Shared and specific signatures of locomotor ataxia in mutant mice

Machado, Ana S; Marques, Hugo Gravato; Duarte, Diogo F; Darmohray, Dana M; Carey, Megan R.

doi:10.7554/elife.55356

Cited by 24 publications

(25 citation statements)

References 62 publications

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“…We first analyzed the locomotor behavior of GluA4-KO mice. Cerebellar dysfunction often leads to gait ataxia during walking, characterized by altered 3D limb trajectories and deficits in interlimb and whole-body coordination in both humans and mice ( Machado et al, 2020a ; Machado et al, 2015 ; Morton and Bastian, 2007 ). Surprisingly, we observed that GluA4-KO mice walked similarly to size-matched WT littermates without obvious gait ataxia ( Video 1 ).…”

Section: Resultsmentioning

confidence: 99%

“…Surprisingly, we observed that GluA4-KO mice walked similarly to size-matched WT littermates without obvious gait ataxia ( Video 1 ). Quantitative analysis of locomotor coordination with the LocoMouse system ( Machado et al, 2020a ; Machado et al, 2015 ; Figure 7A–C ) revealed that their locomotor behavior was largely intact. GluA4-KO mice tended to walk more slowly than controls, but across walking speeds, stride lengths were comparable in mice of both genotypes ( Figure 7D–E , Figure 7—figure supplement 1 ).…”

Section: Resultsmentioning

confidence: 99%

“…Vertical paw motion was also largely normal ( Figure 7H–I ), although there was a small degree of hyperflexion across walking speeds ( Figure 7—figure supplement 1 ). We also explored interlimb coordination, which is often disrupted by cerebellar damage ( Machado et al, 2020a ; Machado et al, 2015 ; Morton and Bastian, 2007 ), during normal walking. We did not observe any differences between WT and GluA4-KO mice, with both genotypes displaying a symmetrical trot pattern across walking speeds ( Figure 7J–K ).…”

Section: Resultsmentioning

confidence: 99%

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GluA4 facilitates cerebellar expansion coding and enables associative memory formation

Kita

Albergaria

Machado

et al. 2021

eLife

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AMPA receptors (AMPARs) mediate excitatory neurotransmission in the CNS and their subunit composition determines synaptic efficacy. Whereas AMPAR subunits GluA1–GluA3 have been linked to particular forms of synaptic plasticity and learning, the functional role of GluA4 remains elusive. Here we demonstrate a crucial function of GluA4 for synaptic excitation and associative memory formation in the cerebellum. Notably, GluA4-knockout mice had ~80% reduced mossy fiber to granule cell synaptic transmission. The fidelity of granule cell spike output was markedly decreased despite attenuated tonic inhibition and increased NMDA receptor-mediated transmission. Computational network modeling incorporating these changes revealed that deletion of GluA4 impairs granule cell expansion coding, which is important for pattern separation and associative learning. On a behavioral level, while locomotor coordination was generally spared, GluA4-knockout mice failed to form associative memories during delay eyeblink conditioning. These results demonstrate an essential role for GluA4-containing AMPARs in cerebellar information processing and associative learning.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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GluA4 facilitates cerebellar expansion coding and enables associative memory formation

Kita

Albergaria

Machado

et al. 2021

eLife

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“…The cerebellum contains approximately 75% of all neurons in the brain ( Lange, 1975 ; Sarko et al, 2009 ) and integrates sensory inputs in order to fine-tune motor output ( Manto et al, 2012 ). This function is critical for motor coordination and motor learning as impairments in the cerebellar circuitry cause ataxia, dystonia, and tremor ( White et al, 2016 ; Bostan and Strick, 2018 ; Darmohray et al, 2019 ; Machado et al, 2020 ). The cerebellum also contributes to non-motor behaviors such as social interaction, reward, and memory ( Wagner et al, 2017 ; Carta et al, 2019 ; McAfee et al, 2019 ; Kelly et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Deleting Mecp2 from the cerebellum rather than its neuronal subtypes causes a delay in motor learning in mice

Achilly

Kim

et al. 2021

eLife

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Rett syndrome is a devastating childhood neurological disorder caused by mutations in MECP2. Of the many symptoms, motor deterioration is a significant problem for patients. In mice, deleting Mecp2 from the cortex or basal ganglia causes motor dysfunction, hypoactivity, and tremor, which are abnormalities observed in patients. Little is known about the function of Mecp2 in the cerebellum, a brain region critical for motor function. Here we show that deleting Mecp2 from the cerebellum, but not from its neuronal subtypes, causes a delay in motor learning that is overcome by additional training. We observed irregular firing rates of Purkinje cells and altered heterochromatin architecture within the cerebellum of knockout mice. These findings demonstrate that the motor deficits present in Rett syndrome arise, in part, from cerebellar dysfunction. For Rett syndrome and other neurodevelopmental disorders, our results highlight the importance of understanding which brain regions contribute to disease phenotypes.

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“…The cerebellum contains approximately 75% of all neurons in the brain (Lang et al, 1975; Sarko et al, 2009) and integrates sensory inputs in order to fine-tune motor output (Manto et al, 2012). This function is critical for motor coordination and motor learning as impairments in cerebellar circuity cause ataxia, dystonia, and tremor (White et al, 2016; Bostan and Strick, 2019; Darmohray et al, 2019; Machado et al, 2020). The cerebellum also contributes to non-motor behaviors such as social interaction, reward, and memory (Wagner et al, 2017; Carta et al, 2019; McAfee et al, 2019; Kelly et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

DeletingMecp2from the entire cerebellum rather than its neuronal subtypes causes a delay in motor learning in mice

Achilly

Kim

et al. 2020

Preprint

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Rett syndrome is a devastating childhood neurological disorder caused by mutations in MECP2. Of the many symptoms, motor deterioration is a significant problem for patients. In mice, deleting Mecp2 from the cortex or basal ganglia causes motor dysfunction, hypoactivity, and tremor, which are abnormalities observed in patients. However, little is known about the consequences of deleting Mecp2 from the cerebellum, a brain region critical for motor function. Here we show that deleting Mecp2 from the entire cerebellum, but not from individual cerebellar cell types, causes a delay in motor learning that is overcome by additional training. We also observed irregular firing rates of Purkinje cells and transcriptional misregulation within the cerebellum of knockout mice. These findings demonstrate that the motor deficits present in Rett syndrome arise, in part, from cerebellar dysfunction. For Rett syndrome as well as other neurodevelopmental disorders, our results highlight the importance of understanding which brain regions contribute to disease phenotypes.

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Shared and specific signatures of locomotor ataxia in mutant mice

Cited by 24 publications

References 62 publications

GluA4 facilitates cerebellar expansion coding and enables associative memory formation

GluA4 facilitates cerebellar expansion coding and enables associative memory formation

Deleting Mecp2 from the cerebellum rather than its neuronal subtypes causes a delay in motor learning in mice

DeletingMecp2from the entire cerebellum rather than its neuronal subtypes causes a delay in motor learning in mice

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