Altered Structural and Functional Synaptic Plasticity with Motor Skill Learning in a Mouse Model of Fragile X Syndrome

Huntington's disease (HD) is a neurodegenerative disease notably characterized by progressive motor symptoms. Although the loss of Medium Spiny Neurons (MSNs) in the striatum has been associated with motor deficits, premanifest patients already present cognitive deficiencies and show early signs of motor disabilities. Here in a YAC128 HD mouse model, we identified impairment in motor skill learning at the age of 11 to 14 weeks. Using optogenetic stimulation, we found that excitatory synaptic transmission from motor cortex to MSNs located in the Dorso Lateral part of the Striatum (DLS) is altered. Using single pellet reaching task, we observed that while motor skill learning is accompanied by a dynamic change in AMPA/NMDA ratio in wild type mice, this form of synaptic plasticity does not occur in YAC128 mice. This study not only proposes new meaningful insight the synaptopathic mechanisms of HD, but also highlights that deficit in motor skill learning dependent synaptic plasticity at motor cortex to DLS synapses represents an early biomarker for Huntington's disease.

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Compensatory Limb Use and Behavioral Assessment of Motor Skill Learning Following Sensorimotor Cortex Injury in a Mouse Model of Ischemic Stroke

Journal of Visualized Experiments ◽

10.3791/51602 ◽

2014 ◽

Cited By ~ 2

Author(s):

Abigail L. Kerr ◽

Kelly A. Tennant

Keyword(s):

Ischemic Stroke ◽

Mouse Model ◽

Sensorimotor Cortex ◽

Motor Skill ◽

Behavioral Assessment ◽

Skill Learning ◽

Motor Skill Learning

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Altered Synaptic Plasticity in Tourette's Syndrome and Its Relationship to Motor Skill Learning

PLoS ONE ◽

10.1371/journal.pone.0098417 ◽

2014 ◽

Vol 9 (5) ◽

pp. e98417 ◽

Cited By ~ 22

Author(s):

Valerie Cathérine Brandt ◽

Eva Niessen ◽

Christos Ganos ◽

Ursula Kahl ◽

Tobias Bäumer ◽

...

Keyword(s):

Synaptic Plasticity ◽

Motor Skill ◽

Skill Learning ◽

Tourette's Syndrome ◽

Tourette’S Syndrome ◽

Motor Skill Learning

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Selective Synaptic Plasticity within the Cerebellar Cortex Following Complex Motor Skill Learning

Neurobiology of Learning and Memory ◽

10.1006/nlme.1998.3827 ◽

1998 ◽

Vol 69 (3) ◽

pp. 274-289 ◽

Cited By ~ 126

Author(s):

Jeffrey A. Kleim ◽

Rodney A. Swain ◽

Kim A. Armstrong ◽

Ruth M.A. Napper ◽

Theresa A. Jones ◽

...

Keyword(s):

Synaptic Plasticity ◽

Cerebellar Cortex ◽

Motor Skill ◽

Skill Learning ◽

Motor Skill Learning ◽

Complex Motor

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Brain-Derived Neurotrophic Factor Rescues Synaptic Plasticity in a Mouse Model of Fragile X Syndrome

Journal of Neuroscience ◽

10.1523/jneurosci.2624-07.2007 ◽

2007 ◽

Vol 27 (40) ◽

pp. 10685-10694 ◽

Cited By ~ 160

Author(s):

J. C. Lauterborn ◽

C. S. Rex ◽

E. Kramar ◽

L. Y. Chen ◽

V. Pandyarajan ◽

...

Keyword(s):

Synaptic Plasticity ◽

Mouse Model ◽

Fragile X Syndrome ◽

Neurotrophic Factor ◽

Fragile X ◽

Brain Derived Neurotrophic Factor

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Selective role of the translin/trax RNase complex in hippocampal synaptic plasticity

10.21203/rs.3.rs-29690/v1 ◽

2020 ◽

Author(s):

Alan Jung Park ◽

Mahesh Shivarama Shetty ◽

Jay M. Baraban ◽

Ted Abel

Keyword(s):

Protein Synthesis ◽

Synaptic Plasticity ◽

Mouse Model ◽

Fragile X Syndrome ◽

Metabotropic Glutamate Receptor ◽

Fragile X ◽

Local Protein Synthesis ◽

Hippocampal Synaptic Plasticity ◽

Local Protein

Abstract Activity-dependent local protein synthesis is critical for synapse-specific, persistent plasticity. Abnormalities in local protein synthesis have been implicated in psychiatric disorders. We have recently identified the translin/trax microRNA-degrading enzyme as a novel mediator of protein synthesis at activated synapses. Additionally, mice lacking translin/trax exhibit some of the behavioral abnormalities found in a mouse model of fragile X syndrome. Therefore, identifying signaling pathways interacting with translin/trax to support persistent synaptic plasticity is a translationally relevant goal. Here, as a first step to achieve this goal, we have assessed the requirement of translin/trax for multiple hippocampal synaptic plasticity paradigms that rely on distinct molecular mechanisms. We found that mice lacking translin/trax exhibited selective impairment in a form of persistent hippocampal plasticity, which requires postsynaptic PKA activity. In contrast, enduring forms of plasticity that are dependent on presynaptic PKA were unaffected. Furthermore, these mice did not display exaggerated metabotropic glutamate receptor-mediated long-term synaptic depression, a hallmark of the mouse model of fragile X syndrome. Taken together, these findings demonstrate that translin/trax mediates long-term synaptic plasticity that is dependent on postsynaptic PKA signaling.

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Homeostatic Inhibitory Control of Cortical Hyperexcitability in Fragile X Syndrome

10.1101/459511 ◽

2018 ◽

Author(s):

C.A. Cea-Del Rio ◽

A. Nunez-Parra ◽

S. Freedman ◽

D. Restrepo ◽

M.M. Huntsman

Keyword(s):

Synaptic Plasticity ◽

Mouse Model ◽

Somatosensory Cortex ◽

Fragile X Syndrome ◽

Fragile X ◽

Synaptic Function ◽

Network Activity ◽

Inhibitory Input ◽

Long Term Depression

AbstractIn mouse models of Fragile X Syndrome (FXS), cellular and circuit hyperexcitability are a consequence of altered brain development [reviewed in (Contractor et al., 2015)]. Mechanisms that favor or hinder plasticity of synapses could affect neuronal excitability. This includes inhibitory long term depression (I-LTD) – a heterosynaptic form of plasticity that requires the activation of metabotropic glutamate receptors (mGluRs). Differential circuit maturation leads to shifted time points for critical periods of synaptic plasticity across multiple brain regions (Harlow et al., 2010; He et al., 2014), and disruptions of the development of excitatory and inhibitory synaptic function are also observed both during development and into adulthood (Vislay et al., 2013). However, little is known about how this hyperexcitable environment affects inhibitory synaptic plasticity. Our results demonstrate that the somatosensory cortex of the Fmr1 KO mouse model of FXS exhibits increased GABAergic spontaneous activity, a faulty mGluR-mediated inhibitory input and impaired plasticity processes. We find the overall diminished mGluR activation in the Fmr1 KO mice leads to both a decreased spontaneous inhibitory postsynaptic input to principal cells and also to a disrupted form of inhibitory long term depression (I-LTD). In cortical synapses, this I-LTD is dependent on mGluR activation and the mobilization endocannabinoids (eCBs). Notably, these data suggest enhanced hyperexcitable phenotypes in FXS may be homeostatically counterbalanced by the inhibitory drive of the network and its altered response to mGluR modulation.Significance StatementFragile X Syndrome is a pervasive neurodevelopmental disorder characterized by intellectual disability, autism, epilepsy, anxiety and altered sensory sensitivity. In both in vitro and in vivo recordings in the somatosensory cortex of the Fmr1 knockout mouse model of Fragile X Syndrome we show that hyperexcitable network activity contributes to ineffective synaptic plasticity at inhibitory synapses. This increased excitability prevents cortical circuits from adapting to sensory information via ineffective plasticity mechanisms.

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Selective role of the translin/trax RNase complex in hippocampal synaptic plasticity

10.1101/2020.05.19.105189 ◽

2020 ◽

Cited By ~ 1

Author(s):

Alan Jung Park ◽

Mahesh Shivarama Shetty ◽

Jay M. Baraban ◽

Ted Abel

Keyword(s):

Protein Synthesis ◽

Synaptic Plasticity ◽

Mouse Model ◽

Fragile X Syndrome ◽

Metabotropic Glutamate Receptor ◽

Fragile X ◽

Local Protein Synthesis ◽

Hippocampal Synaptic Plasticity ◽

Local Protein

AbstractActivity-dependent local protein synthesis is critical for synapse-specific, persistent plasticity. Abnormalities in local protein synthesis have been implicated in psychiatric disorders. We have recently identified the translin/trax microRNA-degrading enzyme as a novel mediator of protein synthesis at activated synapses. Additionally, mice lacking translin/trax exhibit some of the behavioral abnormalities found in a mouse model of fragile X syndrome. Therefore, identifying signaling pathways interacting with translin/trax to support persistent synaptic plasticity is a translationally relevant goal. Here, as a first step to achieve this goal, we have assessed the requirement of translin/trax for multiple hippocampal synaptic plasticity paradigms that rely on distinct molecular mechanisms. We found that mice lacking translin/trax exhibited selective impairment in a form of persistent hippocampal plasticity, which requires postsynaptic PKA activity. In contrast, enduring forms of plasticity that are dependent on presynaptic PKA were unaffected. Furthermore, these mice did not display exaggerated metabotropic glutamate receptor-mediated long-term synaptic depression, a hallmark of the mouse model of fragile X syndrome. Taken together, these findings demonstrate that translin/trax mediates long-term synaptic plasticity that is dependent on postsynaptic PKA signaling.

Download Full-text