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Fig. 5. Schematic depiction of dendritic development in wild-type and fragile X knockout mouse somatosensory whisker barrel cortex. In normal development in the wild type, dendrites initially extend both toward the interior hollow of the dendrite and toward the exterior septae region. As development progresses, hollow-oriented dendrites proliferate, while outwardly oriented dendrites regress. In the knockout mouse, the hollow-oriented dendrites proliferate normally, but the outwardly oriented dendrites exhibit impaired regression. P 0, postnatal day 0. Data are from Galvez et al. (R.Galvez, A.R.Gopal, and W.T.G., unpublished work).

temporal cortex; ref. 28), as illustrated in Fig. 4. Spines in the fragile X samples were significantly longer overall and exhibited a morphology consistent with that of early development: a greater number of long spines with heads and fewer short, stubby, and mushroom-shaped spines were evident in the fragile X cases. No attempt was made to eliminate noninnervated “filopodia,” which cannot be identified in Golgi preparations, but there was no statistically significant difference between groups in the relative frequency of long spines without apparent heads (types A and B in Fig. 4). In addition, the density (number per unit dendrite length) of spines was higher in the patient samples, suggesting a greater number of excitatory inputs to these neurons. The same basic pattern of results was evident on apical shafts, branches from the apical shaft, and basilar branches of the pyramidal neurons examined. We obtained similar findings from analysis of the fmr-1 knockout vs. wild-type FVB/129 hybrid mouse, except that, in the second study, which used animals screened for (and eliminated from the study) the retinal degeneration mutation characteristic of the FVB strain, there was not a significantly greater spine density in the knockout animals (ref. 35 and S.A.I., M.Idupulapati, M.E.Gilbert, J.B.Harris, A.Chakravarti, A.B.Mehta, E.J.Rogers, R.A.Crisostomo, B.P. Larsen, C.J.Alcantara, et al., unpublished work). In these studies of layer V pyramidal neurons, we found no significant differences in the size of the dendritic field or in its pattern of branching in either mouse or human samples (ref. 28 and S.A.I., M.Idupulapati, M.E.Gilbert, J.B.Harris, A.Chakravarti, A.B.Mehta, E.J.Rogers, R.A.Crisostomo, B.P. Larsen, C.J.Alcantara, et al., unpublished work).

One interpretation consistent with these findings is that the knockout mouse has failed, at least in part, to follow the normal maturational pattern of eliminating underused synapses and altering the retained synapses to a more matureappearing form of shorter, fuller spines. It is possible that FMRP or proteins dependent on FMRP for their synthesis are required, either permissively or directly involved, in the synapse stabilization and maturation process. Alternatively, it may be that the FMRP-deficient brain is in a constant state of synaptogenesis, generating new, immature-appearing spines long after elevated rates of synaptogenesis have subsided in the FMRP-containing brain.

A recent experiment may provide a partial answer to this question. Galvez et al. (R.Galvez, A.R.Gopal, and W.T.G., unpublished work) examined the “barrels” in somatosensory cortex that process information from the large facial whiskers in fmr-1 knockout vs. wild-type mice. This structure is one in which the overproduction and regression of dendrites during development is particularly evident, because dendrites of layer IV spiny stellate neurons that initially extend in the wrong direction, toward the septae outside of the barrel rather than toward the hollow at its center, are subsequently retracted, contributing to the asymmetric branching pattern exhibited by these neurons in adult mice (3). Galvez et al. (R.Galvez, A.R. Gopal, and W.T.G., unpublished work) compared the extent of both the properly directed hollow-oriented dendrites and the improperly directed dendrites that grew toward the outside of the barrel. They found the extent of properly oriented dendrites to be statistically identical in knockout and wild-type mice, whereas the knockout mice had retained a greater amount of dendrites oriented in the improper direction (Fig. 5). Thus, in this case, the fmr-1 knockout mice exhibited what seemed to be a failure to undergo the normal dendritic retraction process characteristic of these structures. This result is compatible, at a dendritic level, with what may seem to be a failure of the synapse elimination process when one compares spine density in the two types of animals. Thus, our working hypothesis remains that there is an impairment of mechanisms that promote synapse maturation and pruning in the fmr-1 knockout mouse and that FMRP plays a permissive or directive role in the neural maturation process.

This work was supported by grants from the FRAXA Research Foundation, HD37175 from the National Institute of Child Health and Human Development, MH35321 from the National Institute of Mental Health, and AG10154 from the National Institute on Aging.

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