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

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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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.

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

Molecular Brain ◽

10.1186/s13041-020-00691-5 ◽

2020 ◽

Vol 13 (1) ◽

Author(s):

Alan Jung Park ◽

Mahesh Shivarama Shetty ◽

Jay M. Baraban ◽

Ted Abel

Keyword(s):

Protein Synthesis ◽

Synaptic Plasticity ◽

Molecular Mechanisms ◽

Metabotropic Glutamate Receptor ◽

Fragile X ◽

Local Protein Synthesis ◽

Hippocampal Synaptic Plasticity ◽

Behavioral Abnormalities ◽

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, translin knockout (KO) mice, which lack translin/trax, exhibit some of the behavioral abnormalities found in a mouse model of fragile X syndrome (fragile X mental retardation protein-FMRP-KO mice). 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 protein kinase A (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 (mGluR-LTD), a hallmark of the FMRP KO mice. On the contrary, translin KO mice exhibited deficits in N-methyl-d-aspartate receptor (NMDAR) dependent LTD, a phenotype not observed in the FMRP knockouts. Taken together, these findings demonstrate that translin/trax mediates long-term synaptic plasticity that is dependent on postsynaptic PKA signaling and suggest that translin/trax and FMRP play distinct roles in hippocampal synaptic plasticity.

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

10.21203/rs.3.rs-29690/v2 ◽

2020 ◽

Author(s):

Alan Jung Park ◽

Mahesh Shivarama Shetty ◽

Jay M. Baraban ◽

Ted Abel

Keyword(s):

Protein Synthesis ◽

Synaptic Plasticity ◽

Molecular Mechanisms ◽

Metabotropic Glutamate Receptor ◽

Fragile X ◽

Local Protein Synthesis ◽

Hippocampal Synaptic Plasticity ◽

Behavioral Abnormalities ◽

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, translin knockout (KO) mice, which lack translin/trax, exhibit some of the behavioral abnormalities found in a mouse model of fragile X syndrome (fragile X mental retardation protein-FMRP-KO mice). 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 protein kinase A (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 (mGluR-LTD), a hallmark of the FMRP KO mice. . On the contrary, translin KO mice exhibited deficits in N-methyl-D-aspartate receptor (NMDAR) dependent LTD, a phenotype not observed in the FMRP knockouts. Taken together, these findings demonstrate that translin/trax mediates long-term synaptic plasticity that is dependent on postsynaptic PKA signaling and suggest that translin/trax and FMRP play distinct roles in hippocampal synaptic plasticity.

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A Requirement for Local Protein Synthesis in Neurotrophin-Induced Hippocampal Synaptic Plasticity

Science ◽

10.1126/science.273.5280.1402 ◽

1996 ◽

Vol 273 (5280) ◽

pp. 1402-1406 ◽

Cited By ~ 594

Author(s):

H. Kang ◽

E. M. Schuman

Keyword(s):

Protein Synthesis ◽

Synaptic Plasticity ◽

Local Protein Synthesis ◽

Hippocampal Synaptic Plasticity ◽

Local Protein

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Selective inhibition of glycogen synthase kinase 3α corrects pathophysiology in a mouse model of fragile X syndrome

Science Translational Medicine ◽

10.1126/scitranslmed.aam8572 ◽

2020 ◽

Vol 12 (544) ◽

pp. eaam8572 ◽

Cited By ~ 4

Author(s):

Patrick K. McCamphill ◽

Laura J. Stoppel ◽

Rebecca K. Senter ◽

Michael C. Lewis ◽

Arnold J. Heynen ◽

...

Keyword(s):

Protein Synthesis ◽

Mouse Model ◽

Fragile X Syndrome ◽

Animal Studies ◽

Metabotropic Glutamate Receptor ◽

Glycogen Synthase ◽

Fragile X ◽

Selective Inhibition ◽

Audiogenic Seizures ◽

Glycogen Synthase Kinase

Fragile X syndrome is caused by FMR1 gene silencing and loss of the encoded fragile X mental retardation protein (FMRP), which binds to mRNA and regulates translation. Studies in the Fmr1−/y mouse model of fragile X syndrome indicate that aberrant cerebral protein synthesis downstream of metabotropic glutamate receptor 5 (mGluR5) signaling contributes to disease pathogenesis, but clinical trials using mGluR5 inhibitors were not successful. Animal studies suggested that treatment with lithium might be an alternative approach. Targets of lithium include paralogs of glycogen synthase kinase 3 (GSK3), and nonselective small-molecule inhibitors of these enzymes improved disease phenotypes in a fragile X syndrome mouse model. However, the potential therapeutic use of GSK3 inhibitors has been hampered by toxicity arising from inhibition of both α and β paralogs. Recently, we developed GSK3 inhibitors with sufficient paralog selectivity to avoid a known toxic consequence of dual inhibition, that is, increased β-catenin stabilization. We show here that inhibition of GSK3α, but not GSK3β, corrected aberrant protein synthesis, audiogenic seizures, and sensory cortex hyperexcitability in Fmr1−/y mice. Although inhibiting either paralog prevented induction of NMDA receptor–dependent long-term depression (LTD) in the hippocampus, only inhibition of GSK3α impaired mGluR5-dependent and protein synthesis–dependent LTD. Inhibition of GSK3α additionally corrected deficits in learning and memory in Fmr1−/y mice; unlike mGluR5 inhibitors, there was no evidence of tachyphylaxis or enhanced psychotomimetic-induced hyperlocomotion. GSK3α selective inhibitors may have potential as a therapeutic approach for treating fragile X syndrome.

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Local Protein Synthesis and Spine Morphogenesis: Fragile X Syndrome and Beyond

Journal of Neuroscience ◽

10.1523/jneurosci.1790-06.2006 ◽

2006 ◽

Vol 26 (27) ◽

pp. 7151-7155 ◽

Cited By ~ 115

Author(s):

A. W. Grossman ◽

G. M. Aldridge ◽

I. J. Weiler ◽

W. T. Greenough

Keyword(s):

Protein Synthesis ◽

Fragile X Syndrome ◽

Fragile X ◽

Local Protein Synthesis ◽

Spine Morphogenesis ◽

Local Protein

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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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Metabotropic Receptor-Dependent Long-Term Depression Persists in the Absence of Protein Synthesis in the Mouse Model of Fragile X Syndrome

Journal of Neurophysiology ◽

10.1152/jn.01316.2005 ◽

2006 ◽

Vol 95 (5) ◽

pp. 3291-3295 ◽

Cited By ~ 165

Author(s):

Elena D. Nosyreva ◽

Kimberly M. Huber

Keyword(s):

Protein Synthesis ◽

Mental Retardation ◽

Mouse Model ◽

Fragile X Syndrome ◽

Rna Binding ◽

Fragile X ◽

Surface Expression ◽

Long Term Depression ◽

Fragile X Mental Retardation

Fragile X syndrome (FXS), a form of human mental retardation, is caused by loss of function mutations in the fragile X mental retardation gene ( FMR1). The protein product of FMR1, fragile X mental retardation protein (FMRP) is an RNA-binding protein and may function as a translational suppressor. Metabotropic glutamate receptor–dependent long-term depression (mGluR-LTD) in hippocampal area CA1 is a form of synaptic plasticity that relies on dendritic protein synthesis. mGluR-LTD is enhanced in the mouse model of FXS, Fmr1 knockout (KO) mice, suggesting that FMRP negatively regulates translation of proteins required for LTD. Here we examine the synaptic and cellular mechanisms of mGluR-LTD in KO mice and find that mGluR-LTD no longer requires new protein synthesis, in contrast to wild-type (WT) mice. We further show that mGluR-LTD in KO and WT mice is associated with decreases in AMPA receptor (AMPAR) surface expression, indicating a similar postsynaptic expression mechanism. However, like LTD, mGluR-induced decreases in AMPAR surface expression in KO mice persist in protein synthesis inhibitors. These results are consistent with recent findings of elevated protein synthesis rates and synaptic protein levels in Fmr1 KO mice and suggest that these elevated levels of synaptic proteins are available to increase the persistence of LTD without de novo protein synthesis.

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