Deficient Purposeful Use of Forepaws in Female Mice Modelling Rett Syndrome

Filippis, Bianca De; Musto, Mattia; Altabella, Luisa; Romano, Emilia; Canese, Rossella; Laviola, Giovanni

doi:10.1155/2015/326184

Cited by 16 publications

(26 citation statements)

References 57 publications

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“…Overall, Mecp2 rats had a signi cant impairment in skilled motor function compared to WT controls. In the current study, the reduced forelimb movement speed, as assessed by longer latencies between presses on the task, are consistent with de cits in motor performance in Mecp2 rats (De Filippis et al, 2015;Veeraragavan et al, 2015). Additionally, Mecp2 rats initiated fewer trials during behavioral testing sessions, consistent with motor hypoactivity previously documented with the open eld and rotarod tasks (Bhattacherjee et al, 2017;Guy et al, 2001;Patterson et al, 2016;Samaco et al, 2013;Stearns et al, 2007;Veeraragavan et al, 2015;Wu et al, 2016).…”

Section: Discussionsupporting

confidence: 90%

Deficits in Skilled Motor and Auditory Learning in a Rat Model of Rett Syndrome

Adcock¹,

Blount

Morrison³

et al. 2020

Preprint

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Background: Rett Syndrome is an X-linked neurodevelopmental disorder caused by a mutation in the gene MECP2. Individuals with Rett Syndrome display developmental regression at an early age, and develop a range of motor, auditory, cognitive and social impairments. Several studies have successfully modeled some aspects of dysfunction and Rett Syndrome-like phenotypes in transgenic mouse and rat models bearing mutations in the MECP2 gene. Here, we sought to extend these findings and characterize skilled learning, a more complex behavior known to be altered in Rett syndrome. Methods: We evaluated the acquisition and performance of auditory and motor function on two complex tasks in heterozygous female Mecp2 rats. Animals were trained to perform a speech discrimination task or a skilled forelimb reaching task. Results: Our results reveal that Mecp2 rats display slower acquisition and reduced performance on an auditory discrimination task than wild-type (WT) littermates. Similarly, Mecp2 rats exhibit impaired learning rates and worse performance on a skilled forelimb motor task compared to WT. Conclusions: Together, these findings illustrate novel deficits in skilled learning consistent with clinical manifestation of Rett syndrome and provide a framework for development of therapeutic strategies to improve these complex behaviors.

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Section: Discussionsupporting

confidence: 90%

Deficits in Skilled Motor and Auditory Learning in a Rat Model of Rett Syndrome

Adcock¹,

Blount

Morrison³

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…In contrast, we report a significant increase in Mecp2 ZFN/+ body weight beginning at 2–3 months of age and continuing through development. Several previous mouse studies also report weight gain in heterozygous females (11,13,42,44). …”

Section: Discussionmentioning

confidence: 87%

“…Mecp2 ZFN/+ females demonstrated reduced latency to fall at 9 months of age; however, this difference did emerge after Mecp2 ZFN/+ rats became heavier than WTs, making it difficult to definitively determine a weight-independent effect. Previous studies have reported reductions in latency to fall in heterozygous females as early as PND 30 (22), while others have indicated that motor coordination deficits emerge between 5 weeks and 12 months of age (11,13,22,37,39,42,44,73,74). …”

Section: Discussionmentioning

confidence: 98%

MeCP2 deficiency results in robust Rett-like behavioural and motor deficits in male and female rats

et al. 2016

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Since the identification of MECP2 as the causative gene in the majority of Rett Syndrome (RTT) cases, transgenic mouse models have played a critical role in our understanding of this disease. The use of additional mammalian RTT models offers the promise of further elucidating critical early mechanisms of disease as well as providing new avenues for translational studies. We have identified significant abnormalities in growth as well as motor and behavioural function in a novel zinc-finger nuclease model of RTT utilizing both male and female rats throughout development. Male rats lacking MeCP2 (Mecp2ZFN/y) were noticeably symptomatic as early as postnatal day 21, with most dying by postnatal day 55, while females lacking one copy of Mecp2 (Mecp2ZFN/+) displayed a more protracted disease course. Brain weights of Mecp2ZFN/y and Mecp2ZFN/+ rats were significantly reduced by postnatal day 14 and 21, respectively. Early motor and breathing abnormalities were apparent in Mecp2ZFN/y rats, whereas Mecp2ZFN/+ rats displayed functional irregularities later in development. The large size of this species will provide profound advantages in the identification of early disease mechanisms and the development of appropriately timed therapeutics. The current study establishes a foundational basis for the continued utilization of this rat model in future RTT research.

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“…Many neurological disorders-ranging widely from cerebrovascular and demyelinating disorders to spinal cord injury, peripheral neuropathies and more-impair dexterous movements, and rodent forelimb tasks have become widely used as translational models to investigate neural mechanisms and therapeutic targets (e.g. [8,37,38]). High-speed close-up video of mice handling food has potential for further development as a quantitative assay to investigate how specific aspects of D1-related manual dexterity relate to neural circuit dysfunction in a wide range of neurological disorders.…”

Section: Discussionmentioning

confidence: 99%

Manual dexterity of mice during food-handling involves the thumb and a set of fast basic movements

2020

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The small first digit (D1) of the mouse's hand resembles a volar pad, but its thumb-like anatomy suggests ethological importance for manipulating small objects. To explore this possibility, we recorded high-speed close-up video of mice eating seeds and other food items. Analyses of ethograms and automated tracking with DeepLabCut revealed multiple distinct microstructural features of food-handling. First, we found that mice indeed made extensive use of D1 for dexterous manipulations. In particular, mice used D1 to hold food with either of two grip types: a pincer-type grasp, or a "thumb-hold" grip, pressing with D1 from the side. Thumb-holding was preferentially used for handling smaller items, with the smallest items held between the two D1s alone. Second, we observed that mice cycled rapidly between two postural modes while feeding, with the hands positioned either at the mouth (oromanual phase) or resting below (holding phase). Third, we identified two highly stereotyped D1related movements during feeding, including an extraordinarily fast (~20 ms) "regrip" maneuver, and a fast (~100 ms) "sniff" maneuver. Lastly, in addition to these characteristic simpler movements and postures, we also observed highly complex movements, including rapid D1-assisted rotations of food items and dexterous simultaneous double-gripping of two food fragments. Manipulation behaviors were generally conserved for different food types, and for head-fixed mice. Wild squirrels displayed a similar repertoire of D1-related movements. Our results define, for the mouse, a set of kinematic building-blocks of manual dexterity, and reveal an outsized role for D1 in these actions. OPEN ACCESSCitation: Barrett JM, Raineri Tapies MG, Shepherd GMG (2020) Manual dexterity of mice during foodhandling involves the thumb and a set of fast basic movements. PLoS ONE 15(1): e0226774. https://

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Deficient Purposeful Use of Forepaws in Female Mice Modelling Rett Syndrome

Cited by 16 publications

References 57 publications

Deficits in Skilled Motor and Auditory Learning in a Rat Model of Rett Syndrome

Deficits in Skilled Motor and Auditory Learning in a Rat Model of Rett Syndrome

MeCP2 deficiency results in robust Rett-like behavioural and motor deficits in male and female rats

Manual dexterity of mice during food-handling involves the thumb and a set of fast basic movements

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