Behavioral and Neuroanatomical Phenotypes in Mouse Models of Autism

In order to understand the consequences of the mutation on behavioral and biological phenotypes relevant to autism, mutations in many of the risk genes for autism spectrum disorder have been experimentally generated in mice. Here, we summarize behavioral outcomes and neuroanatomical abnormalities, with a focus on high-resolution magnetic resonance imaging of postmortem mouse brains. Results are described from multiple mouse models of autism spectrum disorder and comorbid syndromes, including the 15q11-13, 16p11.2, 22q11.2, Cntnap2, Engrailed2, Fragile X, Integrinβ3, MET, Neurexin1a, Neuroligin3, Reelin, Rett, Shank3, Slc6a4, tuberous sclerosis, and Williams syndrome models, and inbred strains with strong autism-relevant behavioral phenotypes, including BTBR and BALB. Concomitant behavioral and neuroanatomical abnormalities can strengthen the interpretation of results from a mouse model, and may elevate the usefulness of the model system for therapeutic discovery.

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The online version of this article (doi:10.1007/s13311-015-0360-z) contains supplementary material, which is available to authorized users.     

The HOPA Gene Dodecamer Duplication Is Not a Significant Etiological Factor in Autism

A recent study has suggested that a dodecamer duplication in the HOPA gene in Xq13 may occur in a significant portion of male patients with autism. We have determined the incidence of this duplication in 202 patients from the South Carolina Autism Study. The incidence of the duplication was not significantly different between patients and controls. Three of the female patients inherited the duplication from nonautistic fathers. In addition, there was no systematic skewing of X inactivation in the female patients with the duplication, or in nonautistic mothers and sisters with the duplication. These findings suggest that the dodecamer duplication in the HOPA gene does not play a significant role in the etiology of autism.     

Reorganization of Circuits Underlying Cerebellar Modulation of Prefrontal Cortical Dopamine in Mouse Models of Autism Spectrum Disorder

Imaging, clinical, and pre-clinical studies have provided ample evidence for a cerebellar involvement in cognitive brain function including cognitive brain disorders, such as autism and schizophrenia. We previously reported that cerebellar activity modulates dopamine release in the mouse medial prefrontal cortex (mPFC) via two distinct pathways: (1) cerebellum to mPFC via dopaminergic projections from the ventral tegmental area (VTA) and (2) cerebellum to mPFC via glutamatergic projections from the mediodorsal and ventrolateral thalamus (ThN md and vl). The present study compared functional adaptations of cerebello-cortical circuitry following developmental cerebellar pathology in a mouse model of developmental loss of Purkinje cells (Lurcher) and a mouse model of fragile X syndrome (Fmr1 KO mice). Fixed potential amperometry was used to measure mPFC dopamine release in response to cerebellar electrical stimulation. Mutant mice of both strains showed an attenuation in cerebellar-evoked mPFC dopamine release compared to respective wildtype mice. This was accompanied by a functional reorganization of the VTA and thalamic pathways mediating cerebellar modulation of mPFC dopamine release. Inactivation of the VTA pathway by intra-VTA lidocaine or kynurenate infusions decreased dopamine release by 50 % in wildtype and 20–30 % in mutant mice of both strains. Intra-ThN vl infusions of either drug decreased dopamine release by 15 % in wildtype and 40 % in mutant mice of both strains, while dopamine release remained relatively unchanged following intra-ThN md drug infusions. These results indicate a shift in strength towards the thalamic vl projection, away from the VTA. Thus, cerebellar neuropathologies associated with autism spectrum disorders may cause a reduction in cerebellar modulation of mPFC dopamine release that is related to a reorganization of the mediating neuronal pathways.     

Longitudinal Analyses of Expressive Language Development Reveal Two Distinct Language Profiles Among Young Children with Autism Spectrum Disorders

Although children with Autism spectrum disorders (ASD) show significant variation in language skills, research on what type(s) of language profiles they demonstrate has been limited. Using growth-curve analyses, we investigated how different groups of young children with ASD show increases in the size of their lexicon, morpho-syntactic production as measured by Brown’s 14 grammatical morphemes, and wh-question complexity, compared to TD children, across six time points. Children with ASD who had higher verbal skills were comparable to TD children on most language measures, whereas the children with ASD who had low verbal skills had flatter trajectories in most language measures. Thus, two distinct language profiles emerged for children with ASD.     

Proteomic Approach for the Elucidation of Biological Defects in Autism

Proteomic-based approaches, which examine expressed proteins in tissues or cells, have great potential in the elucidation of biological defects in heterogeneous neurodevelopmental disorders such as autism. In this approach, tissue or cellular proteins from control and affected subjects are separated on two-dimensional (2-D) polyacrylamide gel electrophoresis, and those proteins that show marked changes in the concentration between control and affected subjects are identified by mass spectroscopy. This method has been successfully applied in the elucidation of the molecular biological defect in classic late-infantile neuronal ceroid lipofuscinosis (Sleat et al., 1997). Unlike the classical methods of genome-wide screening for chromosomal localization followed by positional cloning, the proteomic approach requires limited number of tissue samples and the study can be completed in a relatively short time. Currently, these methods are available for relatively abundant proteins and generally are not applicable for hydrophobic proteins because 2-D gel electrophoresis is not very effective in the analysis of hydrophobic proteins. The genetic defect results in either total loss of proteins or changes in molecular weight and/or isoelectric point will be detectable by the proteomic method. Because autism is a neurogenetic disorder, brain is the tissue of choice for proteomic study. For an oligogenic disorder such as autism, at least some of the aberrant (genes) proteins may be identified by this technology.     

An Automated Pipeline for Dendrite Spine Detection and Tracking of 3D Optical Microscopy Neuron Images of In Vivo Mouse Models

The variations in dendritic branch morphology and spine density provide insightful information about the brain function and possible treatment to neurodegenerative disease, for example investigating structural plasticity during the course of Alzheimer’s disease. Most automated image processing methods aiming at analyzing these problems are developed for in vitro data. However, in vivo neuron images provide real time information and direct observation of the dynamics of a disease process in a live animal model. This paper presents an automated approach for detecting spines and tracking spine evolution over time with in vivo image data in an animal model of Alzheimer’s disease. We propose an automated pipeline starting with curvilinear structure detection to determine the medial axis of the dendritic backbone and spines connected to the backbone. We, then, propose the adaptive local binary fitting (aLBF) energy level set model to accurately locate the boundary of dendritic structures using the central line of curvilinear structure as initialization. To track the growth or loss of spines, we present a maximum likelihood based technique to find the graph homomorphism between two image graph structures at different time points. We employ dynamic programming to search for the optimum solution. The pipeline enables us to extract dynamically changing information from real time in vivo data. We validate our proposed approach by comparing with manual results generated by neurologists. In addition, we discuss the performance of 3D based segmentation and conclude that our method is more accurate in identifying weak spines. Experiments show that our approach can quickly and accurately detect and quantify spines of in vivo neuron images and is able to identify spine elimination and formation.     

Cuprizone Treatment Induces Distinct Demyelination, Astrocytosis, and Microglia Cell Invasion or Proliferation in the Mouse Cerebellum

Demyelination of the cerebellum is a well-known phenomenon in human multiple sclerosis (MS). Concordantly, patients with MS frequently developed symptoms deriving from cerebellar lesions, i.e., dysmetria leading to hand dexterity impairment. Important advances in MS research have been made as a direct or indirect consequence of the establishment of adequate animal models. In this study, we used the cuprizone mouse model to investigate cerebellar demyelination in young adult male mice. The myelin status was analyzed by immunohistochemistry for proteolipoprotein and electron microscopy. The expression and presence of oligodendrocyte, astroglial, and microglia markers were supplementary studied. Cuprizone intoxication induced an almost complete demyelination of cerebellar nuclei. Cerebellar cortex regions were not (cortical gray matter) or only marginally (cortical white matter) affected. In addition, the affected areas displayed hypertrophic and hyperplastic astrocytosis accompanied by microglia or macrophage invasion. We conclude that cuprizone-induced demyelination pictures cerebellar deep gray matter involvement but not cerebellar cortex pathology as described for human MS. Behavioral changes after cuprizone described for this animal model may not only result from effects on commissural fiber tracts but also can arise from cerebellar demyelination.     

Cognition in Mouse Models of Schizophrenia Susceptibility Genes

Cognitive deficits are core features of psychiatric disorders and contribute substantially to functional outcome. It is still unclear, however, how cognitive deficits are related to underlying genetic liability and overt clinical symptoms. Fortunately, animal models of susceptibility genes can illuminate how the products of disease-associated genetic variants affect brain function and ultimately alter behavior. Using as a reference findings from the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia program and the SchizophreniaGene database, we review cognitive data from mutant models of rare and common genetic variants associated with schizophrenia.     

Therapeutic Riding or Mindfulness: Comparative Effectiveness of Two Recreational Therapy Interventions for Adolescents with Autism

Journal of Autism and Developmental Disorders - Therapeutic riding (THR) and HeartMath (HM) mindfulness-based interventions have promise for reducing stress in adolescents with autism spectrum...     

Chronic Administration of Pimozide Fails to Attenuate Motor and Pathological Deficits in Two Mouse Models of Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease which presently does not have any efficient therapeutic approach. Pimozide, a Food and Drug Administration (FDA)-approved neuroepileptic drug, has been recently proposed as a promising treatment for ALS patients based on apparent stabilization of right hand muscles after a short-time administration. A new clinical trial started at the end of 2017 to recruit patients with a prolonged drug delivery schedule. Here, our aim was to investigate the effects of chronic administration of pimozide on disease progression and pathological events in two mouse models of ALS. Pimozide was administered every 2 days to transgenic mice bearing the ALS-linked A315T mutation on the human TAR DNA-binding protein 43 (TDP-43) gene and to mice carrying the human superoxide dismutase 1 (SOD1) gene with the ALS-linked G93A mutation. Chronic administration of pimozide exacerbated motor performances in both animal models and reduced survival in SOD1^G93A mice. In TDP-43^A315T, it decreased the percentage of innervated neuromuscular junctions (NMJs) and increased the accumulation of insoluble TDP-43. In SOD1^G93A mice, pimozide had no effects on NMJ innervation or motoneuron loss, but it increased the levels of misfolded SOD1. We conclude that a chronic administration of pimozide did not confer beneficial effects on disease progression in two mouse models of ALS. In light of a new clinical trial on ALS patients with a chronic regime of pimozide, these results with mouse models suggest prudence and careful monitoring of ALS patients subjected to pimozide treatment.     

Reversibility of Tau-Related Cognitive Defects in a Regulatable FTD Mouse Model

The accumulation of proteins such as Tau is a hallmark of several neurodegenerative diseases, e.g., frontotemporal dementia (FTD). So far, many mouse models of tauopathies have been generated by the use of mutated or truncated human Tau isoforms in order to enhance the amyloidogenic character of Tau and to mimic pathological processes similar to those in FTD patients. Our inducible mice express the repeat domain of human Tau (Tau(RD)) carrying the FTDP-17 mutation ΔK280 in a "pro-aggregant" and an "anti-aggregant" version. Based on the enhanced tendency of Tau to aggregate, only the "pro-aggregant" Tau(RD) mice develop Tau pathology (hyperphosphorylation, coassembly of human and mouse Tau, synaptic loss, and neuronal degeneration). We have now carried out behavioral and electrophysiological analyses showing that only the pro-aggregant Tau(RD) mice have impaired learning/memory and a distinct loss of LTP. Remarkably, after suppressing the pro-aggregant human Tau(RD), memory and LTP recover, while neuronal loss persists. Aggregates persist as well but change their composition from mixed human/mouse to mouse Tau only. The rescue of cognition and synaptic plasticity is explained by a partial recovery of spine synapses in the hippocampus. These results indicate a tight relationship between the amyloidogenic character of Tau and brain malfunction, and suggest that the cognitive impairment is caused by toxic human Tau(RD) species rather than by mouse Tau aggregates.     

Evidence of a Distinct Behavioral Phenotype in Young Boys With Fragile X Syndrome and Autism

ObjectiveHow does the behavioral expression of autism in fragile X syndrome (FXS + Aut) compare with idiopathic autism (iAut)? Although social impairments and restricted, repetitive behaviors are common to these variants of autism, closer examination of these symptom domains may reveal meaningful similarities and differences. To this end, the specific behaviors comprising the social and repetitive behavioral domains in young children with FXS + Aut and iAut were profiled.MethodTwenty-three male subjects 3 to 5 years old with FXS + Aut were matched by age to a group of 38 boys with iAut. Repetitive behavior was assessed using the Repetitive Behavior Scales-Revised. Social behavior was evaluated using Autism Diagnostic Observation Schedule social item severity scores.ResultsRates of stereotypy, self-injury, and sameness behaviors did not differ between groups, whereas compulsive and ritual behavior scores were significantly lower for subjects with FXS + Aut compared with those with iAut. Those with FXS + Aut scored significantly lower (less severe) than the iAut group on five Autism Diagnostic Observation Schedule measurements of social behavior: gaze integration, quality of social overtures, social smile, facial expressions, and response to joint attention.ConclusionsThe behavioral phenotype of FXS + Aut and iAut are most similar with respect to lower-order (motoric) restricted, repetitive behaviors and social approach, but differ in more complex forms of restricted, repetitive behaviors and some social response behaviors. These findings highlight the phenotypic heterogeneity of autism overall and its unique presentation in an etiologically distinct condition.     

A Comprehensive Examination of Reading Heterogeneity in Students with High Functioning Autism: Distinct Reading Profiles and Their Relation to Autism Symptom Severity

The goal of this study was to identify unique profiles of readers in a sample of 8–16 year olds with higher functioning autism spectrum disorders (HFASD) and examine the profiles in relation to ASD symptom severity. Eighty-one students were assessed utilizing a comprehensive reading battery that included basic word reading, language, and comprehension. Using Latent Profile Analysis, four empirically distinct profiles of readers emerged. Next, using the Autism Diagnostic Observation Schedule, Second Edition (Lord et al., Autism diagnostic observation schedule, 2nd edn, Western Psychological Services, Torrance, CA, 2012), analyses were conducted to determine if significant differences existed between profiles as a result of ASD symptomatology. Findings demonstrate the heterogeneous nature of reading profiles in students with HFASD and significant differences between the reading profiles and ASD symptom severity.