Abnormal dendritic spine characteristics in the temporal and visual cortices of patients with fragile‐X syndrome: A quantitative examination

Fragile‐X syndrome is a common form of mental retardation resulting from the inability to produce the fragile‐X mental retardation protein. Qualitative examination of human brain autopsy material has shown that fragile‐X patients exhibit abnormal dendritic spine lengths and shapes on parieto‐occipital neocortical pyramidal cells. Similar quantitative results have been obtained in fragile‐X knockout mice, that have been engineered to lack the fragile‐X mental retardation protein. Dendritic spines on layer V pyramidal cells of human temporal and visual cortices stained using the Golgi‐Kopsch method were investigated. Quantitative analysis of dendritic spine length, morphology, and number was carried out on patients with fragile‐X syndrome and normal age‐matched controls. Fragile‐X patients exhibited significantly more long dendritic spines and fewer short dendritic spines than did control subjects in both temporal and visual cortical areas. Similarly, fragile‐X patients exhibited significantly more dendritic spines with an immature morphology and fewer with a more mature type morphology in both cortical areas. In addition, fragile‐X patients had a higher density of dendritic spines than did controls on distal segments of apical and basilar dendrites in both cortical areas. Long dendritic spines with immature morphologies and elevated spine numbers are characteristic of early development or a lack of sensory experience. The fact that these characteristics are found in fragile‐X patients throughout multiple cortical areas may suggest a global failure of normal dendritic spine maturation and or pruning during development that persists throughout adulthood. © 2001 Wiley‐Liss, Inc.     

Dendritic spine and dendritic field characteristics of layer V pyramidal neurons in the visual cortex of fragile-X knockout mice

Fragile-X syndrome is a common form of mental retardation resulting from the inability to produce the fragile-X mental retardation protein. The specific function of this protein is unknown; however, it has been proposed to play a role in developmental synaptic plasticity. Examination of human brain autopsy material has shown that fragile-X patients exhibit abnormalities in dendritic spine structure and number, suggesting a failure of normal developmental dendritic spine maturation and pruning in this syndrome. Similar results using a knockout mouse model have previously been described; however, it was noted in retrospect that the mice used in that study may have carried a mutation for retinal degeneration, which may have affected cell morphology in the visual cortex of those animals. In this study, dendritic spines on layer V pyramidal cells of visual cortices, taken from fragile-X knockout and wild-type control mice without the retinal degeneration mutation and stained using the Golgi-Cox method, were investigated for comparison with the human condition. Quantitative analyses of the lengths, morphologies, and numbers of dendritic spines, as well as amount of dendritic arbor and dendritic branching complexity, were conducted. The fragile-X mice exhibited significantly more long dendritic spines and significantly fewer short dendritic spines than control mice. Similarly, fragile-X mice exhibited significantly more dendritic spines with an immature-like morphology and significantly fewer with a more mature type morphology. However, unlike the human condition, fragile-X mice did not exhibit statistically significant dendritic spine density differences from controls. Fragile-X mice also did not demonstrate any significant differences from controls in dendritic tree complexity or dendritic arbor. Long dendritic spines with immature morphologies are characteristic of early development or a lack of sensory experience. These results are similar to those found in the human condition and further support a role for the fragile-X mental retardation protein specifically in normal dendritic spine developmental processes. They also support the validity of these mice as a model of fragile-X syndrome.     

Abnormal development of the inferior temporal region in fetuses with Down syndrome

Down syndrome (DS) is a genetic condition associated with impairment in several cognitive domains. Previous evidence showed a notable neurogenesis reduction in the hippocampal region of DS fetuses, which may account for the impairment of declarative memory that characterizes DS starting from early life stages. The fusiform gyrus (FG) and the inferior temporal gyrus (ITG) play a key role in visual recognition memory, a function that is impaired in children and adults with DS. The goal of the current study was to establish whether fetuses with DS (17–21 weeks of gestation) exhibit neuroanatomical alterations in the FG and ITG that may underlie recognition memory impairment. We found that the FG and ITG of fetuses with DS had a reduced thickness and fewer cells in comparison with euploid fetuses. Moreover, DS fetuses had fewer cells expressing the neuronal marker NeuN than euploid fetuses, but a similar number of cells expressing the astrocytic marker GFAP and, consequently, a higher percentage of astrocytes. Immunohistochemistry for calretinin (CR), a marker of GABAergic interneurons, showed that in DS fetuses the ratio of CR‐positive vs. CR‐negative cells was greater than in euploid fetuses, both in the FG (177%) and ITG (161%). An increased ratio of CR‐positive vs. CR‐negative cells was also found in the entorhinal cortex, hippocampus and dentate gyrus. Results provide novel evidence that the FG and ITG of DS fetuses exhibit numerous developmental defects. These defects may underlie the functional alterations in visual recognition memory observed in children with DS.     

Drebrin,a dendritic spine protein,is manifold decreased in brains of patients with Alzheimer's disease and Down syndrome

Drebrin, located in the dendritic spines of the neuron, plays a role in the synaptic plasticity together with actin filaments. Although drebrin regulates the morphological changes of spines in neurodegenerative disease such as Alzheimer's disease (AD), drebrin in Down syndrome (DS) showing AD-like neuropathology has not been studied. We used Western blotting to determine protein levels of drebrin and F-actin in frontal, temporal cortex and cerebellum from patients with DS and AD as compared to controls. A monoclonal antibody against drebrin and F-actin was used. Drebrin levels were significantly decreased in frontal (means +/- standard deviation; DS 0.24 +/- 0.52; AD 0.16 +/- 0.14; controls 2.56 +/- 3.48) and temporal cortex (DS 0.07 +/- 0.11; AD 0.07 +/- 0.15; controls 1.71 +/- 1.51) and drebrin was also decreased when normalized with F-actin. No changes were observed in cerebellum. Decreased drebrin could not simply be due to cell loss (F-actin) or neuronal loss (comparable neuron-specific enolase between groups). Reduced drebrin could be responsible for or representing the loss of spine plasticity in DS and may be a useful indicator for the impaired arborization in neurodegenerative disorders.     

An anthropometric study of males with the fragile-X syndrome

Anthropometric methods were used to examine 18 males 18 to 69 years old with the Fragile-X syndrome. Thirteen of 15 subjects had macroorchidism. The average height of the individuals with the Fragile-X was less than that of published standards. Seventeen of the 18 subjects had absolute or relative macrocephaly, and two-thirds of the subjects were dolichocephalic. For the group as a whole, facial and ear lengths were increased, and facial breadth, hand length, and foot length were decreased. It is suggested that relationships between various measurements of an individual may be more important than any single measurements for conveying the characteristic appearance of an individual with the Fragile-X syndrome.     

Neurofibromatosis and fragile-X syndrome in the same patient

We report on an 11 1/2-year-old boy with neurofibromatosis and the fragile-X syndrome. Clinical manifestation of neurofibromatosis include multiple cafe-au-lait spots, axillary freckles, congenital glaucoma, relative macrocephaly, radiologic findings of overtubulation of the long bones, and precocious puberty. The fragile-X syndrome manifests itself as mental retardation with behavior problems, macro-orchidism, and specific cytogenetic findings. The boy has normal serum hormone levels, but a greatly elevated FSH on a first morning void, which contains the nocturnally secreted gonadotropins. This seems to be the first reported occurrence of the fragile-X syndrome with another inherited disease.     

Abnormal temporal dynamics of visual attention in Alzheimer's disease and in dementia with Lewy bodies

Although attentional control processes are disproportionately impaired in dementia with Lewy bodies (DLB) compared with dementia of the Alzheimer type (DAT), previous studies have not compared directly the temporal dynamics of visual attention in DLB and DAT. We examined the magnitude of the attentional blink (AB) effect in these patients, to determine the degree to which each patient group exhibited a deficit in selecting and processing visual stimuli presented in rapid succession. Eighteen DAT, 15 DLB patients, and 33 elderly controls were tested in a rapid serial visual presentation task. Participants were asked to report 1 (single-target condition) or 2 target letters (dual-target condition) embedded in a sequence of digit distracters. The temporal dynamics of visual attention was examined by varying the number of intervening distracters between the 2 targets in the dual-target condition and by estimating the attentional blink effect as the decline in the ability to report the second target correctly after successfully identifying the first. Patients with DLB performed significantly worse than patients with DAT and controls in both the single and dual-targets conditions. In contrast, DAT patients showed a selective impairment in the dual-target condition as compared with controls. As predicted, we found that both patients with DAT and DLB showed a more pronounced and protracted attentional blink than controls, indicating a reduced ability to re-engage attention on the second target. Furthermore, when DAT and DLB patients were able to report the second target, they frequently failed to identify the first, an effect that was absent in elderly controls and particularly large and long-lasting in DLB patients. This study suggests that both DLB and DAT patients show abnormal temporal dynamics of visual selective attention, presumably due to a greater intertarget competition for limited processing capacity. More generally, these findings reinforce the notion that deficits of attentional control processes are more severe in DLB patients as compared with DAT patients.     

Assessment of behavior change in a fragile-X syndrome male treated with folic acid

The effects of folic acid treatment were assessed in a 7-year-old boy with Fragile-X (fra(X] syndrome utilizing a within-subject experimental design. Dependent variables consisted of classroom behavior, activity level/impulsiveness, and attentiveness. While improvements in all dependent variables were observed during folic acid treatment in comparison to initial baseline/placebo conditions, these changes were maintained in a final return to the placebo condition. These results do not support unequivocally the effectiveness of folic acid treatment. Folic acid treatment may have facilitated behavior changes that were then maintained by natural contingencies in the child's environment.     

Gonadal function in men with the Martin-Bell (fragile-X) syndrome

We evaluated testicular function in 15 men with the Martin-Bell (fragile-X) mental retardation syndrome. Macro-orchidism was present in all subjects. Their mean serum LH and FSH levels and plasma testosterone and dihydrotestosterone levels were normal. The mean plasma levels of androstenedione, 17-hydroxyprogesterone, and progesterone were slightly elevated above the normal range, whereas the plasma levels of dehydroepiandrosterone and dehydroepiandrosterone-sulfate were normal. The response in the levels of plasma testosterone following a 5 day period of hCG stimulation was normal in 8 subjects and there was no abnormal accumulation of androgen precursors. The level of 5 alpha-reductase activity and androgen receptor binding was normal in genital skin fibroblasts derived from 3 of these patients. The response of gonadotropin secretion to GnRH stimulation was normal in the 8 men who were tested. Therefore, our data are consistent with the hypothesis that testicular enlargement in men with the Martin-Bell syndrome is not mediated by hormonal factors.     

A dermatoglyphic study of a group of Sicilian children with fragile-X syndrome

In a dermatoglyphic study of 14 fra(X) boys (compared with a control group of 191 normal schoolboys), we observed the following statistically significant (p less than 0.01) differences: 1) lower frequency of ulnar loops on the fingertips, particularly on the 2nd and 3rd fingers, with a corresponding increase of whorls; 2) transverse course of main line A; 3) increased frequency of abnormal palmar creases. The log score index of Simpson et al [1984] identified 71.4% of our patients and that of Rodewald et al [1986] 64.2%. The different values of these indexes can probably be attributed to ethnic differences. We think that by combining the results of dermatoglyphic analysis from several centers a more discriminatory log score index can be obtained.     

Prevalence of the fragile-X syndrome in mentally retarded boys in a Swedish county

In an etiological study of an unselected series of mentally retarded children (IQ less than 70) born 1959-1970 in a northern Swedish county, 12 of 205 boys (5.9%) were found to have a fragile site on the distal end of the C-chromosome (fra (X) (q27]. The incidence of the fra (X) syndrome was calculated to be 1:1500 boys in this county. If this is true for the whole of Sweden, 30-40 new cases of the fra (X) syndrome should be born yearly in Sweden. This must be considered a minimum figure, since a certain proportion of individuals with fra (X) are not observed in groups of mentally retarded patients. Next to trisomy 21, the fragile X syndrome is the most common specific cause of mental retardation among mentally retarded boys in Sweden.     

Spatial and temporal processing in patients with Turner's syndrome

Thirteen females with Turner's syndrome were examined for spatial abilities and serial processing, and their performance was compared with that of normal females matched by age, intelligence, and socioeconomic class. Patients with Turner's syndrome performed significantly poorer on tests of spatial ability than controls, but only on spatial tests requiring the integration of isolated elements as synthetic wholes or the remembering of spatial configurations which could not be verbally mediated. Patients also performed less well than controls on tasks of serial processing when the tasks could not be mediated verbally. It was concluded that patients with Turner's syndrome may have a selective deficit in cortical junctions that are lateralized to the right cerebral hemisphere.The work for this study was performed while the authors were supported by a grant from the Grant Foundation, and while P. H. W. was supported by USPHS Research Grants MH 18332-04 and HD 03 0773 and by USPHS Career Scientist Award MHK 3461.     

Overlapping visual response latency distributions in visual cortices and LP-pulvinar complex of the cat

The visual system of the cat is considered to be organized in both a serial and parallel manner. Studies of visual onset latencies generally suggest that parallel processing occurs throughout the dorsal stream. These studies are at odds with the proposed hierarchies of visual areas based on termination patterns of cortico–cortical projections. In previous studies, a variety of stimuli have been used to compute latencies, and this is problematic as latencies are known to depend on stimulus parameters. This could explain the discrepancy between latency and neuroanatomical based studies. Therefore, the first aim of the present study was to determine whether latencies increased along the hierarchy of visual areas when the same stimuli are used. In addition, the effect of stimulus complexity was assessed. Visual onset latencies were calculated for area 17, PMLS, AMLS, and AEV neurons. Latencies were also computed from neurons in the lateral posterior (LP)-pulvinar complex given the importance of this extrageniculate complex in cortical intercommunication. Latency distributions from all regions overlapped substantially, and no significant difference was present, regardless of the type of stimulus used. The onset latencies in the LP–pulvinar complex were comparable to those seen in cortical areas. The data suggest that the initial processing of information in the visual system is parallel, despite the presence of a neuroanatomical hierarchy. Simultaneous response onsets among cortical areas and the LP-pulvinar suggest that the latter is more than a simple relay station for information headed to cortex. The data are consistent with proposals of the LP-pulvinar as a center for the integration and distribution of information from/to multiple cortical areas.     

Perception of burden among at-risk women of raising a child with fragile-X syndrome

On a self-administered questionnaire 31 women at-risk for bearing children with fragile-X syndrome (FXS) were asked to judge the magnitude of the problems they perceived to be associated with raising an affected child. An age- and education-matched group of women with no family history of FXS was asked to predict the seriousness of problems they might encounter were they to bear a child with a handicapping condition. Mothers of children with FXS reported that they were experiencing fewer and different problems than FXS relatives who did not have affected children predicted they themselves would experience. The perceptions of the burden of raising a handicapped child of FXS relatives without affected children were more similar to those of the comparison group than to those of FXS mothers. This suggests that women who raise a child with FXS learn to cope with an unchangeable situation, and consequently their perceptions of the burdens ease with time. A direct relationship between the acceptability of selective abortion and the perceived seriousness of the problems associated with having an affected child was observed.     

Thinning of sensorimotor cortices in children with Tourette syndrome

The basal ganglia portions of cortico-striato-thalamo-cortical (CSTC) circuits have consistently been implicated in the pathogenesis of Tourette syndrome, whereas motor and sensorimotor cortices in these circuits have been relatively overlooked. Using magnetic resonance imaging, we detected cortical thinning in frontal and parietal lobes in groups of Tourette syndrome children relative to controls. This thinning was most prominent in ventral portions of the sensory and motor homunculi that control the facial, orolingual and laryngeal musculature that is commonly involved in tic symptoms. Correlations of cortical thickness in sensorimotor regions with tic symptoms suggest that these brain regions are important in the pathogenesis of Tourette syndrome.     

Granule cell dendritic spine density in the rat hippocampus varies with spine shape and location

The number of granule cell dendritic spines per micrometer of dendritic length in the dorsal and ventral leaves of the dentate gyrus was quantified using light microscopic-Golgi preparations of normal adult rats. Spines were counted in terms of 3 categories of spine form for the 3 afferent termination zones of the molecular layer and corrected for shading errors. Total spine density averaged 1.6 spines/micron of dendritic length in the dorsal leaf and 1.3 spines/micron of dendritic length in the ventral leaf. Statistically significant differences in spine density existed among the 3 shape categories. Variations in spine density occurred by shape category among the afferent termination zones.     

Retroactive memory of a visual discrimination task in the rat: role of temporal-entorhinal cortices and their connections

Summary It has previously been shown that the temporal and entorhinal cortices may be critically involved in memory. In Experiment 1, rats with either damage to the temporal cortex (TC), lateral entorhinal cortex (LEC), or the medial entorhinal cortex (MEC) were tested for retention of a preoperatively acquired simultaneous brightness discrimination task. TC and LEC lesions impaired retention, whereas MEC lesions were without mnemonic effect. In Experiment 2, rats with either disruptions of the anterior neural connections of TC (TC/Ant), posterior connections of TC (TC/Post), or conjoint disruptions (Ant/Post) were tested for retention of the visual discrimination task. TC/Ant and Post/Ant lesions resulted in relatively mild, but significant memory impairment, whereas a profound effect was seen after TC/Post lesions. The results are discussed in terms of a very important role for LEC and its connections with TC in mnemonic function.     

On the accuracy of evaluations of temporal characteristics of visual perception

We studied the accuracy of evaluations of the temporal characteristics of visual perception: critical frequency of light flickers, time of perception, and time of visual analyzer recovery. Results of comparison of the accuracy of evaluations are presented. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 144, No. 8, pp. 236–237, August, 2007     

Impact of time-dependent changes in spine density and spine shape on the input-output properties of a dendritic branch: a computational study

Populations of dendritic spines can change in number and shape quite rapidly as a result of synaptic activity. Here, we explore the consequences of such changes on the input-output properties of a dendritic branch. We consider two models: one for activity-dependent spine densities and the other for calcium-mediated spine-stem restructuring. In the activity-dependent density model we find that for repetitive synaptic input to passive spines, changes in spine density remain local to the input site. For excitable spines, the spine density increases both inside and outside the input region. When the spine stem resistances are relatively high, the transition to higher dendritic output is abrupt; when low, the rate of increase is gradual and resembles long-term potentiation. In the second model, spine density is held constant, but the stem dimensions are allowed to change as a result of stimulation-induced calcium influxes. The model is formulated so that a moderate amount of synaptic activation results in spine stem elongation, whereas high levels of activation result in stem shortening. Under these conditions, passive spines receiving modest stimulation progressively increase their spine stem resistance and head potentials, but little change occurs in the dendritic output. For excitable spines, modest stimulation frequencies cause a lengthening of both stimulated and neighboring spines and the stimulus eventually propagates. High-frequency stimulation that causes spines to shorten in the stimulated region decreases the amplitude of the dendritic output slightly or drastically, depending on initial spine densities and stem resistances.