scholarly journals Fingolimod (FTY720) enhances hippocampal synaptic plasticity and memory in Huntington's disease by preventing p75NTRup-regulation and astrocyte-mediated inflammation

2015 ◽  
Vol 24 (17) ◽  
pp. 4958-4970 ◽  
Author(s):  
Andrés Miguez ◽  
Gerardo García-Díaz Barriga ◽  
Verónica Brito ◽  
Marco Straccia ◽  
Albert Giralt ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Hippocampal Synaptic Plasticity

scholarly journals Pharmacological modulation of AMPA receptor surface diffusion restores hippocampal synaptic plasticity and memory in Huntington’s disease

2018 ◽  
Author(s):  
Hongyu Zhang ◽  
Chunlei Zhang ◽  
Jean Vincent ◽  
Diana Zala ◽  
Caroline Benstaali ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Signaling Pathway ◽  
Surface Diffusion ◽  
Ampa Receptors ◽  
Molecular Basis ◽  
Super Resolution ◽  
Long Term Potentiation ◽  
Hippocampal Synaptic Plasticity

AbstractImpaired hippocampal synaptic plasticity is increasingly considered to play an important role in cognitive impairment in Huntington’s disease (HD). However, the molecular basis of synaptic plasticity defects is not fully understood. Combining live-cell nanoparticle tracking and super-resolution imaging, we show that dysregulation of AMPA receptors (AMPARs) surface diffusion represents a molecular basis underlying the aberrant hippocampal synaptic plasticity during HD. AMPARs surface diffusion is increased in various HD neuronal models, which results in the failure of AMPARs surface stabilization after long-term potentiation (LTP) stimuli. This appears to result from a defective brain-derived neurotrophic factor (BDNF) - tyrosine receptor kinase B (TrkB) - Ca2+/calmodulin-dependent protein kinase II (CaMKII) signaling pathway that impacts the interaction between the AMPAR auxiliary subunit stargazin and postsynaptic density protein 95 (PSD-95). Notably, the disturbed AMPAR surface diffusion is rescued, via BDNF signaling pathway and by the antidepressant tianeptine. Tianeptine also restores the impaired LTP and hippocampus-dependent memory as well as anxiety/depression-like behavior in different HD mouse models. We thus unveil a mechanistic framework underlying hippocampal synaptic and memory dysfunction and propose a new perspective in HD treatment by targeting AMPAR surface diffusion.

scholarly journals Motor Cortex Plasticity Response to Acute Cardiorespiratory Exercise and Intermittent Theta-Burst Stimulation is Attenuated in Premanifest and Early Huntington’s Disease

2021 ◽  
Author(s):  
Sophie C. Andrews ◽  
Dylan Curtin ◽  
James P. Coxon ◽  
Julie C. Stout
Keyword(s):  
Synaptic Plasticity ◽  
Motor Cortex ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
High Intensity ◽  
High Intensity Exercise ◽  
Moderate Intensity ◽  
Theta Burst Stimulation ◽  
Burst Stimulation ◽  
Theta Burst

Abstract Huntington’s disease (HD) mouse models suggest that cardiovascular exercise may enhance neuroplasticity and delay disease signs, however, the effects of exercise on neuroplasticity in people with HD are unknown. Using a repeated-measures experimental design, we compared the effects of a single bout of high-intensity exercise, moderate-intensity exercise, or rest, on motor cortex synaptic plasticity in 14 HD CAG-expanded participants (9 premanifest & 5 early manifest) and 20 CAG-healthy control participants, using transcranial magnetic stimulation. Measures of cortico-motor excitability, short-interval intracortical inhibition and intracortical facilitation were obtained before and after a 20-minute bout of either high-intensity interval exercise, moderate-intensity continuous exercise, or rest, and again after intermittent theta burst stimulation (iTBS). HD participants showed less inhibition at baseline compared to controls. Whereas the control group showed increased excitability and facilitation following high-intensity exercise and iTBS, the HD group showed no differences in neuroplasticity responses following either exercise intensity or rest, with follow-up Bayesian analyses providing consistent evidence that these effects were absent in the HD group. These findings indicate that exercise-induced synaptic plasticity mechanisms in response to acute exercise may be attenuated in HD, and demonstrate the need for future research to further investigate exercise and plasticity mechanisms in people with HD.

An abnormal striatal synaptic plasticity may account for the selective neuronal vulnerability in Huntington's disease

2001 ◽  
Vol 22 (1) ◽  
pp. 61-62 ◽  
Author(s):  
D. Centonze ◽  
P. Gubellini ◽  
B. Picconi ◽  
E. Saulle ◽  
M. Tolu ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Selective Neuronal Vulnerability

scholarly journals Abnormal Synaptic Plasticity and Impaired Spatial Cognition in Mice Transgenic for Exon 1 of the Human Huntington's Disease Mutation

2000 ◽  
Vol 20 (13) ◽  
pp. 5115-5123 ◽  
Author(s):  
Kerry P. S. J. Murphy ◽  
Rebecca J. Carter ◽  
Lisa A. Lione ◽  
Laura Mangiarini ◽  
Amarbirpal Mahal ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Spatial Cognition ◽  
Disease Mutation ◽  
Exon 1

scholarly journals Reduced Fractalkine Levels Lead to Striatal Synaptic Plasticity Deficits in Huntington’s Disease

2020 ◽  
Vol 14 ◽  
Author(s):  
Anya Kim ◽  
Esther García-García ◽  
Marco Straccia ◽  
Andrea Comella-Bolla ◽  
Andrés Miguez ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Huntington's Disease ◽  
Huntington’S Disease

scholarly journals The mGluR5 positive allosteric modulator VU0409551 improves synaptic plasticity and memory of a mouse model of Huntington's disease

2018 ◽  
Vol 147 (2) ◽  
pp. 222-239 ◽  
Author(s):  
Juliana G. Doria ◽  
Jessica M. de Souza ◽  
Flavia R. Silva ◽  
Isabella G. Olmo ◽  
Toniana G. Carvalho ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Allosteric Modulator ◽  
Positive Allosteric Modulator

scholarly journals Synaptic RTP801 contributes to motor-learning dysfunction in Huntington’s disease

2020 ◽  
Vol 11 (7) ◽  
Author(s):  
Núria Martín-Flores ◽  
Leticia Pérez-Sisqués ◽  
Jordi Creus-Muncunill ◽  
Mercè Masana ◽  
Sílvia Ginés ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Motor Learning ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mouse Models ◽  
Motor Impairment ◽  
Motor Dysfunction ◽  
Protein Levels ◽  
Cellular Models ◽  
Learning Impairment

Abstract RTP801/REDD1 is a stress-responsive protein that mediates mutant huntingtin (mhtt) toxicity in cellular models and is up regulated in Huntington’s disease (HD) patients’ putamen. Here, we investigated whether RTP801 is involved in motor impairment in HD by affecting striatal synaptic plasticity. To explore this hypothesis, ectopic mhtt was over expressed in cultured rat primary neurons. Moreover, the protein levels of RTP801 were assessed in homogenates and crude synaptic fractions from human postmortem HD brains and mouse models of HD. Finally, striatal RTP801 expression was knocked down with adeno-associated viral particles containing a shRNA in the R6/1 mouse model of HD and motor learning was then tested. Ectopic mhtt elevated RTP801 in synapses of cultured neurons. RTP801 was also up regulated in striatal synapses from HD patients and mouse models. Knocking down RTP801 in the R6/1 mouse striatum prevented motor-learning impairment. RTP801 silencing normalized the Ser473 Akt hyperphosphorylation by downregulating Rictor and it induced synaptic elevation of calcium permeable GluA1 subunit and TrkB receptor levels, suggesting an enhancement in synaptic plasticity. These results indicate that mhtt-induced RTP801 mediates motor dysfunction in a HD murine model, revealing a potential role in the human disease. These findings open a new therapeutic framework focused on the RTP801/Akt/mTOR axis.

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