Rapamycin restores BDNF-LTP and the persistence of long-term memory in a model of Down's syndrome

Andrade-Talavera, Yuniesky; Benito, Itziar; Casañas, Juan José; Rodríguez‐Moreno, Antonio; Montesinos, Marı́a Luz

doi:10.1016/j.nbd.2015.09.005

Cited by 34 publications

(34 citation statements)

References 49 publications

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“…Regarding synaptic plasticity, we found that mGluR-LTD is enhanced in Ts1Cje hippocampus. Many forms of synaptic plasticity have been characterized in the Ts1Cje and other DS mouse models (Siarey et al, 2005;Belichenko et al 2007;Andrade-Talavera et al, 2015). mGluR-LTD has been previously studied in the Ts65Dn model but, in contrast to our results, a normal hippocampal mGluR-LTD, compared to WT, was found (Scott-McKean and Costa, 2011).…”

Section: Discussioncontrasting

confidence: 99%

“…Afterwards, other groups reported mTOR hyperactivation in postmortem DS brain (Iyer et al, 2014;Perluigi et al, 2014). We have also found that rapamycin restored both BDNF-LTP and the persistence of LTM in the Barnes maze (Andrade-Talavera et al, 2015). We have here analyzed the performance of Ts1Cje animals in another hippocampal-dependent task, the NOR and found a clear memory index reduction in Ts1Cje mice, compared to WT.…”

Section: Discussionmentioning

confidence: 57%

“…Furthermore, we also found that the BDNF-dependent Long Term Potentiation (LTP) is abolished in the Ts1Cje hippocampus, and that the specific mTOR inhibitor rapamycin fully restored this type of plasticity (Andrade-Talavera et al, 2015). Moreover, we observed that the impaired persistence of long-term memory (LTM) in the Barnes maze of Ts1Cje animals was also restored by rapamycin treatment (Andrade-Talavera et al, 2015).…”

Section: Introductionmentioning

confidence: 79%

“…In a previous work we found that Ts1Cje mice showed neither learning nor memory deficits in the Barnes maze test. Nevertheless, these mice presented impaired LTM persistence, which was restored by rapamycin (Andrade-Talavera et al, 2015). To further characterize the behavior of this DS mouse model, we performed a NOR test.…”

Section: Memory Nor Test Is Impaired In Ts1cje Mice and Is Slightly Imentioning

confidence: 99%

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Prenatal treatment with rapamycin restores enhanced hippocampal mGluR-LTD and mushroom spine size in a Down’s syndrome mouse model

Montesinos

Urbano-Gámez

Benito

et al. 2020

Preprint

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Down syndrome (DS) is the most frequent genetic cause of intellectual disability including hippocampal-dependent memory deficits. We have previously reported hippocampal mTOR (mammalian target of rapamycin) hyperactivation, and related plasticity as well as memory deficits in Ts1Cje mice, a DS experimental model. Here we report that performance of Ts1Cje mice in novel object recognition (NOR) is impaired, but it is ameliorated by rapamycin treatment. Proteome characterization of hippocampal synaptoneurosomes (SNs) from these mice predicted an alteration of synaptic plasticity pathways, including long term depression (LTD), which was reversed by rapamycin. Accordingly, mGluR-LTD (metabotropic Glutamate Receptor-Long Term Depression) is enhanced in the hippocampus of Ts1Cje mice and this is correlated with an increased proportion of a particular category of mushroom spines in hippocampal pyramidal neurons. Remarkably, prenatal treatment of these mice with rapamycin normalized both phenotypes, supporting the therapeutic potential of rapamycin/rapalogs for DS intellectual disability.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 57%

Section: Introductionmentioning

confidence: 79%

Section: Memory Nor Test Is Impaired In Ts1cje Mice and Is Slightly Imentioning

confidence: 99%

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Prenatal treatment with rapamycin restores enhanced hippocampal mGluR-LTD and mushroom spine size in a Down’s syndrome mouse model

Montesinos

Urbano-Gámez

Benito

et al. 2020

Preprint

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“…Since BDNF signaling is impaired in AS mice, whether rapamycin treatment improves BDNF signaling remains an interesting question to be addressed. It is noteworthy that a recent study showed that rapamycin treatment also restored exogenous BDNF-induced LTP in a mouse model of Down syndrome [45]. …”

Section: Discussionmentioning

confidence: 99%

mTORC1–S6K1 inhibition or mTORC2 activation improves hippocampal synaptic plasticity and learning in Angelman syndrome mice

Sun

Liu

Tran

et al. 2016

Cell. Mol. Life Sci.

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Emerging evidence is implicating abnormal activation of the mechanistic target of rapamycin (mTOR) pathway in several monogenetic neuropsychiatric disorders, including Angelman syndrome (AS), which is caused by deficiency in maternally inherited UBE3A. Using an AS mouse model, we show that semi-chronic rapamycin treatment improves long-term potentiation (LTP) and actin polymerization in hippocampal slices, spine morphology, and fear-conditioning learning. Activity of mTORC1 and of its downstream substrate, S6K1, was increased in hippocampus of AS mice. However, mTORC2 activity, as reflected by PKCα levels, was decreased. Both increased mTORC1 and decreased mTORC2 activity were reversed by semi-chronic rapamycin treatment. Acute treatment of hippocampal slices from AS mice with rapamycin or an S6K1 inhibitor, PF4708671, improved LTP, restored actin polymerization, and normalized mTORC1 and mTORC2 activity. These treatments also reduced Arc levels in AS mice. Treatment with Torin 1, an inhibitor of both mTORC1 and mTORC2, partially rescued LTP and actin polymerization in hippocampal slices from AS mice, while partially impairing them in wild-type (WT) mice. Torin 1 decreased mTORC1 and increased mTORC2 activity in slices from AS mice but inhibited mTORC1 and decreased mTORC2 in WT mice. Finally, an mTORC2 activator, A-443654, increased hippocampal LTP in AS mice and actin polymerization in both WT and AS mice. Collectively, these results indicate that events set in motion by increased mTORC1 and decreased mTORC2 activities, including increased Arc translation and impaired actin remodeling, are crucial in AS pathogenesis. Therefore, selectively targeting these two master kinase complexes may provide new therapeutic approaches for AS treatment.

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Computational models of stimulus equivalence: An intersection for the study of symbolic behavior

Tovar

Torres-Chávez

Mofrad

et al. 2023

J Exper Analysis Behavior

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Stimulus equivalence is a central paradigm in the analysis of symbolic behavior, language, and cognition. It describes emergent relations between stimuli that were not explicitly trained and cannot be explained by primary stimulus generalization. In recent years, researchers have developed computational models to simulate the learning of equivalence relations. These models have been used to address primary theoretical and methodological issues in this field, such as exploring the underlying mechanisms that explain emergent equivalence relations and analyzing the effects of training and testing protocols on equivalence outcomes. Nonetheless, although these models build upon general learning principles, their operation is usually obscure for nonmodelers, and in the field of stimulus equivalence computational models have been developed with a variety of approaches, architectures, and algorithms that make it difficult to understand the scope and contributions of these tools. In this paper, we present the state of the art in computational modeling of stimulus equivalence. We seek to provide concise and accessible descriptions of the models' functioning and operation, highlight their main theoretical and methodological contributions, identify the existing software available for researchers to run experiments, and suggest future directions in the emergent field of computational modeling of stimulus equivalence.

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Rapamycin restores BDNF-LTP and the persistence of long-term memory in a model of Down's syndrome

Cited by 34 publications

References 49 publications

Prenatal treatment with rapamycin restores enhanced hippocampal mGluR-LTD and mushroom spine size in a Down’s syndrome mouse model

Prenatal treatment with rapamycin restores enhanced hippocampal mGluR-LTD and mushroom spine size in a Down’s syndrome mouse model

mTORC1–S6K1 inhibition or mTORC2 activation improves hippocampal synaptic plasticity and learning in Angelman syndrome mice

Computational models of stimulus equivalence: An intersection for the study of symbolic behavior

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