Implicit learning impairment identified via predictive saccades in Huntington's disease correlates with extended cortico-striatal atrophy

Cortex ◽  
2019 ◽  
Vol 121 ◽  
pp. 89-103 ◽  
Author(s):  
Israel Vaca-Palomares ◽  
Donald C. Brien ◽  
Brian C. Coe ◽  
Adriana Ochoa-Morales ◽  
Leticia Martínez-Ruano ◽  
...  
1991 ◽  
Vol 29 (12) ◽  
pp. 1213-1221 ◽  
Author(s):  
Frederick W. Bylsma ◽  
George W. Rebok ◽  
Jason Brandt

2020 ◽  
Vol 11 (7) ◽  
Author(s):  
Núria Martín-Flores ◽  
Leticia Pérez-Sisqués ◽  
Jordi Creus-Muncunill ◽  
Mercè Masana ◽  
Sílvia Ginés ◽  
...  

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.


2012 ◽  
Vol 18 (4) ◽  
pp. 689-696 ◽  
Author(s):  
Marieke van Asselen ◽  
Inês Almeida ◽  
Filipa Júlio ◽  
Cristina Januário ◽  
Elzbieta Bobrowicz Campos ◽  
...  

AbstractHuntington's disease (HD) is a genetic neurodegenerative disorder affecting the basal ganglia. These subcortical structures are particularly important for motor functions, response selection and implicit learning. In the current study, we have assessed prodromal and symptomatic HD participants with an implicit contextual learning task that is not based on motor learning, but on a purely visual implicit learning mechanism. We used an implicit contextual learning task in which subjects need to locate a target among several distractors. In half of the trials, the positions of the distractors and target stimuli were repeated. By memorizing this contextual information, attention can be guided faster to the target stimulus. Nine symptomatic HD participants, 16 prodromal HD participants and 22 control subjects were included. We found that the responses of the control subjects were faster for the repeated trials than for the new trials, indicating that their visual search was facilitated when repeated contextual information was present. In contrast, no difference in response times between the repeated and new trials was found for the symptomatic and prodromal HD participants. The results of the current study indicate that both prodromal and symptomatic HD participants are impaired on an implicit contextual learning task. (JINS, 2012, 18, 1–8)


2020 ◽  
Author(s):  
Núria Martín-Flores ◽  
Leticia Pérez-Sisqués ◽  
Jordi Creus-Muncunill ◽  
Mercè Masana ◽  
Sílvia Ginés ◽  
...  

ABSTRACTRTP801/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.Ectopic mhtt was over expressed in cultured rat primary neurons. The protein levels of RTP801 were assessed in homogenates and crude synaptic fractions from human postmortem HD brains and mouse models of HD. 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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