1 Neuroscience and , 2 Medical Scholars Programs, Departments of , 3 Psychology, , 4 Psychiatry, and , 5 Cell and Structural Biology, and the Beckman Institute, University of Illinois, Urbana, IL 61801, USA
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Abstract |
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Introduction |
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Fragile-X syndrome is a common form of mental retardation affecting nearly one in 2000 males and roughly half as many females (Brown, 1996). It is caused by the insertion of extra DNA into the X chromosome that silences the gene encoding FMRP. Phenotypic traits include facial abnormalities, macro-orchidism, developmental delay, mental retardation and autistic-like behaviors (Hagerman and Cronister, 1996
).
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FMRP: Role in Synapse Maturation and Pruning? |
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The synaptic selection/maturation process may be grossly impaired in cases of clinical fragile-X syndrome. A qualitative study of rapid-Golgi-stained human autopsy material from a single fragile-X patient described long, thin, tortuous, dendritic spines with prominent heads and irregular dilations on apical dendrites of pyramidal cells in layers III and V of the parieto-occipital neocortex (Rudelli et al., 1985; Wisniewski et al., 1991
). Reduced mean synaptic contact area was also reported using electron microscopy; however, no other major neuro-pathologies were noted. Two additional fragile-X patients were added to this study by Hinton et al. (Hinton et al., 1991
). Similar dendritic spine characteristics were noted, and no differences in neuronal density between fragile-X patients and controls were found, possibly suggesting normal neurogenesis and cell migration in fragile-X patients; however, a stereological method that would have overcounted larger cells was used.
Despite a lack of evidence for changes in neuronal number or other gross structural deficits, fragile-X patients have been shown to display subtle abnormalities in gross brain anatomy. Two groups (Reiss et al., 1991; Mostofsky et al., 1998
), using magnetic resonance imaging (MRI), showed that fragile-X males exhibited a reduction in the size of the posterior cerebellar vermis and an enlargement of the fourth ventricle. An increased volume in fragile-X patients as compared with controls has also been reported in the hippocampus (Reiss et al., 1994
; Kates et al., 1997
), caudate nucleus (Reiss et al., 1995
), and lateral ventricles (Reiss et al., 1995
). Furthermore, an age-related increase in the volume of the hippocampus and an age-related decrease in the volume of the superior temporal gyrus were found in fragile-X patients (Reiss et al., 1994
). It should be noted that the changes in fragile-X patients found using MRI were subtle and not replicated by physical measurement of autopsy material, but this data was derived from only two different fragile-X patients (Reyniers et al., 1999
).
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Neuronal Morphology in the Fragile-X Brain |
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A quantitative neuroanatomical study of Golgi-Kopsch-stained human autopsy material from three male adult fragile-X patients and three male age-matched controls was carried out in order to quantify and further describe dendritic spine characteristics in fragile-X patients by comparing dendritic spine length, morphology and density along apical shaft, apical oblique and basilar dendrites on layer V pyramidal cells in the temporal cortex of these subjects (Irwin et al., 1999) (S.A. Irwin et al., submitted for publication). The results showed that fragile-X patients had significantly more long spines and significantly fewer short spines than controls on apical shaft, apical oblique and basilar dendrites (Figure 1
). Likewise, fragile-X patients exhibited significantly more spines with immature shapes than did controls on apical dendritic shafts, apical oblique and basilar dendrites (Figures 1 and 2
). These two findings suggest an impairment of normal spine maturation in fragile-X syndrome that is persistent throughout the entire life span of these patients. Fragile-X patients also exhibited a significantly greater spine density on distal segments of apical dendritic shafts and on apical oblique and basilar dendrites (Figure 1
), suggesting a persistent failure of normal synapse pruning processes as well. No differences in dendritic diameter were found for any dendritic branch type.
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These findings suggest that synaptic pruning and maturation may be grossly impaired in cases of fragile-X syndrome, and further imply a role in these processes for FMRP. Further support for a role of FMRP in synaptic plasticity comes from in vitro studies suggesting that this protein is made at synapses in response to synaptic activation (Weiler et al., 1997) (Figure 3
) and in vivo studies demonstrating increased FMRP immunoreactivity in brain regions known to be undergoing: (i) active synaptogenesis in response to motor-skill learning or complex environment rearing or (ii) increased activation in response to repetitive motor activity (Irwin et al., 1998
, 2000
) (S.A. Irwin et al., in preparation) (Figure 4
).
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The results of Comery et al. (Comery et al., 1997) in these mice support the involvement of FMRP in normal spine development, as they demonstrated an increase in spine density and spine length on layer V pyramidal cells in the visual cortex of FraX mice. This has been the only brain abnormality so far reported in these mice (Consortium, 1994
; Godfraind et al., 1996
; Kooy et al., 1996
); however, it was later determined that an unknown number of the mice used in that study may have been homozygous for a recessive retinal degeneration gene that would have been likely to affect cell morphology in the visual cortex of these animals. A quantitative neuroanatomical study of Golgi-Cox-stained material from ten young-adult male Frax mice and ten young-adult wild-type control mice was carried out in order to characterize the structure of dendrites and dendritic spines of layer V pyramidal cells in the visual cortex of non-blind FraX mice (Irwin et al., 1999
) (S.A. Irwin et al., in preparation). The purpose of these investigations was: (i) to confirm the results of Comery et al. (Comery et al., 1997
); (ii) to determine if abnormalities similar to those of fragile-X patients were present; (iii) to examine dendritic-tree characteristics [as dendrites of some cell populations also undergo an overproduction and pruning developmental process (Falls and Gobel, 1979
; Brunjes et al., 1982
; Murphy and Magness, 1984
; Greenough and Chang, 1988b
)]; and (iv) to further evaluate these mice as a model of the human condition.
FraX mice were found to have longer, more immature dendritic spines than wild-type control mice. These mice exhibited more longer and fewer shorter spines than controls on segments of apical dendritic shafts, apical oblique dendrites and basilar dendrites. Similarly, FraX mice exhibited more immature spine shapes and fewer mature shapes on segments of apical dendritic shafts and apical oblique dendrites. No differences in the frequencies of spine shapes along basilar dendrites were found. FraX and wild-type mice did not exhibit statistically significant spine density or dendritic diameter differences along any of the branch types; however, a trend toward a higher spine density in FraX mice along both apical shaft and apical oblique dendrites was evident. For characteristics of apical and basilar dendritic trees, no significant differences in the number of branches at each order, the chance of bifurcation at each order or the amount of dendritic material at constant intervals away from the soma were found between FraX and wild-type mice for layer V pyramidal visual cortical cells.
These findings indicate that FraX mice exhibited similar dendritic spine abnormalities to those of humans afflicted with fragile-X syndrome; however, the differences may be more subtle. These findings also partially replicate those of Comery et al. (Comery et al., 1997), but the absence of a significant spine density difference suggests that the mice in that study may have been affected by the retinal degeneration mutation. The fact that dendritic spine abnormalities are found in FraX mice suggests that they are a viable model for the study of the human condition; however, these mice, unlike the fragile-X patients and the Comery et al. mice, did not exhibit statistically significant abnormalities in spine density. It should be noted that both apical shafts and apical oblique dendrites of these FraX mice exhibited a tendency toward increased spine density. The abnormal spines found in these mice might be associated with their behavioral deficits, and the fact that the spine abnormalities were more subtle in mice than in humans might explain why this subtlety appears to be so, thus far, for the behavioral deficits found in these mice as well. The fact that FraX mice do not show any dendritic arborization abnormalities suggests that the role of FMRP in neurons is limited to the spine/synaptic structure and does not play a crucial regulatory role affecting overall neuronal morphology of pyramidal neurons in the cerebral cortex.
A lack of FMRP leads to abnormal dendritic spine structure and number on layer V pyramidal cells in the temporal cortex of humans and abnormal dendritic spine structure on layer V pyramidal cells in the visual cortex of FraX mice, and the neuronal structural abnormalities in fragile-X appear to be limited to dendritic spines. This presents strong evidence for the involvement of FMRP in synaptic structural transformation processes across brain regions and points to a cause of the behavioral deficits observed in both humans and mice lacking FMRP. What role FMRP plays in this process remains unknown. A lack of a housekeeping protein that would lead to altered metabolism could certainly affect neuronal morphology, as could the lack of a cytoskeletal protein involved in synaptic shape. Where FMRP fits into this spectrum of proteins affecting neuronal morphology also remains a mystery. Comparisons with other forms of mental retardation demonstrate that FMRP is not alone in having morphological effects, as several syndromes have been reported to be associated with neuronal structural abnormalities. However, the deficits associated with these syndromes have not been limited to dendritic spines, nor have any of these syndromes been found to exhibit an increase in dendritic spine number.
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Neuronal Morphological Abnormalities in Other Forms of Mental Retardation |
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Other Evidence Regarding FMRP Function |
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It is perhaps a little curious that FraX mice show more subtle and slightly different abnormalities relative to the fragile-X patients. It must be kept in mind that mice can never be a perfect human model, and that the mice used in this study were young adults as opposed to the middle-to old-aged subjects used in the human study. However, a closer examination of both the human and mouse data side by side might suggest another explanation for these phenomena. The data from the control mice appear more similar than those from the knockout mice to fragile-X syndrome humans. Perhaps housing mice in standard laboratory cages makes them more like a mental retardation model, whereas animals raised in toy and object filled complex environments, which exhibit increased brain connectivity (Turner and Greenough, 1985) and learning capacity (Hebb, 1947; Greenough et al., 1970
; Black et al., 1998
) when compared with animals raised in standard laboratory cages, are more like normal mice. It may be the case that complex environment rearing may produce a more profound difference between control and FraX mice. Evidence for this comes from longitudinal studies that described declines in IQ and in adaptive behavior of fragile-X patients. These scores were reported not to reflect a decline in intellectual or social skills, but rather a widening gap with age between these fragile-X and normally developing individuals (Fisch et al., 1996
). Although experience may widen the gap between normally developing and fragile-X affected humans or animals, it may also serve to ameliorate the deficits. Success along these lines has been found in a rat model of fetal alcohol syndrome (Klintsova et al., 1997
, 1998
). Similarly, others have reported amelioration of genetically related behavioral defi-ciencies by exposing mentally retarded children to an enriched toy and object filled environment (Horner, 1980
) or rearing animals in a more normal environment (Caston et al., 1999
; Rampon et al., 2000
). Studies are underway in our laboratory to investigate how experience affects neuronal structure and learning performance in FraX mice, and these studies may give us a better model and understanding of the human condition and how experience may affect it.
It should be mentioned that FMRP is expressed in a number of tissues, especially early in development, and may play a similar role in structural transformations occurring in tissues other than the brain. Evidence for this comes from studies demonstrating high levels of FMRP expression in a number of tissues during embryonic development (Abitbol et al., 1993; Hinds et al., 1993
), a period of massive cellular proliferation. A role for FMRP in cellular remodeling is further supported by its increased levels after quiescent mouse kidney cells were stimulated to resume proliferation (Khandjian et al., 1995
). In addition, Devys et al. (Devys et al., 1993
) found that dividing layers of epithelial tissues as well as cells during wound healing and pathogenesis that involved active cellular remodeling, such as in heart myocytes of patients with ischemic cardiopathy, exhibited strong FMRP expression. In non-neuronal tissue FMRP may be involved in cellular structural transformations accompanying cellular proliferation, which may have mechanisms in common with neuronal structural transformations, such as synaptogenesis and/or spine maturation and pruning.
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Molecular Roles of FMRP |
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Conclusions |
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Notes |
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Address correspondence to William T. Greenough, University of Illinois at Urbana-Champaign, Beckman Institute, 405 N. Mathews Ave, Urbana, IL 61801, USA. Email: wgreenou{at}s.psych.uiuc.edu.
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