Trends in Neurosciences
Volume 27, Issue 7, 1 July 2004, Pages 370-377
Journal home page for Trends in Neurosciences

The mGluR theory of fragile X mental retardation

https://doi.org/10.1016/j.tins.2004.04.009Get rights and content

Abstract

Many of the diverse functional consequences of activating group 1 metabotropic glutamate receptors require translation of pre-existing mRNA near synapses. One of these consequences is long-term depression (LTD) of transmission at hippocampal synapses. Loss of fragile X mental retardation protein (FMRP), the defect responsible for fragile X syndrome in humans, increases LTD in mouse hippocampus. This finding is consistent with the growing evidence that FMRP normally functions as a repressor of translation of specific mRNAs. Here we present a theory that can account for diverse neurological and psychiatric aspects of fragile X syndrome, based on the assumption that many of the protein-synthesis-dependent functions of metabotropic receptors are exaggerated in fragile X syndrome. The theory suggests new directions for basic research as well as novel therapeutic approaches for the treatment of humans with fragile X, the most frequent inherited cause of mental retardation and an identified cause of autism.

Section snippets

From long-term synaptic depression to fragile X

Synaptic activity in the brain can trigger long-lasting changes in synaptic strength called long-term potentiation (LTP) and long-term depression (LTD). In neonates, the mechanisms of LTP seem to be important for retaining nascent synapses, whereas LTD mechanisms seem to be important for activity-guided synapse elimination. These same mechanisms, working in concert, contribute to learning and memory storage throughout postnatal life [14].

Understanding the mechanisms and functional significance

Emerging functions of FMRP

FMRP has been the subject of several recent reviews 3, 35, 36, 37. The excitement stems in part from the fact that fragile X syndrome is caused by a defect in a single gene, so understanding the function of the missing protein promises to provide insight into the pathophysiology of mental retardation, as well as cognition in general. However, the other reason for sudden interest is that FMRP has proven to be a fascinating molecule; it has captured the attention of neurobiologists interested in

Emerging functions of Gp1 mGluR-stimulated protein synthesis

It has been recognized for many years that the machinery for protein synthesis is present in the dendrites of cortical neurons near synapses 53, 54. Translation of pre-existing mRNAs can be activated in different ways by different signals (e.g. TrkB and NMDA receptor activation), but it is now very clear that activation of Gp1 mGluRs is a potent stimulus for local protein synthesis 52, 55, 56. Moreover, in cases where it has been specifically examined, many functional consequences of Gp1 mGluR

The mGluR theory of fragile X mental retardation

Our studies in the Fmr1 knockout mouse led us to suggest that exaggerated LTD could slow net synaptic maturation (by tipping the balance away from synapse gain towards synapse loss during the critical period of synaptogenesis), and therefore contribute to the developmental delay and cognitive impairment associated with fragile X (Figure 2b). However, FMRP is widely expressed in the brain, including most, if not all, neurons that express Gp1 mGluRs. We therefore considered the possibility that

Predictions and progress

A theory can be tested in two ways: (i) assessing the validity of the underlying assumptions, and (ii) spinning out their consequences [91]. The follow-up Banbury meeting in 2003 revealed that such tests are underway in several laboratories, in addition to our own. It is premature to report on these studies, but we can make some explicit predictions.

The first assumption suggests that many of the long-lasting responses to Gp1 mGluR activation will prove to be protein synthesis dependent. In the

Prospects for treatment of fragile X syndrome with Gp1 mGluR antagonists

The theory portrayed in Figure 3(a) suggests that it might be possible to overcome the loss of FMRP by dampening the protein synthesis triggered by activation of Gp1 mGluRs – this is the conceptual basis for the use of mGluR antagonists to reverse the fragile X phenotype. However, two caveats must be considered.

First, as mentioned previously, recent research suggests that although some proteins are overexpressed in the absence of FMRP (e.g. Arc and MAP1b) [44], others appear to be

Beyond fragile X

There is a great deal left to be learned about how protein synthesis is regulated by, and in turn influences, synaptic transmission in the brain. However, two things are certain: (i) FMRP is only one of many proteins and signaling pathways involved in the synaptic regulation of protein synthesis, and (ii) where there is biology, there is pathology. If we are correct that key aspects of fragile X are due to unregulated synaptic protein synthesis, it seems reasonable to anticipate that other

Acknowledgements

Supported in part by grants from FRAXA Research Foundation and the National Institute for Child Health and Human Development. We thank Mike Tranfaglia and Gül Dolen for helpful comments on the manuscript.

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