they tend to be rather subtle. There was some controversy regarding brain phenotype at
the recent Banbury Conference, as Nimchinsky and Svoboda reported that they were
unable to repeat prior observations of longer and more immature spines in the knockout
mice using their method, fluorescence visualization of neurons that had been virallyinfected with green fluorescent protein. This report is already stimulating collaborative
and individual attempts to optimally characterize the structure of synapses in the
knockout mouse. The published data are reviewed here in the absence of any change in
perspective that may result from this work.
McKinney, B. C., Grossman, A. W., Elisseou, N. M. & Greenough, W. T. (in press).
Dendritic spine abnormalities in the occipital cortex of C57BL/6 Fmr1 knockout mice.
Am. J. Med. Genet.
Galvez, R. & Greenough, W. T. (in press). Sequence of abnormal dendritic spine
development in primary somatosensory cortex of a mouse model of the fragile X mental
retardation syndrome. Am. J. Med. Genet.
Greenough, W. T. & Chang, F. L. (1988). Dendritic pattern formation involves both
oriented regression and oriented growth in the barrels of mouse somatosensory cortex.
Brain Res. 471, 148–152.
Huttenlocher, P. R. & Dabholkar, A. S. (1997). Regional differences in synaptogenesis in
human cerebral cortex. J. Comp. Neurol. 387, 167–178.
Galvez, R., Gopal, A. R. & Greenough, W. T. (2003). Somatosensory cortical barrel
dendritic abnormalities in a mouse model of the fragile X mental retardation syndrome.
Brain Res. 971, 83–89.
Nimchinsky, E. A., Oberlander, A. M. & Svoboda, K. (2001). Abnormal development of
dendritic spines in FMR1 knockout mice. J. Neurosci. 21, 5139–5146.
Irwin, S.A., Idupulapati, M., Gilbert, M.E., Harris, J.B., Chakravarti, A., Rogers, E.J.,
Crisostomo, R.A., Larsen, B.P., Mehta, A.B., Alcantara, C.J., Patel, B., Swain, R.A.,
Weiler, I.J., Oostra, B. A., and Greenough, W.T. Dendritic spine and dendritic field
characteristics of layer V pyramidal neurons in the visual cortex of fragile-x knockout
mice. American Journal of Medical Genetics, 111:140-146, 2002.
Irwin, S.A., Patel, B., Idupulapati, M., Harris, J.B., Cristostomo, R., Larsen, B.P., Kooy,
F., Willems, P.J., Cras, P., Kozlowski, P.B., Swain, R.A., Weiler, I.J., and Greenough,
W.T. Abnormal dendritic spine characteristics in the temporal and visual cortices of
patients with Fragile-X Syndrome: A quantitative examination. American Journal of
Medical Genetics, 98:161-167, 2001.
-----------------------------------B.3. Brain Morphological Phenotype in FXS
Subtle but consistent abnormalities in neuronal structure have been reported in
FXS. Early reports, appearing before the delineation of the fragile X syndrome, showed
that mental retardation of unknown origin was often associated with the presence of an
immature spine morphology in the cerebral cortex (Marin-Padilla, 1972, 1974; Purpura,
1974). Subsequent non-quantitative descriptions of autopsy cases have reported an
apparently very similar result for fragile X syndrome: cerebral cortical spines exhibit a
thin, elongated morphology in Golgi preparations and a reduced synaptic contact size in
electron microscopy (e.g., Rudelli et al., 1985; Hinton et al., 1991), both of which are
also characteristic of the immature, or the experience-deprived synapse in the cerebral
cortex. A detailed quantitative study revealed a similar spine shape phenotype and also
revealed that spine density (number per unit dendrite length) was higher in FXS patients
than in matched controls (Irwin et al., 2001). Hinton et al. (1991) noted that neither gross
pathology nor any indication of cell migratory failures or neuronal density changes is
associated with fragile X syndrome, in contrast to a variety of other mental retardation
syndromes (including Down syndrome). Thus while "dendritic spine dysgenesis" also
occurs in other mental deficiency syndromes, it is the only cellular-level neuropathology
thus far found in fragile X syndrome (Irwin et al., 2001). A similar spine morphology
appears to be present, perhaps less dramatically, in fragile X knockout mice (Comery et
al., 1997; Irwin et al., 2002; McKinney et al., in press). These spine abnormalities were
reported to diminish in the somatosensory barrel cortex during development (Nimchinsky
et al., 2001), but recent research indicates that the abnormalities re-emerge as the mice
mature (Galvez and Greenough, in press). (The oldest mice in the Nimchinsky et al. study
were 27 days postnatal, and Galvez and Greenough saw the phenotype re-emerge
between that age and adulthood, during a period when spine density diminished in WT
control mice.) The excess of long, thin, immature-looking spines has been hypothesized
to reflect impairment of a pruning process that would normally eliminate excess spines
during development, and that normally contributes to the development of patterned brain
circuitry (Huttenlocher et al,, 1997). In a region of the somatosensory whisker barrel
cortex where dendrites are normally withdrawn during development (Greenough and
Chang, 1988), the improperly located dendrites are not withdrawn in FMR1-knockout
mice (Galvez et al., 2003), and diminishing spine density parallels development of the
spine shape phenotype from postnatal week 4 to adulthood (Galvez and Greenough, in
press). Combined with additional evidence for the spine phenotype in a different genetic
background mouse strain (McKinney et al., in press) the weight of the evidence supports
the view that the neuromorphological abnormalities that are seen in both fragile X
syndrome and the mouse model involve, at least in part, a failure to prune synapses and
parts of dendrites that would normally be eliminated during development. A phenotype
on the axonal side of the synapse in the dentate gyrus may similarly arise from a pruning
failure (Ivanco and Greenough, 2002). (The preceding summary was presented at the
2005 Banbury meeting.) In addition to these differences in fine structure, there are also
deficits in gross brain morphology. Reiss, et al. (e.g., 1994) has found some brain
regions to be larger and others reduced in FraXS patients.
was fatally flawed by the inclusion of an unknown number of subjects with a retinal
degeneration syndrome, additional reports have shown a mild morphological phenotype
in the KO mouse that parallels that seen in humans (Irwin et al., in prep.).