Shared developmental gait disruptions across two mouse models of neurodevelopmental disorders

Rahn, Rachel M; Weichselbaum, Claire; Gutmann, David H.; Dougherty, Joseph D.; Maloney, Susan E.

doi:10.1186/s11689-021-09359-0

Cited by 6 publications

(10 citation statements)

References 35 publications

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“…To provide a quantitative description of the HYB, we supplemented the array of standard assays with gait assessment and home cage behavior. The gait of all strains was inconsistent with abnormalities seen in motor disorders ( Preisig et al, 2016 ; Rahn et al, 2021 ), yet every strain exhibited distinct gait patterns that were largely preserved upon aging. In addition, we observed apparent interstrain differences of daily conduct in the home cage, including distinct time division between sheltering, wheel running, and feeding.…”

Section: Discussionmentioning

confidence: 93%

“…A second challenge is to ensure the stability of the tested phenotype under the null condition throughout the study period. In many cases, the effects of a given manipulation are studied over weeks to months ( Prevot et al, 2019 ; Namdar et al, 2020 ; Rahn et al, 2021 ). Deterioration of control phenotypic behavior could confound potential manipulation-based intergroup differences.…”

Section: Discussionmentioning

confidence: 99%

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Hybrid Offspring of C57BL/6J Mice Exhibit Improved Properties for Neurobehavioral Research

Sloin

Bikovski

Levi

et al. 2022

eNeuro

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C57BL/6 is the most commonly used mouse strain in neurobehavioral research, serving as a background for multiple transgenic lines. However, C57BL/6 exhibit behavioral and sensorimotor disadvantages that worsen with age. We bred FVB/NJ females and C57BL/6J males to generate first-generation hybrid offspring (FVB/NJ x C57BL/6J)F1. The hybrid mice exhibit reduced anxiety-like behavior, improved learning, and enhanced long-term spatial memory. In contrast to both progenitors, hybrids maintain sensorimotor performance upon aging and exhibit improved long-term memory. The hybrids are larger than C57BL/6J, exhibiting enhanced running behavior on a linear track during freely-moving electrophysiological recordings. Hybrids exhibit typical rate and phase coding of space by CA1 pyramidal cells. Hybrids generated by crossing FVB/NJ females with transgenic males of a C57BL/6 background support optogenetic neuronal control in neocortex and hippocampus. The hybrid mice provide an improved model for neurobehavioral studies combining complex behavior, electrophysiology, and genetic tools readily available in C57BL/6 mice.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Hybrid Offspring of C57BL/6J Mice Exhibit Improved Properties for Neurobehavioral Research

Sloin

Bikovski

Levi

et al. 2022

eNeuro

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“…Developmental gait trajectories were assessed using the DigiGait Gait Analysis System (Mouse Specifics, Inc) following our previously published methods [ 31 , 32 ]. Briefly, for all mice in cohort 2, gait metrics were assessed on P21, 24, 27, 30 at 20 cm/s and again at one time point after P60 (adulthood) at both 30 cm/s and 40 cm/s (Fig.…”

Section: Methodsmentioning

confidence: 99%

“…If the animal failed to run on the belt after five attempts, it was returned to its homecage. Video processing and body length assessments were conducted as previously described [ 31 , 32 ].…”

Section: Methodsmentioning

confidence: 99%

Characterization of early markers of disease in the mouse model of mucopolysaccharidosis IIIB

McCullough,

Titus,

Reardon

et al. 2024

J Neurodevelop Disord

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Background Mucopolysaccharidosis (MPS) IIIB, also known as Sanfilippo Syndrome B, is a devastating childhood disease. Unfortunately, there are currently no available treatments for MPS IIIB patients. Yet, animal models of lysosomal storage diseases have been valuable tools in identifying promising avenues of treatment. Enzyme replacement therapy, gene therapy, and bone marrow transplant have all shown efficacy in the MPS IIIB model systems. A ubiquitous finding across rodent models of lysosomal storage diseases is that the best treatment outcomes resulted from intervention prior to symptom onset. Therefore, the aim of the current study was to identify early markers of disease in the MPS IIIB mouse model as well as examine clinically-relevant behavioral domains not yet explored in this model. Methods Using the MPS IIIB mouse model, we explored early developmental trajectories of communication and gait, and later social behavior, fear-related startle and conditioning, and visual capabilities. In addition, we examined brain structure and function via magnetic resonance imaging and diffusion tensor imaging. Results We observed reduced maternal isolation-induced ultrasonic vocalizations in MPS IIIB mice relative to controls, as well as disruption in a number of the spectrotemporal features. MPS IIIB also exhibited disrupted thermoregulation during the first two postnatal weeks without any differences in body weight. The developmental trajectories of gait were largely normal. In early adulthood, we observed intact visual acuity and sociability yet a more submissive phenotype, increased aggressive behavior, and decreased social sniffing relative to controls. MPS IIIB mice showed greater inhibition of startle in response to a pretone with a decrease in overall startle response and reduced cued fear memory. MPS IIIB also weighed significantly more than controls throughout adulthood and showed larger whole brain volumes and normalized regional volumes with intact tissue integrity as measured with magnetic resonance and diffusion tensor imaging, respectively. Conclusions Together, these results indicate disease markers are present as early as the first two weeks postnatal in this model. Further, this model recapitulates social, sensory and fear-related clinical features. Our study using a mouse model of MPS IIIB provides essential baseline information that will be useful in future evaluations of potential treatments.

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“…Since mice older than 8-month Camsap3-cKO mice were lighter than their WT littermates (Figure 4A), mice at 4 months old were selected for gait measurement. At this age, gait was fully developed (Akula et al, 2020;Rahn et al, 2021), and Camsap3-cKO mice were not significantly lighter than their WT littermates (Figure 4A). The assessed litter consisted of 6 male mice: 3 WT and 3 Camsap3-cKO.…”

Section: Camsap3-cko Mice Have Slightly Altered Gaitsmentioning

confidence: 95%

Vestibular Hair Cells Require CAMSAP3, a Microtubule Minus-End Regulator, for Formation of Normal Kinocilia

O’Donnell

Zheng²

2022

Front. Cell. Neurosci.

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Kinocilia are exceptionally long primary sensory cilia located on vestibular hair cells, which are essential for transmitting key signals that contribute to mammalian balance and overall vestibular system function. Kinocilia have a “9+2” microtubule (MT) configuration with nine doublet MTs surrounding two central singlet MTs. This is uncommon as most mammalian primary sensory cilia have a “9+0” configuration, in which the central MT pair is absent. It has yet to be determined what the function of the central MT pair is in kinocilia. Calmodulin-regulated spectrin-associated protein 3 (CAMSAP3) regulates the minus end of MTs and is essential for forming the central MT pair in motile cilia, which have the “9+2” configuration. To explore the role of the central MT pair in kinocilia, we created a conditional knockout model (cKO), Camsap3-cKO, which intended to eliminate CAMSAP3 in limited organs including the inner ear, olfactory bulb, and kidneys. Immunofluorescent staining of vestibular organs demonstrated that CAMSAP3 proteins were significantly reduced in Camsap3-cKO mice and that aged Camsap3-cKO mice had significantly shorter kinocilia than their wildtype littermates. Transmission electron microscopy showed that aged Camsap3-cKO mice were in fact missing that the central MT pair in kinocilia more often than their wildtype counterparts. In the examination of behavior, wildtype and Camsap3-cKO mice performed equally well on a swim assessment, right-reflex test, and evaluation of balance on a rotarod. However, Camsap3-cKO mice showed slightly altered gaits including reduced maximal rate of change of paw area and a smaller paw area in contact with the surface. Although Camsap3-cKO mice had no differences in olfaction from their wildtype counterparts, Camsap3-cKO mice did have kidney dysfunction that deteriorated their health. Thus, CAMSAP3 is important for establishing and/or maintaining the normal structure of kinocilia and kidney function but is not essential for normal olfaction. Our data supports our hypothesis that CAMSAP3 is critical for construction of the central MT pair in kinocilia, and that the central MT pair may be important for building long and stable axonemes in these kinocilia. Whether shorter kinocilia might lead to abnormal vestibular function and altered gaits in older Camsap3-cKO mice requires further investigation.

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Shared developmental gait disruptions across two mouse models of neurodevelopmental disorders

Cited by 6 publications

References 35 publications

Hybrid Offspring of C57BL/6J Mice Exhibit Improved Properties for Neurobehavioral Research

Hybrid Offspring of C57BL/6J Mice Exhibit Improved Properties for Neurobehavioral Research

Characterization of early markers of disease in the mouse model of mucopolysaccharidosis IIIB

Vestibular Hair Cells Require CAMSAP3, a Microtubule Minus-End Regulator, for Formation of Normal Kinocilia

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