Metformin ameliorates core deficits in a mouse model of fragile X syndrome

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Abstract

Metformin treatment for 10 d rescues several behavioral deficits related to fragile X syndrome in adult Fmr1−/y mice.

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Autism-related deficits via dysregulated eIF4E-dependent translational control.

Christos Gkogkas, Arkady Khoutorsky, Israeli Ran … (2013)

Hyperconnectivity of neuronal circuits due to increased synaptic protein synthesis is thought to cause autism spectrum disorders (ASDs). The mammalian target of rapamycin (mTOR) is strongly implicated in ASDs by means of upstream signalling; however, downstream regulatory mechanisms are ill-defined. Here we show that knockout of the eukaryotic translation initiation factor 4E-binding protein 2 (4E-BP2)-an eIF4E repressor downstream of mTOR-or eIF4E overexpression leads to increased translation of neuroligins, which are postsynaptic proteins that are causally linked to ASDs. Mice that have the gene encoding 4E-BP2 (Eif4ebp2) knocked out exhibit an increased ratio of excitatory to inhibitory synaptic inputs and autistic-like behaviours (that is, social interaction deficits, altered communication and repetitive/stereotyped behaviours). Pharmacological inhibition of eIF4E activity or normalization of neuroligin 1, but not neuroligin 2, protein levels restores the normal excitation/inhibition ratio and rectifies the social behaviour deficits. Thus, translational control by eIF4E regulates the synthesis of neuroligins, maintaining the excitation-to-inhibition balance, and its dysregulation engenders ASD-like phenotypes.

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Metformin activates an atypical PKC-CBP pathway to promote neurogenesis and enhance spatial memory formation.

Jing WANG, Denis Gallagher, Loren M. DeVito … (2012)

Although endogenous recruitment of adult neural stem cells has been proposed as a therapeutic strategy, clinical approaches for achieving this are lacking. Here, we show that metformin, a widely used drug, promotes neurogenesis and enhances spatial memory formation. Specifically, we show that an atypical PKC-CBP pathway is essential for the normal genesis of neurons from neural precursors and that metformin activates this pathway to promote rodent and human neurogenesis in culture. Metformin also enhances neurogenesis in the adult mouse brain in a CBP-dependent fashion, and in so doing enhances spatial reversal learning in the water maze. Thus, metformin, by activating an aPKC-CBP pathway, recruits neural stem cells and enhances neural function, thereby providing a candidate pharmacological approach for nervous system therapy. Copyright © 2012 Elsevier Inc. All rights reserved.

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Dynamic translational and proteasomal regulation of fragile X mental retardation protein controls mGluR-dependent long-term depression.

Rebecca M. C. Spencer, Richard Paylor, Marcia Antion … (2006)

Genetic deletion of fragile X mental retardation protein (FMRP) has been shown to enhance mGluR-dependent long-term depression (LTD). Herein, we demonstrate that mGluR-LTD induces a transient, translation-dependent increase in FMRP that is rapidly degraded by the ubiquitin-proteasome pathway. Moreover, proteasome inhibitors abolished mGluR-LTD, and LTD was absent in mice that overexpress human FMRP. Neither translation nor proteasome inhibitors blocked the augmentation of mGluR-LTD in FMRP-deficient mice. In addition, mGluR-LTD is associated with rapid increases in the protein levels of FMRP target mRNAs in wild-type mice. Interestingly, the basal levels of these proteins were elevated and their synthesis was improperly regulated during mGluR-LTD in FMRP-deficient mice. Our findings indicate that hippocampal mGluR-LTD requires the rapid synthesis and degradation of FMRP and that mGluR-LTD triggers the synthesis of FMRP binding mRNAs. These findings indicate that the translation, ubiquitination, and proteolysis of FMRP functions as a dynamic regulatory system for controlling synaptic plasticity.

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Author and article information

Journal

Title: Nature Medicine

Abbreviated Title: Nat Med

Publisher: Springer Nature

ISSN (Print): 1078-8956

ISSN (Electronic): 1546-170X

Publication date Created: May 15 2017

Publication date (Print): May 15 2017

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DOI: 10.1038/nm.4335

PubMed ID: 28504725

SO-VID: ad33487e-c32d-4981-9a63-5c9b7c6a3914

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Metformin ameliorates core deficits in a mouse model of fragile X syndrome

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Most cited references 20

Autism-related deficits via dysregulated eIF4E-dependent translational control.

Metformin activates an atypical PKC-CBP pathway to promote neurogenesis and enhance spatial memory formation.

Dynamic translational and proteasomal regulation of fragile X mental retardation protein controls mGluR-dependent long-term depression.

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