Understanding intellectual disability and autism spectrum disorders from common mouse models: synapses to behaviour (original) (raw)
Related papers
Neuroscience & Biobehavioral Reviews, 2018
Recent human genetics studies have identified many genetic variants that may be responsible for autism spectrum disorder (ASD). ASD mouse models with genetic modifications mimicking these rare genetic variants have provided invaluable mechanistic insights into the disruption of various biological processes and brain areas/ circuitry affected in ASD patients. In this review, we begin by reviewing several mouse models for ASD-associated copy number variations (CNVs) to illustrate how they have been employed to establish causal links between their behavioral phenotypes and the affected genes. We then focus on studies using one of the principal behavioral abnormalities associated with ASD, social behavior, to identify the molecular and circuit-level deficits involved. Finally, we end by discussing other mouse models designed to probe how the disruption of specific biological processes such as autophagy and neurogenesis may contribute to ASD pathogenesis. By achieving a greater understanding of the pathophysiology and pathogenic mechanisms involved in ASD and related disorders, novel therapeutic strategies may be devised for ASD patients in the near future.
PLOS ONE, 2015
Autism spectrum disorder comprises several neurodevelopmental conditions presenting symptoms in social communication and restricted, repetitive behaviors. A major roadblock for drug development for autism is the lack of robust behavioral signatures predictive of clinical efficacy. To address this issue, we further characterized, in a uniform and rigorous way, mouse models of autism that are of interest because of their construct validity and wide availability to the scientific community. We implemented a broad behavioral battery that included but was not restricted to core autism domains, with the goal of identifying robust, reliable phenotypes amenable for further testing. Here we describe comprehensive findings from two known mouse models of autism, obtained at different developmental stages, using a systematic behavioral test battery combining standard tests as well as novel, quantitative, computer-vision based systems. The first mouse model recapitulates a deletion in human chromosome 16p11.2, found in 1% of individuals with autism. The second mouse model harbors homozygous null mutations in Cntnap2, associated with autism and Pitt-Hopkins-like syndrome. Consistent with previous results, 16p11.2 heterozygous null mice, also known as Del(7Slx1b-Sept1)4Aam weighed less than wild type littermates displayed hyperactivity and no social deficits. Cntnap2 homozygous null mice were also hyperactive, froze less during testing, showed a mild gait phenotype and deficits in the three-chamber social preference test, although less robust than previously published. In the open field test with exposure to urine of an estrous female, however, the Cntnap2 null mice showed reduced vocalizations. In addition, Cntnap2 null mice performed slightly better in a cognitive procedural learning test. Although finding and replicating robust behavioral phenotypes in animal models is a challenging task, such functional readouts remain important in the development of therapeutics and we anticipate both our positive and negative findings will be utilized as a resource for the broader scientific community.
Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2
Nature, 2012
Autism spectrum disorders comprise a range of neurodevelopmental disorders characterized by deficits in social interaction and communication, and by repetitive behaviour 1 . Mutations in synaptic proteins such as neuroligins 2,3 , neurexins 4 , GKAPs/SAPAPs 5 and ProSAPs/ Shanks 6-10 were identified in patients with autism spectrum disorder, but the causative mechanisms remain largely unknown. ProSAPs/ Shanks build large homo-and heteromeric protein complexes at excitatory synapses and organize the complex protein machinery of the postsynaptic density in a laminar fashion 11,12 . Here we demonstrate that genetic deletion of ProSAP1/Shank2 results in an early, brain-region-specific upregulation of ionotropic glutamate receptors at the synapse and increased levels of ProSAP2/Shank3. Moreover, ProSAP1/Shank2 2/2 mutants exhibit fewer dendritic spines and show reduced basal synaptic transmission, a reduced frequency of miniature excitatory postsynaptic currents and enhanced N-methyl-D-aspartate receptor-mediated excitatory currents at the physiological level. Mutants are extremely hyperactive and display profound autistic-like behavioural alterations including repetitive grooming as well as abnormalities in vocal and social behaviours. By comparing the data on ProSAP1/Shank2 2/2 mutants with ProSAP2/ Shank3ab 2/2 mice, we show that different abnormalities in synaptic glutamate receptor expression can cause alterations in social interactions and communication. Accordingly, we propose that appropriate therapies for autism spectrum disorders are to be carefully matched to the underlying synaptopathic phenotype.
Molecular autism, 2017
Autism spectrum disorder (ASD) is a clinically and biologically heterogeneous condition characterized by social, repetitive, and sensory behavioral abnormalities. No treatments are approved for the core diagnostic symptoms of ASD. To enable the earliest stages of therapeutic discovery and development for ASD, robust and reproducible behavioral phenotypes and biological markers are essential to establish in preclinical animal models. The goal of this study was to identify electroencephalographic (EEG) and behavioral phenotypes that are replicable between independent cohorts in a mouse model of ASD. The larger goal of our strategy is to empower the preclinical biomedical ASD research field by generating robust and reproducible behavioral and physiological phenotypes in animal models of ASD, for the characterization of mechanistic underpinnings of ASD-relevant phenotypes, and to ensure reliability for the discovery of novel therapeutics. Genetic disruption of the SHANK3 gene, a scaffol...
F1000 - Post-publication peer review of the biomedical literature, 2007
Autism spectrum disorders (ASDs) are characterized by impairments in social behaviors that are sometimes coupled to specialized cognitive abilities. A small percentage of ASD patients carry mutations in genes encoding neuroligins, which are postsynaptic cell adhesion molecules. Here we introduce one of these mutations into mice-the R451C-substitution in neuroligin-3. R451Cmutant mice showed impaired social interactions but enhanced spatial learning abilities. Unexpectedly, these behavioral changes were accompanied by an increase in inhibitory synaptic transmission, with no apparent effect on excitatory synapses. Deletion of neuroligin-3, in contrast, did not cause such changes, indicating that the R451C-substitution represents a gain-of-function mutation. These data suggest that increased inhibitory synaptic transmission may contribute to human ASDs and that the R451C KI mice may be a useful model for studying autism-related behaviors. Autism is a widespread cognitive disorder characterized by impairments in social interactions, including verbal communication and social play, and can be accompanied by stereotyped patterns of behavior (1-3). Autism is a heterogeneous condition, prompting the designation of "autism spectrum disorders" (ASDs). Individuals with ASDs occasionally show enhanced cognitive abilities (the 'autistic savant syndrome' [4]). At the other end of the spectrum, ASDs are often associated with mental retardation, and the symptoms of ASDs are part of several neurological diseases, such as fragile X-and Rett-syndrome (5-7). Genetics strongly contributes to ASDs (1,2), and a small number of cases with idiopathic ASD are associated with mutations in a single gene, including genes encoding neuroligins and their associated proteins (8).
Fmr1 and Nlgn3 knockout rats: Novel tools for investigating autism spectrum disorders
Behavioral Neuroscience, 2014
Animal models are critical for gaining insights into autism spectrum disorder (ASD). Despite their apparent advantages to mice for neural studies, rats have not been widely used for disorders of the human CNS, such as ASD, for the lack of convenient genome manipulation tools. Here we describe two of the first transgenic rat models for ASD, developed using zinc-finger nuclease (ZFN) methodologies, and their initial behavioral assessment using a rapid juvenile test battery. A syndromic and nonsyndromic rat model for ASD were created as two separate knockout rat lines with heritable disruptions in the genes encoding Fragile X mental retardation protein (FMRP) and Neuroligin3 (NLGN3). FMRP, a protein with numerous proposed functions including regulation of mRNA and synaptic protein synthesis, and NLGN3, a member of the neuroligin synaptic cell-adhesion protein family, have been implicated in human ASD. Juvenile subjects from both knockout rat lines exhibited abnormalities in ASD-relevant phenotypes including juvenile play, perseverative behaviors, and sensorimotor gating. These data provide important first evidence regarding the utility of rats as genetic models for investigating ASD-relevant genes.
Mouse Model Systems of Autism Spectrum Disorder: Replicability and Informatics Signature
2019
Background: Phenotyping mouse model systems of human disease has proven to be a difficult task, with frequent poor inter- and intra-laboratory replicability and translatability, particularly in behavioral domains such as social and verbal function. However, establishing robust animal model systems with strong construct validity is of fundamental importance as they are central tools for understanding disease pathophysiology and developing therapeutics. To complete our studies of mouse model systems relevant to autism spectrum disorder (ASD), we present a replication of the main findings from our two published studies comprising five genetic mouse model systems of ASD. Methods: To assess the robustness of our previous results, we chose the two model systems that showed the greatest phenotypic differences, the Shank3/F and Cntnap2, and repeated assessments of general health, activity, and social behavior. We additionally explored all five model systems in the same framework, comparing ...
2018
An intriguing question in medical biology is how mutations in functionally distinct genes can lead to similar clinical phenotypes. For example, patients with mutations in distinct epigenetic regulators EHMT1, MBD5, MLL3 or SMARCB1 share the core clinical features of intellectual disability (ID), autism spectrum disorder (ASD) and facial dysmorphisms. To elucidate how these phenotypic similarities are reflected by convergence at the molecular, cellular and neuronal network level, we directly compared the effects of their loss of function in neurons. Interestingly, knockdown of each gene resulted in hyperactive neuronal networks with altered patterns of synchronized activity. At the single-cell level, we found genotype-specific changes in intrinsic excitability and excitatory-inhibitory balance, but in all cases leading to increased excitability. Congruent with our physiological findings, we identified dysregulated genes that converge on biological and cellular pathways related to neu...