Document Detail

Fragile x syndrome and autism: from disease model to therapeutic targets.
Jump to Full Text
MedLine Citation:
PMID:  21547712     Owner:  NLM     Status:  PubMed-not-MEDLINE    
Autism is an umbrella diagnosis with several different etiologies. Fragile X syndrome (FXS), one of the first identified and leading causes of autism, has been modeled in mice using molecular genetic manipulation. These Fmr1 knockout mice have recently been used to identify a new putative therapeutic target, the metabotropic glutamate receptor 5 (mGluR5), for the treatment of FXS. Moreover, mGluR5 signaling cascades interact with a number of synaptic proteins, many of which have been implicated in autism, raising the possibility that therapeutic targets identified for FXS may have efficacy in treating multiple other causes of autism.
Gül Dölen; Mark F Bear
Publication Detail:
Type:  Journal Article     Date:  2009-05-12
Journal Detail:
Title:  Journal of neurodevelopmental disorders     Volume:  1     ISSN:  1866-1955     ISO Abbreviation:  J Neurodev Disord     Publication Date:  2009 Jun 
Date Detail:
Created Date:  2011-05-06     Completed Date:  2011-07-14     Revised Date:  2011-12-20    
Medline Journal Info:
Nlm Unique ID:  101483832     Medline TA:  J Neurodev Disord     Country:  United States    
Other Details:
Languages:  eng     Pagination:  133-40     Citation Subset:  -    
Department of Brain and Cognitive Sciences, Howard Hughes Medical Institute, The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA,
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Full Text
Journal Information
Journal ID (nlm-ta): J Neurodev Disord
ISSN: 1866-1947
ISSN: 1866-1955
Publisher: Springer US, Boston
Article Information
Download PDF
© Springer Science+Business Media, LLC 2009
Received Day: 7 Month: 2 Year: 2009
Accepted Day: 29 Month: 4 Year: 2009
Electronic publication date: Day: 12 Month: 5 Year: 2009
Print publication date: Month: 6 Year: 2009
Volume: 1 Issue: 2
First Page: 133 Last Page: 140
PubMed Id: 21547712
ID: 3164025
Publisher Id: 9015
DOI: 10.1007/s11689-009-9015-x

Fragile x syndrome and autism: from disease model to therapeutic targets
Gül Dölen12 Address:
Mark F. Bear1
1Department of Brain and Cognitive Sciences, Howard Hughes Medical Institute, The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA USA
2Alpert School of Medicine, Brown University, Providence, RI USA


Leo Kanner first described autism in 1943 [1]. It wasn’t until 1980 however, that autism was formally recognized in the Diagnostic and Statistical Manual of Mental disorders (DSM-III), and included as part of a new class, the Pervasive Developmental Disorders (PDD) [2]. At the same time, early psychodynamic theories of the etiology of autism [3] were being abandoned in favor of genetic ones. As early as 1975, case reports of monozygotic twins concordant for autism [4], followed by several systematic twin studies [510] substantiated the strong heritability of autism [1113].

Standardization of diagnostic criteria [2], and improvements in our ability to reliably detect chromosomal abnormalities [14] allowed for the identification in the early 1980’s of the first genetic cause of autism—Fragile X syndrome (FXS) [1517]. Subsequently, the Fragile X gene (FMR1) was discovered [18], and by 1994 the first animal model became available [19]. This genetically engineered Fmr1 knockout mouse (Fmr1 KO), has been validated for FXS, and is currently one of the leading animal models of autism [20].

Using this mutant mouse, we have been able to address the role of the FMR1 gene and the protein it encodes (fragile X mental retardation protein, FMRP) in brain development. Now, over 25 years since FXS was identified as a cause of autism, a new putative therapy has been proposed based on our understanding of the function of FMRP.

Modeling autism: a derailment of synaptic plasticity

Inherited mutations have the potential to disrupt brain development from the moment of fertilization onward; however, a genetic etiology does not preclude pathogenesis involving regulated processes later in development. Symptoms of autism typically present during the early postnatal period, usually between ages 1–3 years [20]. This epoch, the so-called ‘critical period’ [21], corresponds to a dynamic phase of brain development in which neurite outgrowth, maturation of inhibition and signaling, axon myelination, and synaptic plasticity are set in motion by the complex interplay of molecular genetic programs and experience [22]. Disruption of any of one of these processes could hypothetically lead to the characteristic symptoms of autism, which include abnormal social interaction and communication, stereotyped repetitive behaviors, often with co-morbid mental retardation, epilepsy, sleep disturbances, attention deficit and hyperactivity [23]. Thus, it has been tempting to speculate that the pathogenesis of autism involves a derailment of at least one of these developmental processes [2426]. Given this framework, studies of synaptic plasticity in the Fmr1 KO mouse have been an obvious priority.

A potential breakthrough in understanding the pathogenesis of fragile X came from studies of group 1 metabotropic glutamate receptors (Gp1 mGluR) [2731]. Gp1 mGluRs (which are further subdivided into mGluR1 and mGluR5 subtypes) couple to postsynaptic Gq-like G-proteins and phospholipase C (PLC) [32] as well as to extracellular signal-regulated kinase (ERK) transduction pathways [33, 34]. Their activation leads to the synthesis of new protein at the synapse [28, 35, 36], likely through the ERK signaling cascade [37, 38]. A functional consequence of Gp 1 mGluR-dependent protein synthesis in the hippocampus is long-term depression (LTD), a form of synaptic plasticity [29]. In the Fmr1 KO mouse, this mGluR-LTD is exaggerated and no longer protein synthesis-dependent [31, 39].

Meanwhile, studies of FMRP revealed that the expression of the protein is developmentally regulated [40, 41], such that in the post-natal brain it is largely cytoplasmic [42, 43], predominantly expressed in neurons [44, 45] and enriched postsynaptically at glutamatergic synapses [46]. Furthermore, FMRP is an RNA binding protein that co-localizes with polyribosomes [44, 4755] which are found at the base of dendritic spines where they are thought to mediate local translational control of the synapse [56]. Indeed, both in vitro and in vivo metabolic labeling studies have now directly shown that FMRP functions as a repressor of protein synthesis [5760].

Taken together, these findings led to the hypothesis that Gp1 mGluRs and FMRP might work in functional opposition to regulate mRNA translation at the synapse, and that in the absence of FMRP, unchecked mGluR-dependent protein synthesis leads to the pathogenesis of the disease (Fig. 1) [61]. We have recently tested this so-called ‘mGluR theory’ and shown that increased levels of protein synthesis in the Fmr1 KO mouse [59, 60], are restored to wild type (WT) levels by selective reduction of mGluR5 signaling [60]. This manipulation also significantly decreases the magnitude of Gp1 mGluR-LTD in Fmr1 KO mice, confirming the role of mGluR5 in producing the exaggerated synaptic plasticity phenotype [60].

The synapse is too small to be directly visualized by light microscopy. However, dendritic spines (the postsynaptic half of an excitatory synapse) can be visualized, and are used to estimate the number of excitatory synapses in the brain. Dendritic spines are highly modifiable structures, and changes in spine density and morphology have been correlated with synaptic plasticity [62]. Furthermore, abnormalities in dendritic spine morphology have long been associated with human mental retardation of unknown etiology [63], as well as with XLMR (x-linked mental retardation) [64], Down [65], Patau [65], Rett [66] and Fragile X syndromes [67, 68].

Dendritic spine structure is regulated by Gp1 mGluRs. Application of the selective mGluR5 agonist, DHPG, to cultured hippocampal neurons induces a protein synthesis dependent increase in the density of long thin spines [69]. Because DHPG application in cell culture also induces rapid protein synthesis dependent internalization of AMPA and NMDA receptors [70], receptor internalization may be the prelude to morphologic remodeling in response to plasticity inducing stimuli.

This response to stimulation with DHPG parallels spine changes seen in the Fmr1 KO mice, which lent support to the theory that exaggerated signaling through mGluR5 in the absence of FMRP could account for this morphologic correlate of synaptic plasticity [61]. Consistent with this idea, recent studies have shown that that AMPA receptor internalization is exaggerated in the absence of FMRP [71] and both this and the increased spine density phenotype seen in Fmr1 KO mice [60, 7278] are rescued by selective reduction in mGluR5 signaling [60, 71].

Modeling autism: plasticity in vivo

While these in vitro and ex vivo demonstrations of opponent regulation by FMRP and mGluR5 provided the necessary foundation for identifying and correcting synaptic abnormalities, we also wanted to determine whether these interactions regulate circuit-level responses in the intact animal. Landmark studies of in vivo ocular dominance plasticity (ODP) in monkeys and cats [7981] established a role for experience dependent plasticity in shaping the circuitry of the brain during the critical period. Moreover, because ODP occurs on the biologically relevant timescale, in response to perturbations of environmental stimuli using intrinsic patterns of neuronal activity, this paradigm is more readily translated to future studies in human patients (e.g. using visually evoked potentials [82] or transcranial magnetic stimulation [83]).

The development of transgenic technologies [19, 84, 85] and adaptation of the ODP paradigm to rodents [8691] has allowed us to answer mechanistic questions about experience dependent plasticity in vivo. For example, ODP is in-part mGluR5 dependent [60], requires protein synthesis [92], and signals through ERK transduction [93]. In the Fmr1 KO mouse, this plasticity is exaggerated, such that bidirectional modifications that require 7 days of monocular deprivation (MD) in WT mice [91], occur after only 3 days in the absence of FMRP [60]. Significantly this hyper-plastic response is reminiscent of the exaggerated synaptic plasticity phenotype seen in the hippocampal slice [31], and is likewise restored to WT levels by 50% reduction of mGluR5 signaling [60].

Modeling autism: behavioral phenotypes

As mentioned above, epilepsy and mental retardation are both co-morbid features of autism [23]—an estimated 5–38% of autistic patients have seizure or subclinical epileptiform activity [94] while 70% have cognitive impairment [95, 96](but see, [97][98]). Thus, an important goal for modeling the disease is to establish behavioral tasks that recapitulate these symptoms in the Fmr1 KO mouse.

An estimated 20% of human patients with FXS have epileptiform activity or generalized seizure [99, 100]. Audiogenic seizure (AGS) is a robust paradigm for inducing seizure in the Fmr1 KO [60, 101105] and recapitulates this neurologic feature of FXS and autism. Previous studies have not been able to account for increased epileptiform activity in Fmr1-KO mice by any of the anticipated mechanisms. For example, no differences have been observed between WT and Fmr1-KO mice in basal synaptic transmission, excitability, paired pulse facilitation, and long-term potentiation in the CA1 region of the hippocampus [106, 107].

Interestingly, it has been shown that agonists of group I mGluRs act as convulsants in rodents [32, 108] while selective Gp I mGluR antagonists block seizures in a range of rodent models of epilepsy [105, 109, 110]. Increases in epileptiform activity in response to mGluR5 stimulation are protein synthesis dependent [111, 112], suggesting that in addition to synapse specific changes, circuit level modulation of excitability is sensitive to the state of mGluR5 dependent protein synthesis [113]. Consistent with this idea, AGS seen in the Fmr1 KO is attenuated by 50% reduction of mGluR5 signaling [60].

Despite the moderate to severe mental retardation seen in human patients with FXS [114], cognitive phenotypes in the Fmr1 KO mice have been difficult to model [107, 115117]. Inhibitory avoidance (IA) is a contextual (fear) conditioning paradigm used in animals to test hippocampus-based associative learning and memory [118]. IA extinction (IAE) is a paradigm that tests those conditioned responses in the face of contradictory contextual (safe) conditioning [119]. While IA learning is normal in Fmr1 KO mice on the C57-Bl6 background [19, 60], we have recently identified an IAE phenotype in the Fmr1 KO [60].

Although the synaptic mechanisms underlying IAE are not currently known, this behavior, like mGluR5-LTD, is protein synthesis dependent [119]. Furthermore, since both mGluR5-LTD and IAE are exaggerated in the Fmr1 KO mice and rescued by reduction of mGluR5 signaling [60], one interesting possibility is that mGluR5 LTD is the cellular mechanism subserving IAE learning. This mechanism is likely distinct from that which subserves IA, since IA training induces NMDA-LTP [120]and neither IA nor NMDA-LTP [106, 107] is disrupted in the Fmr1 KO on the C57-Bl6 background.

Therapeutic implications

In summary, we have discovered that FMRP is a protein that acts to regulate protein synthesis and synaptic plasticity triggered by Gp1 mGluRs. Understanding this balance between FMRP and mGluR-5 has allowed us to restore normal function in the Fmr1 KO model of autism—metabolic, morphologic, synaptic, circuit, and behavioral disruptions can all be corrected by reducing mGluR5 signaling by 50% [60]. Currently clinical trials based these and related findings are under way to determine safety and efficacy of mGluR modifying drugs in human patients with FXS and autism.

To put these findings in context, it is important to remember that mGluRs and FMRP do not exist in isolation at the synapse. As shown in Fig. 2, a number of other synaptic proteins that interact with the mGluRs either by direct physical contact or biochemical cascades, have also been identified as autism candidate genes [121126] or single gene disorders associated with autism [127134].

For example, Gp1 mGluR signaling converges on transduction cascades also implicated in PTEN hamartoma syndrome and Tuberous sclerosis complex (TSC), which are other single gene causes of autism. PTEN inhibits PI3K-dependent signaling, which couples Gq signaling to the mTOR/S6K pathway for protein synthesis [128]. TSC 1/2 inhibits this same mTOR pathway, by acting as a GTPase-activating protein for the Ras-related small G protein Rheb [135].

Structural proteins within the synapse also interconnect Gp1 mGluRs to various autism candidate genes. For example, both Shank and Homer proteins crosslink mGluR5 to the postsynaptic density [136], and misregulated Homer1b and PSD-95 have been implicated in the pathogenesis of FXS [137, 138]. The Neuroligin/Neurexin complex, important for synapse formation and implicated in autism, is in turn tethered to the synapse via its interaction with PSD-95 [125]. AlphaCaMKII, a major regulatory protein in synaptic plasticity [139] is also tethered to the synapse by PSD-95; absence of inhibitory phosphorylation of alphaCaMKII by UBE3a, has been implicated in Angelman syndrome [132]. Interestingly, mGluR5 stimulated protein synthesis of alphaCaMKII and PSD-95 are impaired in synaptoneurosomes from Fmr1 KO mice [140]. Furthermore, CAMKII dependent phosphorylation of MeCP2 links these synaptic proteins to Rett syndrome, another single gene disorder associated with autism, and transcriptional regulation of brain derived nerve growth factor (BDNF) [141]. In turn, TrkB mediated BDNF signals through ERK, regulates dendritic spine formation [142], and has also been implicated in the pathogenesis of FXS [143].

Together, these results suggest it may be useful to think of autism as a synapsopathy [144]—a disease where disruption of the synapse during development produces a common clinical picture, despite a heterogeneity of interconnected causes. It also raises the interesting possibility that treatments for one cause, such as fragile X, may have efficacy in treating other causes of autism.

1.. Kanner L. Autistic disturbances of affective contactNerv ChildYear: 1943221750
2.. Lotspeich L. Bloom F,Kupfer DAutism and pervasive developmental disordersPsychopharmacology: The fourth generation of progress, Vol. 4Year: 2000NashvilleAmerican College of Neuropsychopharmacology
3.. Bettelheim B. The empty fortress: Infantile autism and the birth of the selfYear: 1967New YorkFree
4.. McQuaid PE. Infantile autism in twinsBr J PsychiatryYear: 1975127530410.1192/bjp.127.6.5301238137
5.. Folstein S,Rutter M. Genetic influences and infantile autismNatureYear: 19772655596726810.1038/265726a0558516
6.. Steffenburg S,et al. A twin study of autism in Denmark, Finland, Iceland, Norway and SwedenJ Child Psychol PsychiatryYear: 19893034051610.1111/j.1469-7610.1989.tb00254.x2745591
7.. Bailey A,et al. Autism as a strongly genetic disorder: evidence from a British twin studyPsychol MedYear: 1995251637710.1017/S00332917000280997792363
8.. Barton M,Volkmar F. How commonly are known medical conditions associated with autism?J Autism Dev DisordYear: 1998284273810.1023/A:10260524175619711483
9.. Trottier G,Srivastava L,Walker CD. Etiology of infantile autism: a review of recent advances in genetic and neurobiological researchJ Psychiatry NeurosciYear: 19992421031510212552
10.. McCauley JL,et al. Genome-wide and Ordered-Subset linkage analyses provide support for autism loci on 17q and 19p with evidence of phenotypic and interlocus genetic correlatesBMC Med GenetYear: 20056110.1186/1471-2350-6-115647115
11.. For comparison, autism has an estimated heritability of 0.9while the heritability of breast cancer is only 0.27—where 1 equals population variance exclusively due to genetics and 0 equals population variance exclusively due to environmental factors [12].
12.. Freitag CM. The genetics of autistic disorders and its clinical relevance: a review of the literatureMol PsychiatryYear: 200712122210.1038/
13.. Lichtenstein P,et al. Environmental and heritable factors in the causation of cancer—analyses of cohorts of twins from Sweden, Denmark, and FinlandN Engl J MedYear: 20003432788510.1056/NEJM20000713343020110891514
14.. Sutherland GR. Fragile sites on human chromosomes: demonstration of their dependence on the type of tissue culture mediumScienceYear: 19771974300265610.1126/science.877551877551
15.. Brown WT,et al. Association of fragile X syndrome with autismLancetYear: 19821826310010.1016/S0140-6736(82)90231-86119460
16.. August GJ. A genetic marker associated with infantile autismAm J PsychiatryYear: 198314068136573856
17.. Brown WT,et al. Fragile X and autism: a multicenter surveyAm J Med GenetYear: 1986231–23415210.1002/ajmg.13202301263513570
18.. Verkerk AJ,et al. Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndromeCellYear: 19916559051410.1016/0092-8674(91)90397-H1710175
19.. Consortium TD-BFXFmr1 knockout mice: a model to study fragile X mental retardationCellYear: 199478123338033209
20.. Bernardet M,Crusio WE. Fmr1 KO mice as a possible model of autistic featuresScientificWorldJournalYear: 2006611647610.1100/tsw.2006.22016998604
21.. Armstrong VL. What is so critical?: a commentary on the reexamination of critical periodsDev PsychobiolYear: 20064843263110.1002/dev.2013516617464
22.. Rice D,Barone S Jr. Critical periods of vulnerability for the developing nervous system: evidence from humans and animal modelsEnviron Health PerspectYear: 2000108Suppl 35113310.2307/345454310852851
23.. Diagnostic and statistical manual of mental disorders IV-TRYear: 20004Washington, DCAmerican Psychiatric Association
24.. Hughes JR. Autism: the first firm finding = underconnectivity?Epilepsy BehavYear: 200711120410.1016/j.yebeh.2007.03.01017531541
25.. Polleux F,Lauder JM. Toward a developmental neurobiology of autismMent Retard Dev Disabil Res RevYear: 20041043031710.1002/mrdd.2004415666334
26.. Courchesne E. Brain development in autism: early overgrowth followed by premature arrest of growthMent Retard Dev Disabil Res RevYear: 20041021061110.1002/mrdd.2002015362165
27.. Dudek SM,Bear MF. A biochemical correlate of the critical period for synaptic modification in the visual cortexScienceYear: 19892464930673510.1126/science.25731522573152
28.. Weiler IJ,Greenough WT. Metabotropic glutamate receptors trigger postsynaptic protein synthesisProc Natl Acad Sci U S AYear: 1993901571687110.1073/pnas.90.15.71688102206
29.. Huber KM,Kayser MS,Bear MF. Role for rapid dendritic protein synthesis in hippocampal mGluR-dependent long-term depressionScienceYear: 200028854691254710.1126/science.288.5469.125410818003
30.. Huber KM,Roder JC,Bear MF. Chemical induction of mGluR5- and protein synthesis–dependent long-term depression in hippocampal area CA1J NeurophysiolYear: 2001861321511431513
31.. Huber KM,et al. Altered synaptic plasticity in a mouse model of fragile X mental retardationProc Natl Acad Sci U S AYear: 2002991177465010.1073/pnas.12220569912032354
32.. Conn PJ,Pin JP. Pharmacology and functions of metabotropic glutamate receptorsAnnu Rev Pharmacol ToxicolYear: 1997372053710.1146/annurev.pharmtox.37.1.2059131252
33.. Thandi S,Blank JL,Challiss RA. Group-I metabotropic glutamate receptors, mGlu1a and mGlu5a, couple to extracellular signal-regulated kinase (ERK) activation via distinct, but overlapping, signalling pathwaysJ NeurochemYear: 200283511395310.1046/j.1471-4159.2002.01217.x12437585
34.. Mao L,et al. Role of protein phosphatase 2A in mGluR5-regulated MEK/ERK phosphorylation in neuronsJ Biol ChemYear: 200528013126021010.1074/jbc.M41170920015661743
35.. Weiler IJ,et al. Fragile X mental retardation protein is translated near synapses in response to neurotransmitter activationProc Natl Acad Sci U S AYear: 19979410539540010.1073/pnas.94.10.53959144248
36.. Job C,Eberwine J. Identification of sites for exponential translation in living dendritesProc Natl Acad Sci U S AYear: 20019823130374210.1073/pnas.23148569811606784
37.. Gallagher SM,et al. Extracellular signal-regulated protein kinase activation is required for metabotropic glutamate receptor-dependent long-term depression in hippocampal area CA1J NeurosciYear: 2004242048596410.1523/JNEUROSCI.5407-03.200415152046
38.. Banko JL,et al. Regulation of eukaryotic initiation factor 4E by converging signaling pathways during metabotropic glutamate receptor-dependent long-term depressionJ NeurosciYear: 200626821677310.1523/JNEUROSCI.5196-05.200616495443
39.. Nosyreva ED,Huber KM. Metabotropic receptor-dependent long-term depression persists in the absence of protein synthesis in the mouse model of fragile X syndromeJ NeurophysiolYear: 20069553291510.1152/jn.01316.200516452252
40.. Abitbol M,et al. Nucleus basalis magnocellularis and hippocampus are the major sites of FMR-1 expression in the human fetal brainNat GenetYear: 1993421475310.1038/ng0693-1478348153
41.. Agulhon C,et al. Expression of FMR1, FXR1, and FXR2 genes in human prenatal tissuesJ Neuropathol Exp NeurolYear: 19995888678010.1097/00005072-199908000-0000910446811
42.. Devys D,et al. The FMR-1 protein is cytoplasmic, most abundant in neurons and appears normal in carriers of a fragile X premutationNat GenetYear: 1993443354010.1038/ng0893-3358401578
43.. Verheij C,et al. Characterization and localization of the FMR-1 gene product associated with fragile X syndromeNatureYear: 19933636431722410.1038/363722a08515814
44.. Feng Y,et al. Fragile X mental retardation protein: nucleocytoplasmic shuttling and association with somatodendritic ribosomesJ NeurosciYear: 19971751539479030614
45.. Bakker CE,et al. Immunocytochemical and biochemical characterization of FMRP, FXR1P, and FXR2P in the mouseExp Cell ResYear: 200025811627010.1006/excr.2000.493210912798
46.. Antar LN,et al. Metabotropic glutamate receptor activation regulates fragile x mental retardation protein and FMR1 mRNA localization differentially in dendrites and at synapsesJ NeurosciYear: 2004241126485510.1523/JNEUROSCI.0099-04.200415028757
47.. Aschrafi A,et al. The fragile X mental retardation protein and group I metabotropic glutamate receptors regulate levels of mRNA granules in brainProc Natl Acad Sci U S AYear: 200510262180510.1073/pnas.040980310215684045
48.. Brown V,et al. Microarray identification of FMRP-associated brain mRNAs and altered mRNA translational profiles in fragile X syndromeCellYear: 200110744778710.1016/S0092-8674(01)00568-211719188
49.. Zalfa F,Achsel T,Bagni C. mRNPs, polysomes or granules: FMRP in neuronal protein synthesisCurr Opin NeurobiolYear: 2006163265910.1016/j.conb.2006.05.01016707258
50.. Siomi MC,et al. Casein kinase II phosphorylates the fragile X mental retardation protein and modulates its biological propertiesMol Cell BiolYear: 2002222484384710.1128/MCB.22.24.8438-8447.200212446764
51.. Schenck A,et al. A highly conserved protein family interacting with the fragile X mental retardation protein (FMRP) and displaying selective interactions with FMRP-related proteins FXR1P and FXR2PProc Natl Acad Sci U S AYear: 200198158844910.1073/pnas.15123159811438699
52.. Darnell JC,et al. Fragile X mental retardation protein targets G quartet mRNAs important for neuronal functionCellYear: 200110744899910.1016/S0092-8674(01)00566-911719189
53.. Stefani G,et al. Fragile X mental retardation protein is associated with translating polyribosomes in neuronal cellsJ NeurosciYear: 200424337272610.1523/JNEUROSCI.2306-04.200415317853
54.. Feng Y,et al. FMRP associates with polyribosomes as an mRNP, and the I304N mutation of severe fragile X syndrome abolishes this associationMol CellYear: 1997111091810.1016/S1097-2765(00)80012-X9659908
55.. Khandjian EW,et al. A heterogeneous set of FMR1 proteins is widely distributed in mouse tissues and is modulated in cell cultureHum Mol GenetYear: 199545783910.1093/hmg/4.5.7837633436
56.. Steward O,Schuman EM. Protein synthesis at synaptic sites on dendritesAnnu Rev NeurosciYear: 20012429932510.1146/annurev.neuro.24.1.29911283313
57.. Laggerbauer B,et al. Evidence that fragile X mental retardation protein is a negative regulator of translationHum Mol GenetYear: 20011043293810.1093/hmg/10.4.32911157796
58.. Li Z,et al. The fragile X mental retardation protein inhibits translation via interacting with mRNANucleic Acids ResYear: 2001291122768310.1093/nar/29.11.227611376146
59.. Qin M,et al. Postadolescent changes in regional cerebral protein synthesis: an in vivo study in the FMR1 null mouseJ NeurosciYear: 2005252050879510.1523/JNEUROSCI.0093-05.200515901791
60.. Dolen G,et al. Correction of Fragile X Syndrome in MiceNeuronYear: 200756695596210.1016/j.neuron.2007.12.00118093519
61.. Bear MF,Huber KM,Warren ST. The mGluR theory of fragile X mental retardationTrends NeurosciYear: 2004277370710.1016/j.tins.2004.04.00915219735
62.. Engert F,Bonhoeffer T. Dendritic spine changes associated with hippocampal long-term synaptic plasticityNatureYear: 19993996731667010.1038/1997810331391
63.. Marin-Padilla M. Pyramidal cell abnormalities in the motor cortex of a child with Down's syndrome. A Golgi studyJ Comp NeurolYear: 19761671638110.1002/cne.901670105131810
64.. Hayashi ML,et al. Altered cortical synaptic morphology and impaired memory consolidation in forebrain- specific dominant-negative PAK transgenic miceNeuronYear: 20044257738710.1016/j.neuron.2004.05.00315182717
65.. Marin-Padilla M. Structural abnormalities of the cerebral cortex in human chromosomal aberrations: a Golgi studyBrain ResYear: 1972442625910.1016/0006-8993(72)90324-14263073
66.. Belichenko PV,et al. Rett syndrome: 3-D confocal microscopy of cortical pyramidal dendrites and afferentsNeuroreportYear: 199451215091310.1097/00001756-199407000-000257948850
67.. Irwin SA,et al. Abnormal dendritic spine characteristics in the temporal and visual cortices of patients with fragile-X syndrome: a quantitative examinationAm J Med GenetYear: 2001982161710.1002/1096-8628(20010115)98:2<161::AID-AJMG1025>3.0.CO;2-B11223852
68.. Hinton VJ,et al. Analysis of neocortex in three males with the fragile X syndromeAm J Med GenetYear: 19914132899410.1002/ajmg.13204103061724112
69.. Vanderklish PW,Edelman GM. Dendritic spines elongate after stimulation of group 1 metabotropic glutamate receptors in cultured hippocampal neuronsProc Natl Acad Sci U S AYear: 200299316394410.1073/pnas.03268109911818568
70.. Snyder EM,et al. Internalization of ionotropic glutamate receptors in response to mGluR activationNat NeurosciYear: 200141110798510.1038/nn74611687813
71.. Nakamoto M,et al. Fragile X mental retardation protein deficiency leads to excessive mGluR5-dependent internalization of AMPA receptorsProc Natl Acad Sci U S AYear: 200710439155374210.1073/pnas.070748410417881561
72.. Comery TA,et al. Abnormal dendritic spines in fragile X knockout mice: maturation and pruning deficitsProc Natl Acad Sci U S AYear: 199794105401410.1073/pnas.94.10.54019144249
73.. Irwin SA,Galvez R,Greenough WT. Dendritic spine structural anomalies in fragile-X mental retardation syndromeCereb CortexYear: 2000101010384410.1093/cercor/10.10.103811007554
74.. Nimchinsky EA,Oberlander AM,Svoboda K. Abnormal development of dendritic spines in FMR1 knock-out miceJ NeurosciYear: 2001211451394611438589
75.. Irwin SA,et al. Dendritic spine and dendritic field characteristics of layer V pyramidal neurons in the visual cortex of fragile-X knockout miceAm J Med GenetYear: 20021112140610.1002/ajmg.1050012210340
76.. McKinney BC,et al. Dendritic spine abnormalities in the occipital cortex of C57BL/6 Fmr1 knockout miceAm J Med Genet B Neuropsychiatr GenetYear: 200513619810215892134
77.. Galvez R,Greenough WT. Sequence of abnormal dendritic spine development in primary somatosensory cortex of a mouse model of the fragile X mental retardation syndromeAm J Med Genet AYear: 200513521556015880753
78.. Grossman AW,et al. Hippocampal pyramidal cells in adult Fmr1 knockout mice exhibit an immature-appearing profile of dendritic spinesBrain ResYear: 2006108411586410.1016/j.brainres.2006.02.04416574084
79.. Hubel DH,Wiesel TN. Effects of Monocular Deprivation in KittensNaunyn Schmiedebergs Arch Exp Pathol PharmakolYear: 1964248492710.1007/BF0034887814316385
80.. Hubel DH,Wiesel TN. The period of susceptibility to the physiological effects of unilateral eye closure in kittensJ PhysiolYear: 19702062419365498493
81.. Hubel DH,Wiesel TN,LeVay S. Plasticity of ocular dominance columns in monkey striate cortexPhilos Trans R Soc Lond B Biol SciYear: 197727896137740910.1098/rstb.1977.005019791
82.. Normann C,et al. Long-term plasticity of visually evoked potentials in humans is altered in major depressionBiol PsychiatryYear: 20076253738010.1016/j.biopsych.2006.10.00617240361
83.. Antal A,Nitsche MA,Paulus W. Transcranial direct current stimulation and the visual cortexBrain Res BullYear: 20066864596310.1016/j.brainresbull.2005.10.00616459203
84.. Mansour SL,Thomas KR,Capecchi MR. Disruption of the proto-oncogene int-2 in mouse embryo-derived stem cells: a general strategy for targeting mutations to non-selectable genesNatureYear: 198833661973485210.1038/336348a03194019
85.. Lu YM,et al. Mice lacking metabotropic glutamate receptor 5 show impaired learning and reduced CA1 long-term potentiation (LTP) but normal CA3 LTPJ NeurosciYear: 1997171351962059185557
86.. Drager UC. Observations on monocular deprivation in miceJ NeurophysiolYear: 19784112842621544
87.. Gordon JA,Stryker MP. Experience-dependent plasticity of binocular responses in the primary visual cortex of the mouseJ NeurosciYear: 199616103274868627365
88.. Porciatti V,Pizzorusso T,Maffei L. The visual physiology of the wild type mouse determined with pattern VEPsVision ResYear: 1999391830718110.1016/S0042-6989(99)00022-X10664805
89.. Sawtell NB,et al. NMDA receptor-dependent ocular dominance plasticity in adult visual cortexNeuronYear: 20033869778510.1016/S0896-6273(03)00323-412818182
90.. Prusky GT,Douglas RM. Developmental plasticity of mouse visual acuityEur J NeurosciYear: 20031711677310.1046/j.1460-9568.2003.02420.x12534981
91.. Frenkel MY,Bear MF. How monocular deprivation shifts ocular dominance in visual cortex of young miceNeuronYear: 20044469172310.1016/j.neuron.2004.12.00315603735
92.. Taha S,Stryker MP. Rapid ocular dominance plasticity requires cortical but not geniculate protein synthesisNeuronYear: 20023434253610.1016/S0896-6273(02)00673-611988173
93.. Cristo G,et al. Requirement of ERK activation for visual cortical plasticityScienceYear: 2001292552523374010.1126/science.105907511423664
94.. Tuchman R,Rapin I. Epilepsy in autismLancet NeurolYear: 200216352810.1016/S1474-4422(02)00160-612849396
95.. Fombonne E. The epidemiology of autism: a reviewPsychol MedYear: 19992947698610.1017/S003329179900850810473304
96.. Fombonne E. Epidemiological surveys of autism and other pervasive developmental disorders: an updateJ Autism Dev DisordYear: 20033343658210.1023/A:102505461055712959416
97.. In addition to autism, the PDD category (also called the autistic spectrum or ASD), includes less severe forms of autism without cognitive impairment, like Asperger’s disease; therefore estimates of relative rates of cognitive impairment are necessarily lower in ASD cohorts [98].
98.. Kawamura Y,Takahashi O,Ishii T. Reevaluating the incidence of pervasive developmental disorders: impact of elevated rates of detection through implementation of an integrated system of screening in ToyotaJapan. Psychiatry Clin NeurosciYear: 2008622152910.1111/j.1440-1819.2008.01748.x
99.. Berry-Kravis E. Epilepsy in fragile X syndromeDev Med Child NeurolYear: 20024411724810.1017/S001216220100283312418611
100.. Musumeci SA,et al. Epilepsy and EEG findings in males with fragile X syndromeEpilepsiaYear: 19994081092910.1111/j.1528-1157.1999.tb00824.x10448821
101.. Chen L,Toth M. Fragile X mice develop sensory hyperreactivity to auditory stimuliNeuroscienceYear: 2001103410435010.1016/S0306-4522(01)00036-711301211
102.. Musumeci SA,et al. Audiogenic seizures susceptibility in transgenic mice with fragile X syndromeEpilepsiaYear: 2000411192310.1111/j.1528-1157.2000.tb01499.x10643918
103.. Qin M,Kang J,Smith CB. A null, mutation for Fmr1 in female mice: effects on regional cerebral metabolic rate for glucose and relationship to behaviorNeuroscienceYear: 20051353999100910.1016/j.neuroscience.2005.06.08116154294
104.. Yan QJ,et al. A phenotypic and molecular characterization of the fmr1-tm1Cgr fragile X mouseGenes Brain BehavYear: 2004363375910.1111/j.1601-183X.2004.00087.x15544577
105.. Yan QJ,et al. Suppression of two major Fragile X Syndrome mouse model phenotypes by the mGluR5 antagonist MPEPNeuropharmacologyYear: 200549710536610.1016/j.neuropharm.2005.06.00416054174
106.. Godfraind JM,et al. Long-term potentiation in the hippocampus of fragile X knockout miceAm J Med GenetYear: 19966422465110.1002/(SICI)1096-8628(19960809)64:2<246::AID-AJMG2>3.0.CO;2-S8844057
107.. Paradee W,et al. Fragile X mouse: strain effects of knockout phenotype and evidence suggesting deficient amygdala functionNeuroscienceYear: 19999411859210.1016/S0306-4522(99)00285-710613508
108.. Tizzano JP,Griffey KI,Schoepp DD. Induction or protection of limbic seizures in mice by mGluR subtype selective agonistsNeuropharmacologyYear: 19953481063710.1016/0028-3908(95)00083-I8532155
109.. Thomsen C,et al. (S)-4-carboxy-3-hydroxyphenylglycine, an antagonist of metabotropic glutamate receptor (mGluR) 1a and an agonist of mGluR2, protects against audiogenic seizures in DBA/2 miceJ NeurochemYear: 19946262492510.1046/j.1471-4159.1994.62062492.x8189254
110.. Chapman AG,et al. Anticonvulsant activity of two metabotropic glutamate group I antagonists selective for the mGlu5 receptor: 2-methyl-6-(phenylethynyl)-pyridine (MPEP), and (E)-6-methyl-2-styryl-pyridine (SIB 1893)NeuropharmacologyYear: 200039915677410.1016/S0028-3908(99)00242-710854901
111.. Merlin LR,Bergold PJ,Wong RK. Requirement of protein synthesis for group I mGluR-mediated induction of epileptiform dischargesJ NeurophysiolYear: 1998802989939705485
112.. Wong RK,et al. Role of metabotropic glutamate receptors in epilepsyAdv NeurolYear: 1999796859810514855
113.. Stoop R,et al. Activation of metabotropic glutamate 5 and NMDA receptors underlies the induction of persistent bursting and associated long-lasting changes in CA3 recurrent connectionsJ NeurosciYear: 2003231356344412843266
114.. Freund LS,Reiss AL. Cognitive profiles associated with the fra(X) syndrome in males and femalesAm J Med GenetYear: 1991384542710.1002/ajmg.13203804092063895
115.. Dam D,et al. Spatial learning, contextual fear conditioning and conditioned emotional response in Fmr1 knockout miceBehav Brain ResYear: 20001171–21273611099766
116.. Kooy RF,et al. Transgenic mouse model for the fragile X syndromeAm J Med GenetYear: 1996642241510.1002/(SICI)1096-8628(19960809)64:2<241::AID-AJMG1>3.0.CO;2-X8844056
117.. D'Hooge R,et al. Mildly impaired water maze performance in male Fmr1 knockout miceNeuroscienceYear: 19977623677610.1016/S0306-4522(96)00224-29015322
118.. Gold PE. The use of avoidance training in studies of modulation of memory storageBehav Neural BiolYear: 1986461879810.1016/S0163-1047(86)90927-13015121
119.. Power AE,et al. Anisomycin infused into the hippocampus fails to block “reconsolidation” but impairs extinction: the role of re-exposure durationLearn MemYear: 2006131273410.1101/lm.9120616452651
120.. Whitlock JR,et al. Learning induces long-term potentiation in the hippocampusScienceYear: 200631357901093710.1126/science.112813416931756
121.. Szatmari P,et al. Mapping autism risk loci using genetic linkage and chromosomal rearrangementsNat GenetYear: 20073933192810.1038/ng198517322880
122.. Kim HG,et al. Disruption of neurexin 1 associated with autism spectrum disorderAm J Hum GenetYear: 200882119920710.1016/j.ajhg.2007.09.01118179900
123.. Moessner R,et al. Contribution of SHANK3 mutations to autism spectrum disorderAm J Hum GenetYear: 200781612899710.1086/52259017999366
124.. Durand CM,et al. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disordersNat GenetYear: 200739125710.1038/ng193317173049
125.. Chubykin AA,et al. Dissection of synapse induction by neuroligins: effect of a neuroligin mutation associated with autismJ Biol ChemYear: 200528023223657410.1074/jbc.M41072320015797875
126.. Jamain S,et al. Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autismNat GenetYear: 200334127910.1038/ng113612669065
127.. Samaco RC,Hogart A,LaSalle JM. Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3Hum Mol GenetYear: 20051444839210.1093/hmg/ddi04515615769
128.. Kwon CH,et al. Pten regulates neuronal arborization and social interaction in miceNeuronYear: 20065033778810.1016/j.neuron.2006.03.02316675393
129.. Peters SU,et al. Autism in Angelman syndrome: implications for autism researchClin GenetYear: 2004666530610.1111/j.1399-0004.2004.00362.x15521981
130.. Smalley SL. Autism and tuberous sclerosisJ Autism Dev DisordYear: 19982854071410.1023/A:10260524216939813776
131.. Tavazoie SF,et al. Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2Nat NeurosciYear: 200581217273410.1038/nn156616286931
132.. Woerden GM,et al. Rescue of neurological deficits in a mouse model for Angelman syndrome by reduction of alphaCaMKII inhibitory phosphorylationNat NeurosciYear: 2007103280210.1038/nn184517259980
133.. Abrahams BS,Geschwind DH. Advances in autism genetics: on the threshold of a new neurobiologyNat Rev GenetYear: 2008953415510.1038/nrg234618414403
134.. Guy J,et al. Reversal of neurological defects in a mouse model of Rett syndromeScienceYear: 200731558151143710.1126/science.113838917289941
135.. Manning BD,Cantley LC. Rheb fills a GAP between TSC and TORTrends Biochem SciYear: 20032811573610.1016/j.tibs.2003.09.00314607085
136.. Tu JC,et al. Coupling of mGluR/Homer and PSD-95 complexes by the Shank family of postsynaptic density proteinsNeuronYear: 19992335839210.1016/S0896-6273(00)80810-710433269
137.. Giuffrida R,et al. A reduced number of metabotropic glutamate subtype 5 receptors are associated with constitutive homer proteins in a mouse model of fragile X syndromeJ NeurosciYear: 2005253989081610.1523/JNEUROSCI.0932-05.200516192381
138.. Zalfa F,et al. A new function for the fragile X mental retardation protein in regulation of PSD-95 mRNA stabilityNat NeurosciYear: 200710557858710.1038/nn189317417632
139.. Lisman J,Schulman H,Cline H. The molecular basis of CaMKII function in synaptic and behavioural memoryNat Rev NeurosciYear: 2002331759010.1038/nrn75311994750
140.. Muddashetty RS,et al. Dysregulated metabotropic glutamate receptor-dependent translation of AMPA receptor and postsynaptic density-95 mRNAs at synapses in a mouse model of fragile X syndromeJ NeurosciYear: 2007272053384810.1523/JNEUROSCI.0937-07.200717507556
141.. Zhou Z,et al. Brain-specific phosphorylation of MeCP2 regulates activity-dependent Bdnf transcription, dendritic growth, and spine maturationNeuronYear: 20065222556910.1016/j.neuron.2006.09.03717046689
142.. Alonso M,Medina JH,Pozzo-Miller L. ERK1/2 activation is necessary for BDNF to increase dendritic spine density in hippocampal CA1 pyramidal neuronsLearn MemYear: 2004112172810.1101/lm.6780415054132
143.. Castren M,et al. BDNF regulates the expression of fragile X mental retardation protein mRNA in the hippocampusNeurobiol DisYear: 2002111221910.1006/nbdi.2002.054412460560
144.. Bear MF,et al. Fragile X: translation in actionNeuropsychopharmacologyYear: 200833184710.1038/sj.npp.130161017940551


[Figure ID: Fig1]
Fig. 1 

Opponent regulation of protein synthesis by FMRP and GpI mGluRs. FMRP is a negative regulator of translation at the synapse. Stimulation of GpI mGluRs with DHPG leads to the synthesis of proteins. Furthermore, many of the long-term consequences of Gp1 mGluR activation are protein synthesis dependent. The mGluR theory posits that in the absence of FMRP, as is the case in Fragile X syndrome, this balance between FMRP and Gp1 mGluRs is lost, and unchecked protein synthesis at the synapse leads to the characteristic features of the disease. Furthermore, this balance could be restored by reducing Gp1 mGluR activity at the synapse, by either knockdown or pharmacological blockade of the receptor. The therapeutic implication of the theory is that symptoms of FXS syndrome could be corrected by appropriate modulation of GpI mGluR signaling

[Figure ID: Fig2]
Fig. 2 

Autism as a synapsopathy. mGluR5 interacts with a number of postsynaptic proteins. Some of these have been identified as autism candidate genes (shown in purple; HOMER, SHANK, Neuroligin, Neurexin); others are proteins associated with single gene causes of autism (shown in red: FMRP/FXS, TSC/Tuberous Sclerosis, PTEN/ Hamartoma syndrome, MeCP2/Rett syndrome, E3A/Angelman’s syndrome)

Article Categories:
  • Article

Keywords: Keywords Fragile X, FXS, Metabotropic, Glutamate, Receptor, mglur, mglur5, FMRP, Fragile x mental retardation protein, Synaptic plasticity, Long term depression, LTD, Protein synthesis, Translation, Ocular, Dominance, Plasticity, Visual, Cortex, Hippocampus, Inhibitory avoidance, Passive avoidance, Extinction, Autism, HOMER, SHANK, Neuroligin, Neurexin, Tuberous sclerosis, TSC, TSC1, TSC2, Rett, MeCP, BDNF, PTEN, Hamartoma, Angelman, UBE3, Dendritic spine, Synapse, Development, Synapsopathy, Audiogenic seizure, Seizure, Mental retardation, Cognitive, Impairment.

Previous Document:  The pathophysiology of restricted repetitive behavior.
Next Document:  Tuberous sclerosis complex: everything old is new again.