RTP801 regulates motor cortex synaptic transmission and learning

Pérez‐Sisqués, Leticia; Martín‐Flores, Núria; Masana, Mercè; Solana‐Balaguer, Júlia; Llobet, A; Romaní-Aumedes, Joan; Canal, Mercè; Campoy‐Campos, Genís; García-García, Esther; Sánchez-Fernández, Núria; Fernández-García, Sara; Gilbert, James P.; Rodrı́guez, Manuel J.; Man, Heng Ye; Feinstein, Elena; Williamson, David L.; Soto, David; Gasull, Xavier; Alberch, Jordi; Malagelada, Cristina

doi:10.1016/j.expneurol.2021.113755

Cited by 5 publications

(7 citation statements)

References 57 publications

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“…We also confirmed the decreased levels of synaptic markers such as PSD-95, GluA1 AMPAR subunit, and TrkB.FL receptor in the R6/1 mouse hippocampus [ 18 , 48 , 49 ]. Remarkably, a mild restoration of GluA1 and TrkB.FL synaptic levels was observed, in line with previous results from our group [ 29 , 31 ]. Indeed, the RTP801 total knockout mouse shows increased levels of cortical GluA1 and TrkB.FL, in good correlation with the enhanced synaptic transmission observed in these animals [ 31 ], and RTP801 striatal silencing in the R6/1 model enhances the expression of both synaptic proteins in this brain area [ 29 ].…”

Section: Discussionsupporting

confidence: 92%

“…Remarkably, a mild restoration of GluA1 and TrkB.FL synaptic levels was observed, in line with previous results from our group [ 29 , 31 ]. Indeed, the RTP801 total knockout mouse shows increased levels of cortical GluA1 and TrkB.FL, in good correlation with the enhanced synaptic transmission observed in these animals [ 31 ], and RTP801 striatal silencing in the R6/1 model enhances the expression of both synaptic proteins in this brain area [ 29 ]. On the one hand, AMPAR subunit GluA1 confers calcium permeability to the receptor, promoting the activation of intracellular signaling cascades critical for synaptic transmission and plasticity [ 55 , 56 , 57 , 58 ].…”

Section: Discussionsupporting

confidence: 92%

“…RTP801 mediates synaptic transmission and motor learning behavior in physiological conditions. Moreover, RTP801 abrogation increases GluA1 and TrkB levels [ 31 ]. RTP801 protein levels are also elevated in Parkinson’s disease (PD) [ 32 , 33 ], major depression [ 34 ] and Alzheimer’s disease (AD) [ 35 ].…”

Section: Introductionmentioning

confidence: 99%

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RTP801/REDD1 Is Involved in Neuroinflammation and Modulates Cognitive Dysfunction in Huntington’s Disease

et al. 2021

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RTP801/REDD1 is a stress-regulated protein whose levels are increased in several neurodegenerative diseases such as Parkinson’s, Alzheimer’s, and Huntington’s diseases (HD). RTP801 downregulation ameliorates behavioral abnormalities in several mouse models of these disorders. In HD, RTP801 mediates mutant huntingtin (mhtt) toxicity in in vitro models and its levels are increased in human iPSCs, human postmortem putamen samples, and in striatal synaptosomes from mouse models of the disease. Here, we investigated the role of RTP801 in the hippocampal pathophysiology of HD. We found that RTP801 levels are increased in the hippocampus of HD patients in correlation with gliosis markers. Although RTP801 expression is not altered in the hippocampus of the R6/1 mouse model of HD, neuronal RTP801 silencing in the dorsal hippocampus with shRNA containing AAV particles ameliorates cognitive alterations. This recovery is associated with a partial rescue of synaptic markers and with a reduction in inflammatory events, especially microgliosis. Altogether, our results indicate that RTP801 could be a marker of hippocampal neuroinflammation in HD patients and a promising therapeutic target of the disease.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 92%

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RTP801/REDD1 Is Involved in Neuroinflammation and Modulates Cognitive Dysfunction in Huntington’s Disease

et al. 2021

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“…Spikes were identified and quantified as previously described [ 89 ]. In brief, we applied a high-pass filter with a 200 Hz Butterworth 2nd-order filter.…”

Section: Methodsmentioning

confidence: 99%

Meridianins Inhibit GSK3β In Vivo and Improve Behavioral Alterations Induced by Chronic Stress

et al. 2022

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Major depression disorder (MDD) is a severe mental alteration with a multifactorial origin, and chronic stress is one of the most relevant environmental risk factors associated with MDD. Although there exist some therapeutical options, 30% of patients are still resistant to any type of treatment. GSK3β inhibitors are considered very promising therapeutic tools to counteract stress-related affectations. However, they are often associated with excessive off-target effects and undesired secondary alterations. Meridianins are alkaloids with an indole framework linked to an aminopyrimidine ring from Antarctic marine ascidians. Meridianins could overcome several of the aforementioned limitations since we previously demonstrated that they can inhibit GSK3β activity without the associated neurotoxic or off-target effects in rodents. Here, we show that meridianins delivered into the lateral ventricle inhibited GSK3β in several brain regions involved with stress-related symptoms. We also observed changes in major signaling pathways in the prefrontal cortex (Akt and PKA) and hippocampus (PKC and GluR1). Moreover, meridianins increased synaptic activity, specifically in the CA1 but not in the CA3 or other hippocampal subfields. Finally, we chronically treated the mice subjected to an unpredictable mild chronic stress (CUMS) paradigm with meridianins. Our results showed improvements produced by meridianins in behavioral alterations provoked by CUMS. In conclusion, meridianins could be of therapeutic interest to patients with stress-related disorders such as MDD.

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“…Besides, PSD-95 or VGLUT-1 puncta were increased after EVs treatment (Figure S4A,B). Nonetheless, PSD-95 or VGLUT-1 levels (mean intensity), as a readout of synaptic strength of the individual spines, and the area of the clusters, as a readout of spine maturation (Arellano et al, 2007;Béïque & Andrade, 2003;Pérez-Sisqués et al, 2021), remained unaltered (Figure S4C-E). This might indicate that, although EVs-treatment increases the number of synapses, it might not trigger their consolidation.…”

Section:  Neuron-derived Evs Induce Spine Formation In Recipient Ne...mentioning

confidence: 99%

Neuron‐derived extracellular vesicles contain synaptic proteins, promote spine formation, activate TrkB‐mediated signalling and preserve neuronal complexity

Solana‐Balaguer,

Campoy‐Campos,

Martín‐Flores

et al. 2023

J of Extracellular Vesicle

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Extracellular vesicles (EVs) play an important role in intercellular communication as carriers of signalling molecules such as bioactive miRNAs, proteins and lipids. EVs are key players in the functioning of the central nervous system (CNS) by influencing synaptic events and modulating recipient neurons. However, the specific role of neuron‐to‐neuron communication via EVs is still not well understood. Here, we provide evidence that primary neurons uptake neuron‐derived EVs in the soma, dendrites, and even in the dendritic spines, and carry synaptic proteins. Neuron‐derived EVs increased spine density and promoted the phosphorylation of Akt and ribosomal protein S6 (RPS6), via TrkB‐signalling, without impairing the neuronal network activity. Strikingly, EVs exerted a trophic effect on challenged nutrient‐deprived neurons. Altogether, our results place EVs in the spotlight for synaptic plasticity modulation as well as a possible therapeutic tool to fight neurodegeneration.

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RTP801 regulates motor cortex synaptic transmission and learning

Cited by 5 publications

References 57 publications

RTP801/REDD1 Is Involved in Neuroinflammation and Modulates Cognitive Dysfunction in Huntington’s Disease

RTP801/REDD1 Is Involved in Neuroinflammation and Modulates Cognitive Dysfunction in Huntington’s Disease

Meridianins Inhibit GSK3β In Vivo and Improve Behavioral Alterations Induced by Chronic Stress

Neuron‐derived extracellular vesicles contain synaptic proteins, promote spine formation, activate TrkB‐mediated signalling and preserve neuronal complexity

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