Dysfunctional dopaminergic neurotransmission in asocial BTBR mice

Squillace, Marta; Dodero, Luca; Federici, Mauro; Migliarini, Sara; Errico, Francesco; Napolitano, Francesco; Krashia, Paraskevi; Maio, Anna; Galbusera, Alberto; Bifone, Angelo; Scattoni, María Luisa; Pasqualetti, Massimo; Mercuri, Nicola Biagio; Usiello, Alessandro; Gozzi, Alessandro

doi:10.1038/tp.2014.69

Cited by 62 publications

(63 citation statements)

References 95 publications

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“…Dodero et al [151] replicated what was found in the study by Ellegood et al [133], similarly comparing BTBR with B6, but also reported resting-state fMRI connectivity differences in the BTBR mouse, including a significant reduction in the cerebral blood volume that is indicative of a reduced basal metabolism. The same group also examined dopaminergic neurotransmission in BTBR mice using fMRI, highlighting possible dysfunctions in the dopaminergic system [152]. These findings in BTBR mice implicate abnormalities in white matter, in particular interhemispheric connections, as common phenotypes across mouse models of autism.…”

Section: Recent Investigations (2010-14)mentioning

confidence: 98%

Behavioral and Neuroanatomical Phenotypes in Mouse Models of Autism

2015

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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 highresolution 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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Section: Recent Investigations (2010-14)mentioning

confidence: 98%

Behavioral and Neuroanatomical Phenotypes in Mouse Models of Autism

2015

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“…An important limitation of current ASD translational research is its inability to reliably model “idiopathic” autism, which is the most frequent diagnostic label for ASD-related behavioral manifestations. Attempts to use forward genetic approaches in inbred mouse lines exhibiting ASD-like behaviors without a specific genetic determinant have been proposed, with the inbred BTBR mouse line probably being the most notable example in the field (Silverman et al, 2010b; Gogolla et al, 2014; Squillace et al, 2014). Translational relevance of neuro-behavioral findings obtained by comparing genetically homogeneous inbred lines like asocial BTBR and “normosocial” B6 mice is, however, debated (Dodero et al, 2013; Squillace et al, 2014).…”

Section: Limitations and Future Perspectivesmentioning

confidence: 99%

“…Attempts to use forward genetic approaches in inbred mouse lines exhibiting ASD-like behaviors without a specific genetic determinant have been proposed, with the inbred BTBR mouse line probably being the most notable example in the field (Silverman et al, 2010b; Gogolla et al, 2014; Squillace et al, 2014). Translational relevance of neuro-behavioral findings obtained by comparing genetically homogeneous inbred lines like asocial BTBR and “normosocial” B6 mice is, however, debated (Dodero et al, 2013; Squillace et al, 2014). Nevertheless, novel neuromolecular approaches and the use of induced pluripotent stem cells (iPSCs) from patients have begun to reveal common downstream neurobiological pathways in idiopathic forms of autism characterized by shared neuroanatomical features [e.g., macrocephaly (Nicolini et al, 2015; Marchetto et al, 2016)].…”

Section: Limitations and Future Perspectivesmentioning

confidence: 99%

Can Mouse Imaging Studies Bring Order to Autism Connectivity Chaos?

Liska

Gozzi

2016

Front. Neurosci.

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Functional Magnetic Resonance Imaging (fMRI) has consistently highlighted impaired or aberrant functional connectivity across brain regions of autism spectrum disorder (ASD) patients. However, the manifestation and neural substrates of these alterations are highly heterogeneous and often conflicting. Moreover, their neurobiological underpinnings and etiopathological significance remain largely unknown. A deeper understanding of the complex pathophysiological cascade leading to aberrant connectivity in ASD can greatly benefit from the use of model organisms where individual pathophysiological or phenotypic components of ASD can be recreated and investigated via approaches that are either off limits or confounded by clinical heterogeneity. Despite some obvious limitations in reliably modeling the full phenotypic spectrum of a complex developmental disorder like ASD, mouse models have played a central role in advancing our basic mechanistic and molecular understanding of this syndrome. Recent progress in mouse brain connectivity mapping via resting-state fMRI (rsfMRI) offers the opportunity to generate and test mechanistic hypotheses about the elusive origin and significance of connectional aberrations observed in autism. Here we discuss recent progress toward this goal, and illustrate initial examples of how the approach can be employed to establish causal links between ASD-related mutations, developmental processes, and brain connectional architecture. As the spectrum of genetic and pathophysiological components of ASD modeled in the mouse is rapidly expanding, the use of rsfMRI can advance our mechanistic understanding of the origin and significance of the connectional alterations associated with autism, and their heterogeneous expression across patient cohorts.

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“…By way of example, we apply this approach to functional and structural connectivity data from BTBR T+Itpr3tf/J mice (BTBR) (Han et al, 2014; Squillace et al, 2014), an inbred mouse line with ACC, using the normo-callosal C57Bl6/J (B6) mice as comparators. This is an ideal model to validate our approach, and to investigate the differential effects of a pathological condition on structural and functional connectivity.…”

Section: Introductionmentioning

confidence: 99%

Differential Effects of Brain Disorders on Structural and Functional Connectivity

et al. 2017

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Different measures of brain connectivity can be defined based on neuroimaging read-outs, including structural and functional connectivity. Neurological and psychiatric conditions are often associated with abnormal connectivity, but comparing the effects of the disease on different types of connectivity remains a challenge. In this paper, we address the problem of quantifying the relative effects of brain disease on structural and functional connectivity at a group level. Within the framework of a graph representation of connectivity, we introduce a kernel two-sample test as an effective method to assess the difference between the patients and control group. Moreover, we propose a common representation space for structural and functional connectivity networks, and a novel test statistics to quantitatively assess differential effects of the disease on different types of connectivity. We apply this approach to a dataset from BTBR mice, a murine model of Agenesis of the Corpus Callosum (ACC), a congenital disorder characterized by the absence of the main bundle of fibers connecting the two hemispheres. We used normo-callosal mice (B6) as a comparator. The application of the proposed methods to this data-set shows that the two types of connectivity can be successfully used to discriminate between BTBR and B6, meaning that both types of connectivity are affected by ACC. However, our novel test statistics shows that structural connectivity is significantly more affected than functional connectivity, consistent with the idea that functional connectivity has a robust topology that can tolerate substantial alterations in its structural connectivity substrate.

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Dysfunctional dopaminergic neurotransmission in asocial BTBR mice

Cited by 62 publications

References 95 publications

Behavioral and Neuroanatomical Phenotypes in Mouse Models of Autism

Behavioral and Neuroanatomical Phenotypes in Mouse Models of Autism

Can Mouse Imaging Studies Bring Order to Autism Connectivity Chaos?

Differential Effects of Brain Disorders on Structural and Functional Connectivity

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