FXR1P Limits Long-Term Memory, Long-Lasting Synaptic Potentiation, and De Novo GluA2 Translation

Cook, Denise; Nuro, Erin; Jones, Emma V.; Altimimi, Haider F.; Farmer, W. Todd; Gandin, Valentina; Hanna, Edith; Zong, Ruiting; Barbon, Alessandro; Nelson, David L.; Topisirović, Ivan; Rochford, Joseph; Stellwagen, David; Béı̈que, Jean-Claude; Murai, Keith K.

doi:10.1016/j.celrep.2014.10.028

Cited by 41 publications

(53 citation statements)

References 56 publications

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“…As mentioned above, FXR1P has been detected in neurons at dendritic spines where it is associated with ribosomes, suggesting a role in both mRNA transport and translation (Cook et al, 2011). Accordingly, a very recent paper using a conditional Fxr1 KO reveals a role of FXR1P in Long Term Potentiation (LTP) and memory storage (Cook et al, 2014). Interestingly, FXR1P limits the synthesis and synaptic incorporation of the AMPA GluA2 subunit but this ability is not shared by FMRP or FXR2P, highlighting a specific role of FXR1P in synaptic plasticity (Cook et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…Accordingly, a very recent paper using a conditional Fxr1 KO reveals a role of FXR1P in Long Term Potentiation (LTP) and memory storage (Cook et al, 2014). Interestingly, FXR1P limits the synthesis and synaptic incorporation of the AMPA GluA2 subunit but this ability is not shared by FMRP or FXR2P, highlighting a specific role of FXR1P in synaptic plasticity (Cook et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

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Fragile X mental retardation protein (FMRP) interacting proteins exhibit different expression patterns during development

Bonaccorso

Spatuzza

Marco

et al. 2015

Intl J of Devlp Neuroscience

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Fragile X syndrome is caused by the lack of expression of fragile X mental retardation protein (FMRP), an RNA-binding protein involved in mRNA transport and translation. FMRP is a component of mRNA ribonucleoprotein complexes and it can interact with a range of proteins either directly or indirectly, as demonstrated by two-hybrid selection and co-immunoprecipitation, respectively. Most of FMRP-interacting proteins are RNA-binding proteins such as FXR1P, FXR2P and 82-FIP. Interestingly, FMRP can also interact directly with the cytoplasmic proteins CYFIP1 and CYFIP2, which do not bind RNA and link FMRP to the RhoGTPase pathway. The interaction with these different proteins may modulate the functions of FMRP by influencing its affinity to RNA and by affecting the FMRP ability of cytoskeleton remodeling through Rho/Rac GTPases. To better define the relationship of FMRP with its interacting proteins during brain development, we have analyzed the expression pattern of FMRP and its interacting proteins in the cortex, striatum, hippocampus and cerebellum at different ages in wild type (WT) mice. FMRP and FXR2P were strongly expressed during the first week and gradually decreased thereafter, more rapidly in the cerebellum than in the cortex. FXR1P was also expressed early and showed a reduction at later stages of development with a similar developmental pattern in these two regions. CYFIP1 was expressed at all ages and peaked in the third post-natal week. In contrast, CYFIP2 and 82-FIP (only in forebrain regions) were moderately expressed at P3 and gradually increased after P7. In general, the expression pattern of each protein was similar in the regions examined, except for 82-FIP, which exhibited a strong expression at P3 and low levels at later developmental stages in the cerebellum. Our data indicate that FMRP and its interacting proteins have distinct developmental patterns of expression and suggest that FMRP may be preferentially associated to certain proteins in early and late developmental periods. In particular, the RNA-binding and cytoskeleton remodeling functions of FMRP may be differently modulated during development.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Fragile X mental retardation protein (FMRP) interacting proteins exhibit different expression patterns during development

Bonaccorso

Spatuzza

Marco

et al. 2015

Intl J of Devlp Neuroscience

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“…Furthermore, FXR1P has been recently identified as a negative regulator for the translation of the ionotopic-glutamate AMPA receptor subunit GluA2. As a consequence of this, FXR1P would act as an inhibitor of protein synthesis-dependent longterm potentiation (49). In this context, it is possible that by increasing FXR1P, GSK3β inhibition can act as a buffer by limiting synaptic plasticity.…”

Section: Discussionmentioning

confidence: 99%

FXR1P is a GSK3β substrate regulating mood and emotion processing

Del’Guidice

Latapy

Rampino

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

112

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Inhibition of glycogen synthase kinase 3β (GSK3β) is a shared action believed to be involved in the regulation of behavior by psychoactive drugs such as antipsychotics and mood stabilizers. However, little is known about the identity of the substrates through which GSK3β affects behavior. We identified fragile X mental retardation-related protein 1 (FXR1P), a RNA binding protein associated to genetic risk for schizophrenia, as a substrate for GSK3β. Phosphorylation of FXR1P by GSK3β is facilitated by prior phosphorylation by ERK2 and leads to its down-regulation. In contrast, behaviorally effective chronic mood stabilizer treatments in mice inhibit GSK3β and increase FXR1P levels. In line with this, overexpression of FXR1P in the mouse prefrontal cortex also leads to comparable mood-related responses. Furthermore, functional genetic polymorphisms affecting either FXR1P or GSK3β gene expression interact to regulate emotional brain responsiveness and stability in humans. These observations uncovered a GSK3β/FXR1P signaling pathway that contributes to regulating mood and emotion processing. Regulation of FXR1P by GSK3β also provides a mechanistic framework that may explain how inhibition of GSK3β can contribute to the regulation of mood by psychoactive drugs in mental illnesses such as bipolar disorder. Moreover, this pathway could potentially be implicated in other biological functions, such as inflammation and cell proliferation, in which FXR1P and GSK3 are known to play a role.

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“…Even in the latter case, anti-translational activity may be relatively selective, as regulated translation of mRNAs with highly complex 5’UTRs is more sensitive to disruptions of ribosome supply than constitutive translation of housekeeping mRNAs [62]. Of note, 5’UTR-dependent regulation of translation contributes to hippocampal LTP which may share a common mechanism with PTZ kindling as discussed above [63,56,57]. …”

Section: Discussionmentioning

confidence: 99%

RNA Polymerase 1 Is Transiently Regulated by Seizures and Plays a Role in a Pharmacological Kindling Model of Epilepsy

et al. 2018

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Ribosome biogenesis, including the RNA polymerase 1 (Pol1)-mediated transcription of rRNA, is regulated by the pro-epileptogenic mTOR pathway. Therefore, hippocampal Pol1 activity was examined in mouse models of epilepsy including kainic acid- and pilocarpine-induced status epilepticus (SE) as well as a single seizure in response to pentylenetetrazole (PTZ). Elevated 47S pre-rRNA levels were present acutely after induction of SE suggesting activation of Pol1. Conversely, after a single seizure, 47S pre-rRNA was transiently downregulated with increased levels of unprocessed 18S rRNA precursors in the cornu Ammonis (CA) region. At least in the dentate gyrus (DG), the pilocarpine SE-mediated transient activation of Pol1 did not translate into long-term changes of pre-rRNA levels or total ribosome content. Unaltered hippocampal ribosome content was also found after a 20-day PTZ kindling paradigm with increasing pro-convulsive effects of low dose PTZ that was injected every other day. However, after selectively deleting the essential Pol1 co-activator, transcription initiation factor-1A (Tif1a/Rrn3) from excitatory neurons, PTZ kindling was impaired while DG total ribosome content was moderately reduced and no major neurodegeneration was observed throughout the hippocampus. Therefore, Pol1 activity of excitatory neurons is required for PTZ kindling. As seizures affect ribosome biogenesis without long-term effects on the total ribosome content, such a requirement may be associated with a need to produce specialized ribosomes that promote pro-epileptic plasticity.

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FXR1P Limits Long-Term Memory, Long-Lasting Synaptic Potentiation, and De Novo GluA2 Translation

Cited by 41 publications

References 56 publications

Fragile X mental retardation protein (FMRP) interacting proteins exhibit different expression patterns during development

Fragile X mental retardation protein (FMRP) interacting proteins exhibit different expression patterns during development

FXR1P is a GSK3β substrate regulating mood and emotion processing

RNA Polymerase 1 Is Transiently Regulated by Seizures and Plays a Role in a Pharmacological Kindling Model of Epilepsy

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