks that maintain synaptic and circuit homeostasis, which is fundamental to normal brain development.     

Diminished social interaction incentive contributes to social deficits in mouse models of autism spectrum disorder

One of the core symptoms of autism spectrum disorder (ASD) is impaired social interaction. Currently, no pharmacotherapies exist for this symptom due to complex biological underpinnings and distinct genetic models which fail to represent the broad disease spectrum. One convincing hypothesis explaining social deficits in human ASD patients is amotivation, however it is unknown whether mouse models of ASD represent this condition. Here we used two highly trusted ASD mouse models (male Shank3‐deficient [Shank3^+/ΔC] mice modeling the monogenic etiology of ASD, and inbred BTBR mice [both male and female] modeling the idiopathic and highly polygenic pathology for ASD) to evaluate the level of motivation to engage in a social interaction. In the behavioral paradigms utilized, a social stimulus was placed in the open arm of the elevated plus maze (EPM), or the light compartment of the light‐dark box (LDB). To engage in a social interaction, mice were thus required to endure innately aversive conditions (open areas, height, and/or light). In the modified EPM paradigm, both Shank3^+/ΔC and BTBR mice demonstrated decreased open‐arm engagement with a social stimulus but not a novel object, suggesting reduced incentive to engage in a social interaction in these models. However, these deficits were not expressed under the less severe aversive pressures of the LDB. Collectively, we show that ASD mouse models exhibit diminished social interaction incentive, and provide a new investigation strategy facilitating the study of the neurobiological mechanisms underlying social reward and motivation deficits in neuropsychiatric disorders.     

Reduced scent marking and ultrasonic vocalizations in the BTBR T+tf/J mouse model of autism

Qualitative impairments in communication, such as delayed language and poor interactive communication skills, are fundamental to the diagnosis of autism. Investigations into social communication in adult BTBR T+tf/J (BTBR) mice are needed to determine whether this inbred strain incorporates phenotypes relevant to the second diagnostic symptom of autism, communication deficits, along with its strong behavioral phenotypes relevant to the first and third diagnostic symptoms, impairments in social interactions and high levels of repetitive behavior. The aim of the present study was to simultaneously measure female urine‐elicited scent marking and ultrasonic vocalizations in adult male BTBR mice, in comparison with a standard control strain with high sociability, C57BL/6J (B6), for the assessment of a potential communication deficit in BTBR. Adult male BTBR mice displayed lower scent marking and minimal ultrasonic vocalization responses to female urine obtained from both B6 and BTBR females. Lower scent marking and ultrasonic vocalizations in a social setting by BTBR, as compared with B6, are consistent with the well‐replicated social deficits in this inbred mouse strain. Our findings support the interpretation that BTBR incorporate communication deficits, and suggest that scent marking and ultrasonic vocalizations offer promising measures of interest in social cues that may be widely applicable to investigations of mouse models of autism.     

Behavioral phenotypes of amyloid-based genetically modified mouse models of Alzheimer's disease

Alzheimer's disease (AD) is the most common neurodegenerative affliction of the elderly, presenting with progressive memory loss and dementia and terminating with death. There have been significant advances in understanding the biology and subsequent diagnosis of AD; however, the furious pace of research has not yet translated into a disease-modifying treatment. While scientific inquiry in AD is largely centered on identifying biological players and pathological mechanisms, the day-to-day realities of AD patients and their caregivers revolve around their steady and heartbreaking cognitive decline. In the past decade, AD research has been fundamentally transformed by the development of genetically modified animal models of amyloid-driven neurodegeneration. These important in vivo models not only replicate some of the hallmark pathology of the disease, such as plaque-like amyloid accumulations and astrocytic inflammation, but also some of the cognitive impairments relevant to AD. In this article, we will provide a detailed review of the behavioral and cognitive deficits present in several transgenic mouse models of AD and discuss their functional changes in response to experimental treatments.     

Maternal and offspring methylenetetrahydrofolate‐reductase genotypes interact in a mouse model to induce autism spectrum disorder‐like behavior

Individuals with autism constitute a variable population whose members are spread along the autism spectrum. Subpopulations within that spectrum exhibit other conditions, such as anxiety, intellectual disabilities, hyperactivity and epilepsy, with different severities and co‐occurrences. Among the genes associated with the increased risk for autism is the methylenetetrahydrofolate‐reductase (MTHFR) 677C>T polymorphism, which impairs one‐carbon (C1) metabolic pathway efficiency. The frequency of the MTHFR677TT homozygote is markedly higher among autism patients and their mothers than in the general population. Here, we report on the Mthfr heterozygous knockout (KO) mouse as a rodent model of autism that shows the contributions of maternal and offspring genotypes to the development of autistic‐like behaviors. Maternal Mthfr‐deficiency was associated with developmental delays in morphogenic features and sensory‐motor reflexes in offspring. In the adult male mouse, behaviors representing core autism symptoms, such as repetitive behavior and restricted interest, were affected by maternal genotype while social behaviors were affected by both maternal and offspring genotypes. In females and males, behaviors associated with autism such as memory impairment, social aggression and anxiety were affected by both the maternal and offspring Mthfr genotypes, with sex‐dependent differences. Mthfr‐deficient male mice with observable impacts on behavior presented a particular laminar disturbance in parvalbumin interneuron density and innervation in superficial and deep layers of the cingulate cortex. This mouse model of autism will help to elucidate the molecular mechanisms that predispose a significant subgroup of autistic patients to abnormal development and to distinguish between the in‐utero and autonomous factors involved in autism.     

Altered nociceptive behavior and emotional contagion of pain in mouse models of autism

Individuals with autism spectrum disorder (ASD) have altered sensory processing but may ineffectively communicate their experiences. Here, we used a battery of nociceptive behavioral tests to assess sensory alterations in two commonly used mouse models of ASD, BTBR T⁺Itpr3^tf/J (BTBR), and fragile-X mental retardation-1 knockout (Fmr1-KO) mice. We also asked whether emotional contagion, a primitive form of empathy, was altered in BTBR and Fmr1 KO mice when experiencing pain with a social partner. BTBR mice demonstrated mixed nociceptive responses with hyporesponsivity to mechanical/thermal stimuli and intraplantar injections of formalin and capsaicin while displaying hypersensitivity on the acetic acid test. Fmr1-KO mice were hyposensitive to mechanical stimuli and intraplantar injections of capsaicin and formalin. BTBR and Fmr1-KO mice developed significantly less mechanical allodynia following intraplantar injections of complete Freund's adjuvant, while BTBR mice developed slightly more thermal hyperalgesia. Finally, as measured by the formalin and acetic acid writhing tests, BTBR and Fmr1-KO mice did not show emotional contagion of pain. In sum, our findings indicate that depending on the sensation, pain responses may be mixed, which reflects findings in ASD individuals.     

Activation of the medial preoptic area (MPOA) ameliorates loss of maternal behavior in a Shank2 mouse model for autism

Impairments in social relationships and awareness are features observed in autism spectrum disorders (ASDs). However, the underlying mechanisms remain poorly understood. Shank2 is a high‐confidence ASD candidate gene and localizes primarily to postsynaptic densities (PSDs) of excitatory synapses in the central nervous system (CNS). We show here that loss of Shank2 in mice leads to a lack of social attachment and bonding behavior towards pubs independent of hormonal, cognitive, or sensitive deficits. Shank2 ^−/− mice display functional changes in nuclei of the social attachment circuit that were most prominent in the medial preoptic area (MPOA) of the hypothalamus. Selective enhancement of MPOA activity by DREADD technology re‐established social bonding behavior in Shank2 ^−/− mice, providing evidence that the identified circuit might be crucial for explaining how social deficits in ASD can arise.     

Motor and cognitive stereotypies in the BTBR T+tf/J mouse model of autism

The BTBR T+tf/J inbred mouse strain displays a variety of persistent phenotypic alterations similar to those exhibited in autism spectrum disorders (ASDs). The unique genetic background of the BTBR strain is thought to underlie its lack of reciprocal social interactions, elevated repetitive self-directed grooming, and restricted exploratory behaviors. In order to clarify the existence, range, and mechanisms of abnormal repetitive behaviors within BTBR mice, we performed detailed analyses of the microstructure of self-grooming patterns and noted increased overall grooming, higher percentages of interruptions in grooming bouts and a concomitant decrease in the proportion of incorrect sequence transitions compared to C57BL/6J inbred mice. Analyses of active phase home-cage behavior also revealed an increase in stereotypic bar-biting behavior in the BTBR strain relative to B6 mice. Finally, in a novel object investigation task, the BTBR mice exhibited greater baseline preference for specific unfamiliar objects as well as more patterned sequences of sequential investigations of those items. These results suggest that the repetitive, stereotyped behavior patterns of BTBR mice are relatively pervasive and reflect both motor and cognitive mechanisms. Furthermore, other pre-clinical mouse models of ASDs may benefit from these more detailed analyses of stereotypic behavior.     

Magel2 knockout mice manifest altered social phenotypes and a deficit in preference for social novelty

MAGEL2 is one of five protein‐coding, maternally imprinted, paternally expressed genes in the Prader–Willi syndrome (PWS)‐critical domain on chromosome 15q11‐q13. Truncating pathogenic variants of MAGEL2 cause Schaaf‐Yang syndrome (SHFYNG) (OMIM #615547), a neurodevelopmental disorder related to PWS. Affected individuals manifest a spectrum of neurocognitive and behavioral phenotypes, including intellectual disability and autism spectrum disorder (ASD). Magel2 knockout mice carrying a maternally inherited, imprinted wild‐type (WT) allele and a paternally inherited Magel2‐lacZ knock‐in allele, which abolishes endogenous Magel2 gene function, exhibit several features reminiscent of the human Prader–Willi phenotypes, including neonatal growth retardation, excessive weight gain after weaning and increased adiposity in adulthood. They were shown to have altered circadian rhythm, reduced motor activity and reduced fertility. An extensive assessment for autism‐like behaviors in this mouse model was warranted, because of the high prevalence of ASD in human patients. The behavior of Magel2 knockout mice and their WT littermates were assayed via open field, elevated plus maze, tube, three‐chamber and partition tests. Our studies confirm decreased horizontal activity of male and female mice and increased vertical activity of females, in the open field. Both sexes spent more time in the open arm of the elevated plus maze, suggestive of reductions in anxiety. Both sexes displayed a lack of preference for social novelty, via a lack of discrimination between known and novel partners in the partition test. The in‐depth investigation of behavioral profiles caused by Magel2 loss‐of‐function helps to elucidate the etiology of behavioral phenotypes both for SHFYNG and PWS in general.     

Inchworming: A Novel Motor Stereotypy in the BTBR T+ Itpr3tf/J Mouse Model of Autism

Autism Spectrum Disorder (ASD) is a behaviorally defined neurodevelopmental disorder characterized by decreased reciprocal social interaction, abnormal communication, and repetitive behaviors with restricted interest. As diagnosis is based on clinical criteria, any potentially relevant rodent models of this heterogeneous disorder should ideally recapitulate these diverse behavioral traits. The BTBR T⁺ Itpr3^tf/J (BTBR) mouse is an established animal model of ASD, displaying repetitive behaviors such as increased grooming, as well as cognitive inflexibility. With respect to social interaction and interest, the juvenile play test has been employed in multiple rodent models of ASD. Here, we show that when BTBR mice are tested in a juvenile social interaction enclosure containing sawdust bedding, they display a repetitive synchronous digging motion. This repetitive motor behavior, referred to as "inchworming," was named because of the stereotypic nature of the movements exhibited by the mice while moving horizontally across the floor. Inchworming mice must use their fore- and hind-limbs in synchrony to displace the bedding, performing a minimum of one inward and one outward motion. Although both BTBR and C56BL/6J (B6) mice exhibit this behavior, BTBR mice demonstrate a significantly higher duration and frequency of inchworming and a decreased latency to initiate inchworming when placed in a bedded enclosure. We conclude that this newly described behavior provides a measure of a repetitive motor stereotypy that can be easily measured in animal models of ASD.     

Assessing the developmental trajectory of mouse models of neurodevelopmental disorders: Social and communication deficits in mice with Neurexin 1α deletion

Neurexin 1α mutations are strongly associated with neurodevelopmental disorders such as autism spectrum disorders and schizophrenia in humans. Studies using the Neurexin 1α knock‐out mouse have showed behavioral abnormalities of relevance to these disorders and baseline deficits in excitatory synaptic function have been described. However, little is known about the effect of Neurexin 1α deletion on behavior during development. This study examined the effects of Neurexin 1α deletion on behavior across a range of developmental time points to determine whether potential abnormalities follow a developmental trajectory. Pups lacking Neurexin 1α emitted a reduced number of ultrasonic vocalizations early in development combined with a restricted repertoire of calls indicative of a loss in complexity in vocal production and showed delays in reaching certain developmental milestones. Behavioral testing showed that juvenile and adult male Neurexin 1α knock‐out mice exhibited social deficits and increased levels of aggression, confirming previous findings. No increases in repetitive behaviors or deficits in motor learning or olfaction were seen. In conclusion, this research showed that Neurexin 1α deletion does result in social and communication deficits that follow a developmental trajectory. These are the first experimental data that associate a deletion of Neurexin 1α with alterations in behaviors relevant to autism spectrum disorder across development and highlight the importance of assessing the developmental trajectory in mouse models of neurodevelopmental disorders.     

Sex‐dependent effects of Cacna1c haploinsufficiency on juvenile social play behavior and pro‐social 50‐kHz ultrasonic communication in rats

As cross‐disorder risk gene, CACNA1C is implicated in the etiology of all major neuropsychiatric disorders characterized by deficits in social behavior and communication and there is evidence for sex‐dependent influences of single‐nucleotide polymorphisms within CACNA1C on diagnosis, course, and recovery in humans. In this study, we aimed, therefore, at further exploring the role of Cacna1c in regulating behavioral phenotypes, focusing on sex‐specific differences in social behavior and communication during the critical developmental period of adolescence in rats. Specifically, we compared rough‐and‐tumble play, concomitant emission of pro‐social 50‐kHz ultrasonic vocalizations, and social approach behavior in response to playback of 50‐kHz ultrasonic vocalizations between constitutive heterozygous Cacna1c ^+/? females and wildtype Cacna1c ^+/+ littermate controls, and contrasted present female findings to data previously reported in males. Our results show for the first time that partial depletion of Cacna1c leads to sex‐dependent alterations in social behavior and communication in rats. In females, Cacna1c haploinsufficiency led to hypermasculinization, with rough‐and‐tumble play behavior, in general, and pinning behavior, in particular, being even higher than in males without affecting concomitant 50‐kHz ultrasonic vocalizations. In males, in contrast, rough‐and‐tumble play behavior was not altered, yet emission of 50‐kHz ultrasonic vocalizations was diminished following partial Cacna1c depletion. The behavioral responses elicited by playback of 50‐kHz ultrasonic vocalizations were reduced upon partial Cacna1c depletion in both sexes. It thus can be concluded that Cacna1c plays a prominent sex‐dependent role in regulating juvenile rat social play behavior and pro‐social 50‐kHz ultrasonic communication with relevance to sex‐specific effects seen in neuropsychiatric disorders.     

Comprehensive analysis of two Shank3 and the Cacna1c mouse models of autism spectrum disorder

To expand, analyze and extend published behavioral phenotypes relevant to autism spectrum disorder (ASD), we present a study of three ASD genetic mouse models: Feng's Shank3^tm2Gfng model, hereafter Shank3/F, Jiang's Shank3^tm1Yhj model, hereafter Shank3/J and the Cacna1c deletion model. The Shank3 models mimick gene mutations associated with Phelan–McDermid Syndrome and the Cacna1c model recapitulates the deletion underlying Timothy syndrome. This study utilizes both standard and novel behavioral tests with the same methodology used in our previously published companion report on the Cntnap2 null and 16p11.2 deletion models. We found that some but not all behaviors replicated published findings and those that did replicate, such as social behavior and overgrooming in Shank3 models, tended to be milder than reported elsewhere. The Shank3/F model, and to a much lesser extent, the Shank3/J and Cacna1c models, showed hypoactivity and a general anxiety‐like behavior triggered by external stimuli which pervaded social interactions. We did not detect deficits in a cognitive procedural learning test nor did we observe perseverative behavior in these models. We did, however, find differences in exploratory patterns of Cacna1c mutant mice suggestive of a behavioral effect in a social setting. In addition, only Shank3/F showed differences in sensory‐gating. Both positive and negative results from this study will be useful in identifying the most robust and replicable behavioral signatures within and across mouse models of autism. Understanding these phenotypes may shed light of which features to study when screening compounds for potential therapeutic interventions.     

Behavioral flexibility in a mouse model for obsessive‐compulsive disorder: Impaired Pavlovian reversal learning in SAPAP3 mutants

Obsessive‐compulsive disorder (OCD) is characterized by obsessive thinking, compulsive behavior and anxiety, and is often accompanied by cognitive deficits. The neuropathology of OCD involves dysregulation of cortical‐striatal circuits. Similar to OCD patients, SAPAP3 knockout mice 3 (SAPAP3^?/?) exhibit compulsive behavior (grooming), anxiety and dysregulated cortical‐striatal function. However, it is unknown whether SAPAP3^?/? display cognitive deficits and how these different behavioral traits relate to one another. SAPAP3^?/? and wild‐type (WT) littermates were trained in a Pavlovian conditioning task pairing visual cues with the delivery of sucrose solution. After mice learned to discriminate between a reward‐predicting conditioned stimulus (CS+) and a non‐reward stimulus (CS?), contingencies were reversed (CS+ became CS? and vice versa). Additionally, we assessed grooming, anxiety and general activity. SAPAP3^?/? acquired Pavlovian approach behavior similarly to WT, albeit less vigorously and with a different strategy. However, unlike WT, SAPAP3^?/? were unable to adapt their behavior after contingency reversal, exemplified by a lack of re‐establishing CS+ approach behavior (sign tracking). Surprisingly, such behavioral inflexibility, decreased vigor, compulsive grooming and anxiety were unrelated. This study shows that SAPAP3^?/? are capable of Pavlovian learning, but lack flexibility to adapt associated conditioned approach behavior. Thus, SAPAP3^?/? not only display compulsive‐like behavior and anxiety, but also cognitive deficits, confirming and extending the validity of SAPAP3^?/? as a suitable model for the study of OCD. The observation that compulsive‐like behavior, anxiety and behavioral inflexibility were unrelated suggests a non‐causal relationship between these traits and may be of clinical relevance for the treatment of OCD.     

Autism‐related behaviors in the cyclooxygenase‐2‐deficient mouse model

Prostaglandin E2 (PGE2) is an endogenous lipid molecule involved in normal brain development. Cyclooxygenase‐2 (COX2) is the main regulator of PGE2 synthesis. Emerging clinical and molecular research provides compelling evidence that abnormal COX2/PGE2 signaling is associated with autism spectrum disorder (ASD). We previously found that COX2 knockout mice had dysregulated expression of many ASD genes belonging to important biological pathways for neurodevelopment. The present study is the first to show the connection between irregular COX2/PGE2 signaling and autism‐related behaviors in male and female COX2‐deficient knockin, (COX)‐2^?, mice at young (4‐6 weeks) or adult (8‐11 weeks) ages. Autism‐related behaviors were prominent in male (COX)‐2^? mice for most behavioral tests. In the open field test, (COX)‐2^? mice traveled more than controls and adult male (COX)‐2^? mice spent less time in the center indicating elevated hyperactive and anxiety‐linked behaviors. (COX)‐2^? mice also buried more marbles, with males burying more than females, suggesting increased anxiety and repetitive behaviors. Young male (COX)‐2^? mice fell more frequently in the inverted screen test revealing motor deficits. The three‐chamber sociability test found that adult female (COX)‐2^? mice spent less time in the novel mouse chamber indicative of social abnormalities. In addition, male (COX)‐2^? mice showed altered expression of several autism‐linked genes: Wnt2, Glo1, Grm5 and Mmp9. Overall, our findings offer new insight into the involvement of disrupted COX2/PGE2 signaling in ASD pathology with age‐related differences and greater impact on males. We propose that (COX)‐2^? mice might serve as a novel model system to study specific types of autism.     

Hyperactive and anxiolytic‐like behaviors result from loss of COUP‐TFI/Nr2f1 in the mouse cortex

The nuclear receptor COUP TFI (also known as Nr2f1) plays major roles in specifying distinct neuronal subtypes during patterning of the neocortical motor and somatosensory cortex, as well as in regulating the longitudinal growth of the hippocampus during development. In humans, mutations in the NR2F1 gene lead to a global developmental delay and intellectual disabilities. While more than 30% of patients show behavioral features of autism spectrum disorder, 16% of haploinsufficient children show signs of hyperactivity and impulsivity. Loss of COUP‐TFI in the cortical mouse primordium results in altered area organization and serotonin distribution, abnormal coordination of voluntary movements and learning and memory deficits. Here, we asked whether absence of COUP‐TFI affects locomotor activity, anxiety, as well as depression. Mice mutant for COUP‐TFI have normal motor coordination, but significant traits of hyperactivity, which does not seem to respond to N‐Methyl‐D‐aspartate (NMDA) antagonists. However, no changes in anxiety, despite increased locomotor performances, were observed in the open field task. On the contrary, elevated plus maze and dark‐light test explorations indicate a decreased anxiety‐like behavior in COUP‐TFI mutant mice. Finally, significantly reduced immobility in the forced swim test and no changes in anhedonia in the sucrose preference task suggest no particular depressive behaviors in mutant mice. Taken together, our study shows that loss of COUP‐TFI leads to increased locomotor activity but less anxiety and contributes in further deciphering the pathophysiology of patients haploinsufficient for NR2F1.     

Absence of deficits in social behaviors and ultrasonic vocalizations in later generations of mice lacking neuroligin4

Mutations in NLGN4X have been identified in individuals with autism spectrum disorders and other neurodevelopmental disorders. A previous study reported that adult male mice lacking neuroligin4 (Nlgn4) displayed social approach deficits in the three‐chambered test, altered aggressive behaviors and reduced ultrasonic vocalizations. To replicate and extend these findings, independent comprehensive analyses of autism‐relevant behavioral phenotypes were conducted in later generations of the same line of Nlgn4 mutant mice at the National Institute of Mental Health in Bethesda, MD, USA and at the Institut Pasteur in Paris, France. Adult social approach was normal in all three genotypes of Nlgn4 mice tested at both sites. Reciprocal social interactions in juveniles were similarly normal across genotypes. No genotype differences were detected in ultrasonic vocalizations in pups separated from the nest or in adults during reciprocal social interactions. Anxiety‐like behaviors, self‐grooming, rotarod and open field exploration did not differ across genotypes, and measures of developmental milestones and general health were normal. Our findings indicate an absence of autism‐relevant behavioral phenotypes in subsequent generations of Nlgn4 mice tested at two locations. Testing environment and methods differed from the original study in some aspects, although the presence of normal sociability was seen in all genotypes when methods taken from Jamain et al. (2008) were used. The divergent results obtained from this study indicate that phenotypes may not be replicable across breeding generations, and highlight the significant roles of environmental, generational and/or procedural factors on behavioral phenotypes.     

Brain and behaviour phenotyping of a mouse model of neurofibromatosis type‐1: an MRI/DTI study on social cognition

Neurofibromatosis type‐1 (NF1) is a common neurogenetic disorder and an important cause of intellectual disability. Brain‐behaviour associations can be examined in vivo using morphometric magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) to study brain structure. Here, we studied structural and behavioural phenotypes in heterozygous Nf1 mice (Nf1^+/?) using T2‐weighted imaging MRI and DTI, with a focus on social recognition deficits. We found that Nf1^+/? mice have larger volumes than wild‐type (WT) mice in regions of interest involved in social cognition, the prefrontal cortex (PFC) and the caudate‐putamen (CPu). Higher diffusivity was found across a distributed network of cortical and subcortical brain regions, within and beyond these regions. Significant differences were observed for the social recognition test. Most importantly, significant structure–function correlations were identified concerning social recognition performance and PFC volumes in Nf1^+/? mice. Analyses of spatial learning corroborated the previously known deficits in the mutant mice, as corroborated by platform crossings, training quadrant time and average proximity measures. Moreover, linear discriminant analysis of spatial performance identified 2 separate sub‐groups in Nf1^+/? mice. A significant correlation between quadrant time and CPu volumes was found specifically for the sub‐group of Nf1^+/? mice with lower spatial learning performance, suggesting additional evidence for reorganization of this region. We found strong evidence that social and spatial cognition deficits can be associated with PFC/CPu structural changes and reorganization in NF1.     

Resistance to change and vulnerability to stress: autistic‐like features of GAP43‐deficient mice

There is an urgent need for animal models of autism spectrum disorder (ASD) to understand the underlying pathology and facilitate development and testing of new treatments. The synaptic growth‐associated protein‐43 (GAP43) has recently been identified as an autism candidate gene of interest. Our previous studies show many brain abnormalities in mice lacking one allele for GAP43 [GAP43 (+/?)] that are consistent with the disordered connectivity theory of ASD. Thus, we hypothesized that GAP43 (+/?) mice would show at least some autistic‐like behaviors. We found that GAP43 (+/?) mice, relative to wild‐type (+/+) littermates, displayed resistance to change, consistent with one of the diagnostic criteria for ASD. GAP43 (+/?) mice also displayed stress‐induced behavioral withdrawal and anxiety, as seen in many autistic individuals. In addition, both GAP43 (+/?) mice and (+/+) littermates showed low social approach and lack of preference for social novelty, consistent with another diagnostic criterion for ASD. This low sociability is likely because of the mixed C57BL/6J 129S3/SvImJ background. We conclude that GAP43 deficiency leads to the development of a subset of autistic‐like behaviors. As these behaviors occur in a mouse that displays disordered connectivity, we propose that future anatomical and functional studies in this mouse may help uncover underlying mechanisms for these specific behaviors. Strain‐specific low sociability may be advantageous in these studies, creating a more autistic‐like environment for study of the GAP43‐mediated deficits of resistance to change and vulnerability to stress.