The BTBR T+tf/J mouse model for autism spectrum disorders–in search of biomarkers

Meyza, Ksenia Z.; Defensor, Erwin B.; Jensen, Ashley Layne; Corley, Michael J.; Pearson, Brandon L.; Pobbe, Roger L.H.; Bolivar, Valerie J.; Blanchard, D. Caroline; Blanchard, Robert J.

doi:10.1016/j.bbr.2012.07.021

Cited by 125 publications

(105 citation statements)

References 118 publications

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“…4e). These findings strongly support previous studies that suggested a social behaviour deficiency in the BTBR mouse strain 29,31 . Moreover, we found that by using four social behaviour features collected by the system in a single testing day, we could predict the mouse strain with an accuracy of about 90-95% (see Methods and Supplementary Fig.…”

Section: Resultssupporting

confidence: 92%

“…The integrated video-RFID system was applied to test two inbred mouse strains: C57BL/6 Â 129Sv (C57 Â 129) and BTBR T þ tf/J (BTBR), which were previously reported to exhibit significantly different behavioural phenotypes [29][30][31] . Three independent groups of mice were tested for each of the mouse strains (that is, a total of six experiments), using an identical standard operation protocol; the duration of each experiment was 8 days.…”

Section: Resultsmentioning

confidence: 99%

“…Finally, it should be noted that the BTBR mouse strain, unlike the C57 Â 129 strain, is known to present severe socio-behavioural deficiencies and other behavioural abnormalities 30 , and is routinely used as a mouse model for studying autism 3,29 . This is the first time that deficiency in group social organization is reported in a mouse model for autism.…”

Section: Article Nature Communications | Doi: 101038/ncomms3018mentioning

confidence: 99%

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Automated long-term tracking and social behavioural phenotyping of animal colonies within a semi-natural environment

et al. 2013

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Social behaviour has a key role in animal survival across species, ranging from insects to primates and humans. However, the biological mechanisms driving natural interactions between multiple animals, over long-term periods, are poorly studied and remain elusive. Rigorous and objective quantification of behavioural parameters within a group poses a major challenge as it requires simultaneous monitoring of the positions of several individuals and comprehensive consideration of many complex factors. Automatic tracking and phenotyping of interacting animals could thus overcome the limitations of manual tracking methods. Here we report a broadly applicable system that automatically tracks the locations of multiple, uniquely identified animals, such as mice, within a semi-natural setting. The system combines video and radio frequency identified tracking data to obtain detailed behavioural profiles of both individuals and groups. We demonstrate the usefulness of these data in characterizing individual phenotypes, interactions between pairs and the collective social organization of groups.

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Section: Resultssupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Article Nature Communications | Doi: 101038/ncomms3018mentioning

confidence: 99%

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Automated long-term tracking and social behavioural phenotyping of animal colonies within a semi-natural environment

et al. 2013

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“…The complex phenotypes of autism are difficult to model in mice (Moy et al, 2006;Patterson, 2011;Silverman et al, 2010b), thereby slowing the development of successful therapies. Nonetheless, the three diagnostic criteria of autism (eg, impaired sociability, abnormal communication, and excessive stereotypic behaviors) are expressed by the BTBR T þ Itpr3 tf /J (formerly BTBR T þ tf/J and hereafter 'BTBR') inbred strain (McFarlane et al, 2008;Meyza et al, 2013;Scattoni et al, 2011). These findings indicate that the BTBR strain might be a useful model for aspects of idiopathic (polygenetic) autism.…”

Section: Introductionmentioning

confidence: 99%

Long-Term Memory Deficits are Associated with Elevated Synaptic ERK1/2 Activation and Reversed by mGluR5 Antagonism in an Animal Model of Autism

Seese

Maske

Lynch

et al. 2014

Neuropsychopharmacol

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A significant proportion of patients with autism exhibit some degree of intellectual disability. The BTBR T þ Itpr3 tf /J mouse strain exhibits behaviors that align with the major diagnostic criteria of autism. To further evaluate the BTBR strain's cognitive impairments, we quantified hippocampus-dependent object location memory (OLM) and found that one-third of the BTBR mice exhibited robust memory, whereas the remainder did not. Fluorescence deconvolution tomography was used to test whether synaptic levels of activated extracellular signal-regulated kinase 1/2 (ERK1/2), a protein that contributes importantly to plasticity, correlate with OLM scores in individual mice. In hippocampal field CA1, the BTBRs had fewer post-synaptic densities associated with high levels of phosphorylated (p-) ERK1/2 as compared with C57BL/6 mice. Although counts of p-ERK1/2 immunoreactive synapses did not correlate with OLM performance, the intensity of synaptic p-ERK1/2 immunolabeling was negatively correlated with OLM scores across BTBRs. Metabotropic glutamate receptor (mGluR) 5 signaling activates ERK1/2. Therefore, we tested whether treatment with the mGluR5 antagonist MPEP normalizes synaptic and learning measures in BTBR mice: MPEP facilitated OLM and decreased synaptic p-ERK1/2 immunolabeling intensity without affecting numbers of p-ERK1/2 þ synapses. In contrast, semi-chronic ampakine treatment, which facilitates memory in other models of cognitive impairment, had no effect on OLM in BTBRs. These results suggest that intellectual disabilities associated with different neurodevelopmental disorders on the autism spectrum require distinct therapeutic strategies based on underlying synaptic pathology.

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“…Further, these types of mice have been analyzed using various behavioral tests including an elevated plus maze, a mouse defense battery, an elevated zero-maze, a three-chambered social approach test, etc. (Bolivar et al, 2007;Meyza et al, 2013;Moy et al, 2007;Pobbe et al, 2011;Silverman et al, 2010;Wohr et al, 2011). Since numerous immune abnormalities have been reported in autism (Ashwood & van de Water, 2004;Stigler et al, 2009), the current study investigated the immune system of BTBR mice.…”

Section: Discussionmentioning

confidence: 99%

Aberrant IgG isotype generation in mice with abnormal behaviors

Kim

et al. 2015

Journal of Immunotoxicology

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BTBR T+tf/J (BTBR) mice were recently cited as a suitable animal model for the study of autism because of their behavioral characteristics and immunological changes similar to those reported from autistic subjects. The BTBR mouse was reported to have significantly higher levels of serum IgG, brain IgG deposits and anti-brain IgG than highly social C57BL/6 mice, suggesting involvement of aberrant immune responses in the occurrence of autism. Upregulation of IgG production was investigated here, with a focus on the pattern of IgG isotype distribution compared with that in FVB/NJ (FVB) mice, another highly social control strain. The results indicated that levels of serum IgG 1 , IgG 2b and IgG 3 in post-natal day 21 BTBR mice was significantly higher than FVB mice, regardless of sex, resulting in higher IgG 1 :IgG 2a ratios in BTBR mice than in FVB mice (statistical significance in males). A similar outcome regarding the IgG 1 :IgG 2a ratio was observed in culture supernatants of bone marrow cells from these hosts. A presence of brain-reactive IgG in the sera of BTBR was higher than in FVB mice; levels of brainreactive IgG against whole brain homogenates were higher in BTBR than in FVB mice, with significant differences seen in the striatum and substantia nigra regions. Levels of IgG 1 deposited in the cerebellum, cortex, hippocampus or striatum of both BTBR male and female mice were significantly higher than in FVB counterparts. Overall, these results suggest that alterations in IgG isotype production or deposition in the brain could be implicated in the aberrant immune reactivities of BTBR mice.

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The BTBR T+tf/J mouse model for autism spectrum disorders–in search of biomarkers

Cited by 125 publications

References 118 publications

Automated long-term tracking and social behavioural phenotyping of animal colonies within a semi-natural environment

Automated long-term tracking and social behavioural phenotyping of animal colonies within a semi-natural environment

Long-Term Memory Deficits are Associated with Elevated Synaptic ERK1/2 Activation and Reversed by mGluR5 Antagonism in an Animal Model of Autism

Aberrant IgG isotype generation in mice with abnormal behaviors

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