1 Departments of Pathology, , 2 Neurology, , 3 Pediatrics, and , 4 Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine and the , 5 Kennedy Krieger Institute, 707 N. Broadway, Baltimore, MD 21205, USA
![]() |
Abstract |
---|
![]() |
Introduction |
---|
For the purposes of this review, we will define as MR-associated disorders those conditions characterized by a non-progressive global cognitive deficit (e.g. Down syndrome, DS). We will focus on genetic syndromes, because they provide the potential for understanding the pathogenetic mechanisms of dendritic anomalies, and will also make some reference to childhood degenerative disorders that during their evolution display a cognitive profile that resembles MR (Kaufmann, 1996). The review includes a survey of disorders associated with dendritic anomalies, analyses of the relationships between dendritic pathology, cognitive phenotype and synaptic abnormalities, and the characterization of dendritic pathology in animal models relevant to MR. We conclude with a proposal for pathways linking specific gene mutations and dendritic phenotype.
![]() |
Dendritic Spine Dysgenesis and Unclassified MR |
---|
|
![]() |
Genetic Disorders with Definitive Dendritic Involvement: DS, RS, Fragile-X Syndrome |
---|
Dendritic length has also been evaluated in DS neocortex. In the previously cited study by Takashima and collaborators (Takashima et al., 1981), 14 fetuses and infants with DS were compared with normal age-matched controls. They found that shorter basilar dendrites were present only in those DS subjects who were older than 4 months. In a subsequent quantitative study of multiple dendritic branch parameters in eight infants and children with DS they showed that dendritic branching (measured as intersections using the Sholl's concentric circle) and length, in both apical and basilar dendrites, was greater than in controls in DS infants less than 6 months old (Becker et al., 1986
). Subsequent to this age, there was a steady decrease in these measures to below normal in subjects older than 2 years. These changes seemed more dramatic in apical dendrites of layer III neurons (Becker et al., 1986
). Additional cross-sectional studies have demonstrated marked reductions in dendritic branching, length and spine density in aged DS subjects (Takashima et al., 1989
) [reviewed by Becker et al. (Becker et al., 1991
)]. In these older individuals degenerative neuronal changes, such as those described by Marin-Padilla (Marin-Padilla, 1976
), were also associated with dendritic abnormalities. In the last decade, these findings have been corroborated by two other reports on pyramidal (Schulz and Scholz, 1992
) and non-pyramidal neurons (Prinz et al., 1997
) from the parietal and motor cortices, respectively. Normal or increased branching in DS infants (Schulz and Scholz, 1992
; Prinz et al., 1997
) contrasts with reduced dendrites and degenerative changes in older DS children (Schulz and Scholz, 1992
).
In contrast to DS, reductions in dendritic arborizations are present throughout life in RS (Armstrong et al., 1995). RS is a developmental disorder that affects females almost exclusively, with a large proportion of cases linked to mutations in the X chromosome gene MeCP2 (Amir et al., 1999
). The latter codes for a transcriptional regulator protein, linked to transcriptional repression of methylated gene sequences (Stratling and Yu, 1999
). MeCP2 mutations in RS would lead to altered functional domains of the protein (Amir et al., 1999
; Wan et al., 1999
). RS is characterized by an apparently normal perinatal period, followed by physical and neurological developmental arrest. Between ages 2 and 10 years (stages II and III) there is a regression of language and motor skills, seizures, and appearance of characteristic stereotypic movements. Severe neurologic impairment, including MR, stabilizes by late childhood (Naidu et al., 1995
; Naidu, 1997
). Initial neuroanatomic evaluations showed that cortical structure, including neuronal number and lamination, are relatively preserved in RS (Jellinger and Seitelberger, 1986
; Jellinger et al., 1988
). Cytoarchitectonic studies by Bauman and colleagues (Bauman et al., 1995
) showed that while neuronal size is reduced there is an increase in neuronal cell packing density. Consistent with this increased neuronal packing, Armstrong and collaborators (Armstrong et al., 1995
) demonstrated that basilar and, in some instances, apical branches of pyramidal cells from frontal, motor and inferior temporal cortices were significantly reduced when compared with normal controls. Relative preservation of posterior cortices is suggested by both volumetric neuroimaging (Reiss et al., 1993
) and these post-mortem dendritic (Armstrong et al., 1995
) studies. Basilar dendrites were more affected than apical ones, particularly in layer V neurons (Armstrong et al., 1995
). A more recent investigation by the same group provided additional evidence for the specificity of the dendritic abnormalities in RS cerebral cortex. When compared with neurons from individuals with DS, dendritic arborizations from RS subjects showed the greatest reductions again in premotor, motor and inferior temporal cortices (Armstrong et al., 1998
). These data underscore the severe nature of the dendritic tree disturbances in RS neocortex. Belichenko and collaborators (Belichenko et al., 1994
), using the lipophilic dye labeling technique and confocal microscopy, were able to delineate the 3-D structure of dendrites from prefrontal, motor and middle temporal areas. They demonstrated that apical dendrites were asymmetric and reduced, and that dendritic spines were markedly decreased, with some segments devoid of these elements. Apparently these spine changes did not correspond to spine dysgenesis, since illustrations in this publication show rather short but otherwise unremarkable spines (Belichenko et al., 1994
). Dendrites of hippocampal neurons have also been analyzed in RS. Armstrong et al. (Armstrong et al., 1995
) showed reduced dendritic arborizations confined to neurons of layers II and IV of the subiculum, and none in CA1. These data are somewhat at variance with cytoarchitectonic evaluations that reported higher neuronal density throughout the pyramidal layer (including CA1) and, to a lesser extent, in the subiculum (Bauman et al., 1995
).
Fragile-X syndrome (FraX) is the second most genetically determined form of MR [reviewed by Moser and Kaufmann and Reiss (Moser, 1995; Kaufmann and Reiss, 1999
)]. Despite its high frequency, FraX has been studied less extensively with neuropathological techniques than DS or RS. Only two publications have addressed the issue of neuronal abnormalities. Hinton and colleagues (Hinton et al., 1991
) extended the data on one subject previously reported by Rudelli et al. (Rudelli et al., 1985
). Neocortical analyses of the three mildly to moderately mentally retarded adult FraX subjects showed that neuronal density in the posterior cingulate and anterior temporal regions was similar to controls. However, Golgi preparations showed long tortuous dendritic spines with prominent heads. The less than optimal quality of the Golgi impregnations precluded an analysis of the dendritic branch or spine density (Hinton et al., 1991
). No subsequent studies have been reported in FraX subjects, although dendritic labeling by Golgi techniques has been applied to the mouse model of this condition, as described in a following section.
![]() |
Genetic Disorders with Probable Dendritic Involvement: Williams Syndrome, Rubinstein-Taybi Syndrome |
---|
Preliminary studies of cortical cytoarchitecture have been performed in two genetic disorders associated with MR: Williams syndrome (WS) and Rubinstein-Taybi syndrome (R-TS). WS is caused by a submicroscopic deletion on chromosome 7q11.23, which includes the elastin gene and the HPC-1/ syntaxin 1A (STX1A) gene that codes for a protein involved in the docking of synaptic vesicles [reviewed by Bellugi et al. and Botta et al. (Bellugi et al., 1999a; Botta et al., 1999
)]. Patients with WS show a distinctive cognitive and social phenotype. While they demonstrate relatively preserved language and face processing abilities, they are typically impaired in visuospatial domains. In addition, they are hypersociable, with engaging personality and excessive sociability with strangers (Bellugi et al., 1999a
,b
). Neuropathological data on WS are limited to descriptions of associations with CNS malformations (Pober and Filiano, 1995
) and AD-like changes (Golden et al., 1995
). A single study of one patient by Galaburda and colleagues (Galaburda et al., 1994
) reported several cytoarchitectonical anomalies, which included a reduction in columnar organization throughout the cortex, abnormal neuronal orientation and a generalized increase in cell packing density. These findings appeared to be more severe in posterior cortical regions, where there was a decrease in volume (Galaburda et al., 1994
), as had previously been shown by quantitative neuroimaging (Jernigan et al., 1993
). As the authors of both publications point out, this topographic distribution of severity of abnormalities is in general agreement with the WS cognitive phenotype. In conclusion, preliminary data indicate that in WS there is selective cortical hypoplasia associated with cytoarchitectonical features previously described in unclassified MR and DS (reduced laminar organization and abnormal neuronal orientation), and in autism and RS (increased neuronal cell packing density).
The second MR-related disorder in which cytoarchitectonics suggests dendritic abnormalities is R-TS. With an approximately similar incidence in the general population to RS (Moser, 1995), this condition is characterized by MR and a specific pattern of somatic abnormalities. The initial description by Rubinstein and Taybi (Rubinstein and Taybi, 1963
) emphasized short stature, facial dysmorphia, broad thumbs and first toes, and MR. More recent work has demonstrated a wider spectrum of physical and neurologic abnormalities, which include deficits in expressive language and maladaptive behavior (Stevens et al., 1990
). The genetic defect in R-TS (16p13.3) has been reported to involve cyclic AMP response element binding protein (CREB)-binding protein (CBP) (Petrij et al., 1995
), a protein that is recruited by CREB to bind DNA and activates the basal transcription factorenzyme complex (Kaufmann and Worley, 1999
). Limited neuroimaging and neuropathologic investigations have shown an association between R-TS and several CNS malformations, such as agenesis of the corpus callosum (Stevens et al., 1990
), Dandy-Walker malformation (Bonioli et al., 1989
) and cortical clefts (Sener, 1995
). The most comprehensive neuropathologic evaluation of a R-TS brain was carried out by Pogacar and collaborators (Pogacar et al., 1973
). These authors reported one adult male case (33 years) with mild reduction in brain weight, preserved general cortical architecture, but decreased neuronal size and a marked increase (semi-quantitative) in cell packing density. As the latter findings closely resembled those reported in RS (Kaufmann et al., 1998
), a reduction in dendritic arborizations appears also to be a feature of R-TS.
Two other relatively frequent genetic disorders, neurofibromatosis-1 and tuberous sclerosis (Bourneville disease, BD), usually present with mild MR or learning disorders (Harrison et al., 1999; Ozonoff, 1999
), and display focal cytoarchitectonic abnormalities suggestive of dendritic pathology. Direct dendritic evaluations have been carried out only in BD. Cortical tubers, the hallmark lesion in BD, are foci of disrupted laminar cortical architecture containing large and disorganized cells. Ferrer and colleagues (Ferrer et al., 1984
) and Machado-Salas (Machado-Salas, 1984
) demonstrated that tubers consist of maloriented pyramidal neurons, with simplified structure and aberrant dendritic branches and spines. Moreover, large numbers of stellate neurons and astrocytes are also present in these clusters. Machado-Salas (Machado-Salas, 1984
) even suggested neuronoglial formations with specialized contacts. Huttenlocher and Heydemann (Huttenlocher and Heydemann, 1984
) confirmed most of these findings and examined the neocortex intervening between tubers. Despite its normal architecture and dendritic morphology, this adjacent cortex shows a decrease in dendritic branch length. These authors emphasized the similarity between these dendritic reductions and those found in several forms of MR. Table 1
summarizes the dendritic and cytoarchitectonic abnormalities found in genetic disorders with definitive and probable dendritic involvement, respectively.
|
![]() |
Dendritic Abnormalities and Cognitive Profile |
---|
Are dendritic abnormalities a specific feature of MR? Huttenlocher (Huttenlocher, 1991) and others (Williams et al., 1978
) in their studies of dendrites have emphasized the existence of confounding variables, such as cardiac malformations in chromosopathies. Even after these factors are taken into account, the description of similar changes in several metabolic disorders that affect primarily the cerebral cortex and present with a degenerative-dementing course (Della Giustina, et al., 1981
; Takashima et al., 1985
) support the concept that marked dendritic abnormalities are an index of major neuronal disruption. However, there are some differences between the findings in metabolic-degenerative disorders and those of genetic MR. First, neuronal migration defect or severe lamination disturbance are relatively common in the progressive metabolic disorders (Barth, 1987
) but absent in the non-progressive genetic disorders such as DS. Second, in many metabolic disorders there is accumulation of storage material in neuronal somata and proximal dendrites and axons that leads to distinctive Golgi impregnation patterns (Williams et al., 1977
; Purpura, 1978
; Takashima et al., 1985
). The dendritic aberrations in storage disorders such as gangliosidoses and neuronal ceroid lipofuscinoses are associated with abnormalities of the axon and the presynaptic domain, and include anomalous spatial configuration of cortical neurons (Purpura and Suzuki, 1976
). Phenylketonuria (PKU) shows a yet different pattern. This aminoacidopathy, which leads to MR when untreated, has been characterized from the neuropathologic standpoint to be associated with changes in the white matter. There is no storage. However, Bauman and Kemper (Bauman and Kemper, 1982
) with the aid of Golgi techniques have shown that gray matter pathology, particularly dendritic changes, is even more pronounced than that in the white matter. They found reductions in dendritic arborizations and spine dysgenesis that were similar to those reported in unclassified MR and DS. It appears therefore that metabolic-degenerative disorders show qualitative and quantitative alterations of dendritic morphology that correlate with cognitive impairment as in MR. However, these changes are dynamic and share with MR only the diffuse and severe magnitude of the dendritic pathology (Kaufmann, 1992
).
If severe dendritic changes are a reflection of generalized cortical dysfunction, milder cognitive impairment should be associated with milder dendritic abnormalities. Two studies have partially addressed this issue. The first compared cortical areas with significant dendritic reductions in RS, in which there is profound cognitive impairment, with comparable samples from DS patients. All three premotor, motor and visual cortices in RS had reduced dendritic length compared with DS, with the greatest reductions affecting the frontal regions (Armstrong et al., 1998). As cognitive impairment is, in general, greater in RS than DS, these comparisons suggest a direct relationship between dendritic pathology and cognitive deficit. A more direct assessment was carried out by Yan et al. (Yan et al., 1989
), who demonstrated a parallel between dendritic decreases and degree of MR in adult cretinism. Unfortunately, virtually no data about dendritic anomalies are available in individuals with learning disabilities. If severity and extent of dendritic pathology correlates with cognitive function, it is expected that learning disabled subjects would show mild dendritic abnormalities. In support of this hypothesis are the findings in three cases with FraX, with IQ in the 4060 range. Hinton and collaborators (Hinton et al., 1991
) reported the presence of dendritic spine abnormalities without cytoarchitectonic changes.
If dendritic abnormalities are a signature of global cognitive dysfunction, do they play a role in the selective cognitive deficits observed in many syndromes associated with MR? Neuropathologic and neuroimaging studies have already shown some correlations between cortical regional volume and specific impairment. For instance, in DS there is a reduction in temporal and frontal lobe volumes that, in general terms, is in agreement with the selective impairment in language in these patients (Kemper, 1988; Jernigan et al. 1993
). Similar associations have been demonstrated for visuospatial impairment and parietooccipital volumes in WS (Jernigan et al., 1993
). These topographical surveys, which require the evaluation of a large number of cortical regions, can be correlated with neuroimaging approaches, particularly when large blocks of cortex are measured. A more difficult task is the quantitative or semiquantitative study of cytoarchitectonics or Golgi-based dendritic evaluations of multiple cortical areas. To our knowledge, complete qualitative cytoarchitectonic surveys have only been reported for DS [multiple subjects (Kemper, 1988
)], RS [three patients (Bauman et al., 1995
)] and WS [one individual (Galaburda et al., 1994
)]. Only the latter study attempted to relate pattern of cortical structure and cognitive profile, and no cytoarchitectonic investigation has yet reported measures of multiple cortical regions. In terms of dendritic arborizations, a single study of RS evaluated several cortical regions and neuronal populations within each area (Armstrong et al., 1995
). Areas related to preparation (area 6, frontal premotor) and execution (area 4, frontal motor) of movements were affected in RS, whereas the occipital visual cortex (area 17) was relatively preserved. These findings are consistent with the RS phenotype, in which there is severe motor impairment (hypotonia, poor hand use, stereotypic movements, gait disturbances) with relative sparing of visual function (Naidu, 1997
). A follow-up study confirmed and expanded the initial observations, but also showed preservation of the superior temporal cortex (Armstrong et al., 1998
), a region involved in language processing. As language delay and regression are typical features of RS (Naidu, 1997
), these later studies do not support the postulate that dendritic abnormalities reflect cortical dysfunction. More studies are needed to evaluate the relationship between dendritic abnormalities and cognitive profile in MR.
Another critical feature shown by several MR-associated disorders is the diminished maturational increment of cognition and sometimes-frank decline. This has been evaluated from the dendritic viewpoint in three of the main genetic syndromes: DS (Hayes and Batshaw, 1993), RS (Naidu, 1997
) and FraX (Fisch et al., 1999a
). Studies of DS have suggested dendritic changes as a basis for cognitive decline, but there is as yet no evidence for such a relationship for the other two disorders. In cross-sectional analyses of dendritic growth (length) in DS (Takashima et al., 1981
; Becker et al., 1986
), dendritic arborizations appeared to be overproduced initially, with a tendency to regress towards the end of the first year, a temporal pattern that parallels cognitive evaluations. In contrast, Armstrong and collaborators (Armstrong et al., 1995
) did not find a relationship between dendritic length and age. It should be noted, however, that their regression analyses covered a wide age range (2.935 years), which could have masked the declining phase of cognition that occurs between ages 2 and 10 years.
![]() |
Dendritic Abnormalities and Synaptic Circuitry and MR |
---|
|
![]() |
Animal Models of MR and Dendritic Pathology |
---|
|
![]() |
From Genotype to Dendritic Phenotype |
---|
|
|
![]() |
Concluding Comments |
---|
![]() |
Notes |
---|
Address correspondence to Walter E. Kaufmann, MD, Department of Developmental Cognitive Neurology, Kennedy Krieger Institute, Room 522, 707 N. Broadway, Baltimore, MD 21205, USA. Email: wekaufma{at}jhmi.edu.
![]() |
References |
---|
Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY (1999) Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nature Genet 23:185188.[ISI][Medline]
Armstrong D, Dunn JK, Antalffy B, Trivedi R (1995) Selective dendritic alterations in the cortex of Rett syndrome. J Neuropathol Exp Neurol 54:195201.[ISI][Medline]
Armstrong DD, Dunn K, Antalffy B (1998) Decreased dendritic branching in frontal, motor and limbic cortex in Rett syndrome compared with trisomy 21. J Neuropathol Exp Neurol 57:10131017.[ISI][Medline]
Bading H (1999) Nuclear calcium-activated gene expression: possible roles in neuronal plasticity and epileptogenesis. Epilepsy Res 36: 225231.[ISI][Medline]
Barth PG (1987) Disorders of neuronal migration. Can J Neurol Sci 14: 116.[ISI][Medline]
Batshaw ML (1993) Mental retardation. Pediatr Clin North Am 40: 507521.[ISI][Medline]
Bauman ML, Kemper TL (1982) Morphologic and histoanatomic observations of the brain in untreated phenylketonuria. Acta Neuropathol (Berl) 58:5563.[ISI][Medline]
Bauman M, Kemper TL (1985) Histoanatomic observations of the brain in early infantile autism. Neurology 35:866874.[Abstract]
Bauman ML, Kemper TL, Arin DM (1995) Pervasive neuroanatomic abnormalities of the brain in three cases of Rett's syndrome. Neurology 45:15811586.[Abstract]
Becker LE, Armstrong DL, Chan F (1986) Dendritic atrophy in children with Down's syndrome. Ann Neurol 20:520526.[ISI][Medline]
Becker L, Mito T, Takashima S, Onodera K (1991) Growth and development of the brain in Down syndrome. Prog Clin Biol Res 373:133152.[Medline]
Belichenko PV, Oldfors A, Hagberg B, Dahlström A (1994) Rett syndrome: 3-D confocal microscopy of cortical pyramidal dendrites and afferents. NeuroReport 5:15091513.[ISI][Medline]
Bellugi U, Lichtenberger L, Mills D, Galaburda A, Korenberg JR (1999a) Bridging cognition, the brain and molecular genetics: evidence from Williams syndrome. Trends Neurosci 22:197207.[ISI][Medline]
Bellugi U, Adolphs R, Cassady C, Chiles M (1999b) Towards the neural basis for hypersociability in a genetic syndrome. NeuroReport 10: 16531657.[ISI][Medline]
Benitez-Bribiesca L, De la Rosa-Alvarez I, Mansilla-Olivares A (1999) Dendritic spine pathology in infants with severe protein-calorie malnutrition. Pediatrics 104:e21.[Medline]
Bodick N, Stevens JK, Sasaki S, Purpura DP (1982) Microtubular disarray in cortical dendrites and neurobehavioral failure. II. Computer reconstruction of perturbed microtubular arrays. Brain Res 281:299309.[Medline]
Bonioli E, Bellini C, Di Stefano A (1989) Unusual association: Dandy-Walker-like malformation in the Rubinstein-Taybi syndrome. Am J Med Genet 33:420421.[ISI][Medline]
Borchelt DR, Wong PC, Sisodia SS, Price DL (1998) Transgenic mouse models of Alzheimer's disease and amyotrophic lateral sclerosis. Brain Pathol 8:735757.[ISI][Medline]
Botta A, Sangiuolo F, Calza L, Giardino L, Potenza S, Novelli G, Dallapiccola B (1999) Expression analysis and protein localization of the human HPC-1/Syntaxin 1A, a gene deleted in Williams syndrome. Genomics 62:525528.[ISI][Medline]
Buell SJ (1982) GolgiCox and rapid Golgi methods as applied to autopsied human brain tissue: widely disparate results. J Neuropathol Exp Neurol 41:500507.[ISI][Medline]
Ceman S, Brown V, Warren ST (1999) Isolation of an FMRP-associated messenger ribonucleoprotein particle and identification of nucleolin and the fragile X-related proteins as components of the complex. Mol Cell Biol 19:79257932.
Comery TA, Harris JB, Willems PJ, Oostra BA, Irwin SA, Weiler IJ, Greenough WT (1997) Abnormal dendritic spines in fragile X knockout mice: maturation and pruning deficits. Proc Natl Acad Sci USA 94:54015404.
Cordero ME, D'Acuna E, Benveniste S, Prado R, Nunez JA, Colombo M (1993) Dendritic development in neocortex of infants with early postnatal life undernutrition. Pediatr Neurol 9:457464.[ISI][Medline]
Coy JF, Sedlacek Z, Bachner D, Delius H, Poustka A (1999) A complex pattern of evolutionary conservation and alternative polyadenylation within the long 3'-untranslated region of the methyl-CpG-binding protein 2 gene (MeCP2) suggests a regulatory role in gene expression. Hum Mol Genet 8:12531262.
Cragg BG (1975) The density of synapses and neurons in normal, mentally defective and aging human brains. Brain 98:8190.[ISI][Medline]
Crino PB, Eberwine J (1997) Cellular and molecular basis of cerebral dysgenesis. J Neurosci Res 50:907916.[ISI][Medline]
Crome L, Stern J (1972) Pathology of mental retardation. Edinburgh: Churchill Livingstone.
Crosby EC, Humphrey T, Lauer EW (1962) Correlative anatomy of the nervous system. New York: Macmillan.
Della Giustina E, Goffinet AM, Landrieu P (1981) A Golgi study of the brain malformation in Zellweger's cerebro-hepato-renal disease. Acta Neuropathol (Berl) 55:2328.[ISI][Medline]
DeLong GR (1993) Effects of nutrition on brain development in humans. Am J Clin Nutr 57(2 Suppl):286S290S.[Abstract]
Diaz-Cintra S, Cintra L, Ortega A, Kemper T, Morgane PJ (1990) Effects of protein deprivation on pyramidal cells of the visual cortex in rats of three age groups. J Comp Neurol 292:117126.[ISI][Medline]
Diaz-Cintra S, Garcia-Ruiz M, Corkidi G, Cintra L (1994) Effects of prenatal malnutrition and postnatal nutritional rehabilitation on CA3 hippocampal pyramidal cells in rats of four ages. Brain Res 662:117126.[ISI][Medline]
Dickson DW (1997) The pathogenesis of senile plaques. J Neuropathol Exp Neurol 56:321339.[ISI][Medline]
Ferrer I, Gullotta F (1990) Down's syndrome and Alzheimer's disease: dendritic spine counts in the hippocampus. Acta Neuropathol (Berl) 79:680685.[ISI][Medline]
Ferrer I, Fabregues I, Coll J, Ribalta T, Rives A (1984) Tuberous sclerosis: a Golgi study of cortical tuber. Clin Neuropathol 3:4751.[ISI][Medline]
Fisch GS, Carpenter N, Holden JJ, Howard-Peebles PN, Maddalena A, Borghgraef M, Steyaert J, Fryns JP (1999a) Longitudinal changes in cognitive and adaptive behavior in fragile X females: a prospective multicenter analysis. Am J Med Genet 83:308312.[ISI][Medline]
Fisch GS, Hao HK, Bakker C, Oostra BA (1999b) Learning and memory in the FMR1 knockout mouse. Am J Med Genet 84:277282.[ISI][Medline]
Freytag E, Lindenberg R (1967) Neuropathologic findings in patients of a hospital for the mentally deficient. A survey of 359 cases. Johns Hopkins Med J 121:379392.[ISI][Medline]
Galaburda AM, Wang PP, Bellugi U, Rossen M (1994) Cytoarchitectonic anomalies in a genetically based disorder: Williams syndrome. Neuro-Report 5:753757.[ISI][Medline]
Golden JA, Hyman BT (1994) Development of the superior temporal neocortex is anomalous in trisomy 21. J Neuropathol Exp Neurol 53:513520.[ISI][Medline]
Golden JA, Nielsen GP, Pober BR, Hyman BT (1995) The neuropathology of Williams syndrome. Report of a 35-year-old man with presenile beta/A4 amyloid plaques and neurofibrillary tangles. Arch Neurol 52:209212.[Abstract]
Greenough WT (1984) Structural correlates of information storage in the mammalian brain: a review and hypothesis. Trends Neurosci 7: 229233.[ISI]
Hannigan JH, Berman RF (2000) Amelioration of fetal alcohol-related neurodevelopmental disorders in rats: exploring pharmacological and environmental treatments. Neurotoxicol Teratol 22:103111.[ISI][Medline]
Harrison JE, O'Callaghan FJ, Hancock E, Osborne JP, Bolton PF (1999) Cognitive deficits in normally intelligent patients with tuberous sclerosis. Am J Med Genet 88:642646.[ISI][Medline]
Haydar TF, Blue ME, Molliver ME, Krueger BK, Yarowsky PJ (1996) Consequences of trisomy 16 for mouse brain development: corticogenesis in a model of Down syndrome. J Neurosci 16: 61756182.
Hayes A, Batshaw ML (1993) Down syndrome. Pediatr Clin North Am 40:523535.[ISI][Medline]
Hinton VJ, Brown WT, Wisniewski K, Rudelli RD (1991) Analysis of neocortex in three males with the fragile X syndrome. Am J Med Genet 41:289294.[ISI][Medline]
Hohmann CF, Kwiterovich KK, Oster-Granite ML, Coyle JT (1991) Newborn basal forebrain lesions disrupt cortical cytodifferentiation as visualized by rapid Golgi staining. Cereb Cortex 1:143157.[Abstract]
Holtzman DM, Santucci D, Kilbridge J, Chua-Couzens J, Fontana DJ, Daniels SE, Johnson RM, Chen K, Sun Y, Carlson E, Alleva E, Epstein CJ, Mobley WC (1996) Developmental abnormalities and age-related neurodegeneration in a mouse model of Down syndrome. Proc Natl Acad Sci USA 93:1333313338.
Hornykiewicz O (1963) Die topische Lokalisation und das Verhalten von Noradrenalin und Dopamin (3-Hydroxytyramin) in der Sustantia Nigra des normalen und Parkinson kranken Meschen. Wien Klin Wochenschr 75:309312.
Huttenlocher PR (1970) Dendritic development and mental defect. Neurology 20:381.
Huttenlocher PR (1974) Dendritic development in neocortex of children with mental defect and infantile spasms. Neurology 24:203210.[ISI][Medline]
Huttenlocher PR (1991) Dendritic and synaptic pathology in mental retardation. Pediat Neurol 7:7985.[ISI][Medline]
Huttenlocher PR (1999) Dendritic and synaptic development in human cerebral cortex: time course and critical periods. Devl Neuropsychol 16:347349.[ISI]
Huttenlocher PR, Heydemann PT (1984) Fine structure of cortical tubers in tuberous sclerosis: a Golgi study. Ann Neurol 16:595602.[ISI][Medline]
Ipina SL, Ruiz-Marcos A (1986) Dendritic structure alterations induced by hypothyroidism in pyramidal neurons of the rat visual cortex. Brain Res 394:6167.[Medline]
Jellinger K (1972) Neuropathological features of unclassified mental retardation. In: The brain in unclassified mental retardation (Cavanagh JB, ed.), pp. 293306. London: Churchill Livingstone.
Jellinger K, Seitelberger F (1986) Neuropathology of Rett syndrome. Am J Med Genet Suppl 1:259288.[Medline]
Jellinger K, Armstrong D, Zoghbi HY, Percy AK (1988) Neuropathology of Rett syndrome. Acta Neuropathol (Berl) 76:142158.[ISI][Medline]
Jernigan TL, Bellugi U, Sowell E, Doherty S, Hesselink JR (1993) Cerebral morphologic distinctions between Williams and Down syndromes. Arch Neurol 50:186191.[Abstract]
Kaufmann WE (1992) Editorial. Cerebrocortical changes in AIDS. Lab Invest 66:261264.[ISI][Medline]
Kaufmann WE (1996) Mental retardation and learning disabilities: a neuropathologic differentiation. In: Developmental disabilities in infancy and childhood (Capute AJ, Accardo PJ, eds), vol. 2, pp. 4970. Baltimore, MD: Paul H. Brookes Publishing.
Kaufmann WE (1999) Cytoskeletal determinants of dendritic development and function: implications for mental retardation. Devl Neuropsychol 16:341346.[ISI]
Kaufmann WE, Galaburda AM (1989) Cerebrocortical microdysgenesis in neurologically normal subjects: a histopathologic study. Neurology 39:238244.[Abstract]
Kaufmann WE, Reiss AL (1999) Molecular and cellular genetics of Fragile X syndrome. Am J Med Genet (Neuropsychol Genet) 88:1124.
Kaufmann WE, Worley PF (1999) The role of early neural activity in regulating immediate early gene expression in the cerebral cortex. MRDD Res Rev 5:4150.
Kaufmann WE, Yamagata K, Andreasson KI, Worley PF (1994) Rapid response genes as markers of cellular signaling during cortical histogenesis: their potential in understanding mental retardation. Int J Devl Neurosci 12:263271.[ISI][Medline]
Kaufmann WE, Naidu S, Budden S (1995) Abnormal expression of microtubule-associated protein 2 (MAP-2) in neocortex in Rett syndrome. Neuropediatrics 26:109113.[ISI][Medline]
Kaufmann WE, Worley PF, Taylor CV, Bremer M, Isakson PC (1997a) Cyclooxygenase 2 expression during rat neocortical development and in Rett syndrome. Brain Dev 19:2534.[ISI][Medline]
Kaufmann WE, Taylor CV, Hohmann CF, Sanwal IB, Naidu S (1997b) Abnormalities in neuronal maturation in Rett syndrome neocortex: preliminary molecular correlates. Eur Child Adolesc Psychiat 6(Suppl 1):7577.[ISI][Medline]
Kaufmann WE, Pearlson GD, Naidu S (1998) The neuroanatomy of Rett syndrome: neuropathological and neuroimaging studies. Riv Med 4:187199.
Kemper TL (1988) Neuropathology of Down syndrome. In: The psychobiology of Down syndrome (Nadel L, ed.), pp. 269289. Cambridge, MA: MIT Press.
Kemper TL, Bauman M (1998) Neuropathology of infantile autism. J Neuropathol Exp Neurol 57:645652.[ISI][Medline]
Lacey DJ (1985) Normalization of dendritic spine numbers in rat hippocampus after termination of phenylacetate injections (PKU model). Brain Res 329:354355.[ISI][Medline]
Liu J, Tan Y, Zhuang Z, Shi Z, Chen B, Zhang J (1989) Influence of iodine deficiency on human fetal thyroid gland and brain. In: Iodine and the brain (DeLong GR, Robbins J, Condliffe PG, eds), pp. 249258. New York: Plenum.
Logdberg B, Brun A (1993) Prefrontal neocortical disturbances in mental retardation. J Intellect Disabil Res 37:459468.[ISI][Medline]
Ludlow JR, Allen LM (1979) The effect of early intervention and pre-school stimulus on the development of the Down's syndrome child. J Ment Defic Res 23:2944.[ISI][Medline]
Machado-Salas JP (1984) Abnormal dendritic patterns and aberrant spine development in Bourneville's diseasea Golgi survey. Clin Neuropathol 3:5258.[ISI][Medline]
Marin-Padilla M (1972) Structural abnormalities of the cerebral cortex in human chromosomal aberrations. A Golgi study. Brain Res 44: 625629.[ISI][Medline]
Marin-Padilla M (1974) Structural organization of the cerebral cortex (motor area) in human chromosomal aberrations. A Golgi study. I. D1 (1315) trisomy, Patau syndrome. Brain Res 66:373391.
Marin-Padilla M (1976) Pyramidal cell abnormalities in the motor cortex of a child with Down's syndrome: a Golgi study. J Comp Neurol 167: 6382.[ISI][Medline]
Masliah E, Heaton RK, Marcotte TD, Ellis RJ, Wiley CA, Mallory M, Achim CL, McCutchan JA, Nelson JA, Atkinson JH, Grant I (1997) Dendritic injury is a pathological substrate for human immunodeficiency virus-related cognitive disorders. HNRC Group. The HIV Neurobehavioral Research Center. Ann Neurol 42:963972.[ISI][Medline]
McAllister AK, Katz LC, Lo DC (1997) Opposing roles for endogenous BDNF and NT-3 in regulating cortical dendritic growth. Neuron 18: 767778.[ISI][Medline]
Moser HW (1995) A role for gene therapy in mental retardation. MRDD Res Rev 1:46.
Naidu S, Hyman S, Harris EL, Narayanan V, Johns D, Castora F (1995) Rett syndrome studies of natural history and search for a genetic marker. Neuropediatrics 26:6366.[ISI][Medline]
Naidu S (1997) Rett syndrome: a disorder affecting early brain growth. Ann Neurol 42:310.[ISI][Medline]
Nigam MP, Labar DR (1979) The effect of hyperphenylalaninemia on size and density of synapses in rat neocortex. Brain Res 179:195198.[ISI][Medline]
Nunez J, Couchie D, Aniello F, Bridoux AM (1992) Thyroid hormone effects on neuronal differentiation during brain development. Acta Med Aust 19(Suppl 1):3639.[ISI][Medline]
Ozonoff S (1999) Cognitive impairment in neurofibromatosis type 1. Am J Med Genet 89:4552.[ISI][Medline]
Petit TL, LeBoutillier JC, Alfano DP, Becker LE (1984) Synaptic development in the human fetus: a morphometric analysis of normal and Down's syndrome neocortex. Exp Neurol 83:1323.[ISI][Medline]
Petit TL, LeBoutillier JC, Gregorio A, Libstug H (1988) The pattern of dendritic development in the cerebral cortex of the rat. Devl Brain Res 41:209219.[ISI]
Petrij F, Giles RH, Dauwerse HG, Saris JJ, Hennekam RC, Masuno M, Tommerup N, van Ommen GJ, Goodman RH, Peters DJ, et al. (1995) Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP. Nature 376:348351.[ISI][Medline]
Pober BR, Filiano JJ (1995) Association of Chiari I malformation and Williams syndrome. Pediatr Neurol 12:8488.[ISI][Medline]
Pogacar S, Nora NF, Kemper TL (1973) Neuropathological findings in Rubinstein-Taybi syndrome. R I Med J 56:114121.[Medline]
Prinz M, Prinz B, Schulz E (1997) The growth of non-pyramidal neurons in the primary motor cortex of man: a Golgi study. Histol Histopathol 12:895900.[ISI][Medline]
Purpura DP (1974) Dendritic spine dysgenesis and mental retardation. Science 186:11261128.[ISI][Medline]
Purpura DP (1975a) Dendritic differentiation in human cerebral cortex: normal and aberrant developmental patterns. Adv Neurol 12:91116.[ISI][Medline]
Purpura DP (1975b) Normal and aberrant neuronal development in the cerebral cortex of human fetus and young infant. UCLA Forum Med Sci 18:141169.[Medline]
Purpura DP (1978) Ectopic dendritic growth in mature pyramidal neurones in human ganglioside storage disease. Nature 276:520521.[ISI][Medline]
Purpura DP, Suzuki K (1976) Distortion of neuronal geometry and formation of aberrant synapses in neuronal storage disease. Brain Res 116:121.[ISI][Medline]
Purpura DP, Bodick N, Suzuki K, Rapin I, Wurzelmann S (1982) Microtubule disarray in cortical dendrites and neurobehavioral failure. I. Golgi and electron microscopic studies. Brain Res 281: 287297.[Medline]
Raymond GV, Bauman ML, Kemper TL (1996) Hippocampus in autism: a Golgi analysis. Acta Neuropathol (Berl) 91:117119.[ISI][Medline]
Reiss AL, Faruque F, Naidu S, Abrams M, Beaty T, Bryan RN, Moser H (1993) Neuroanatomy of Rett syndrome: a volumetric imaging study. Ann Neurol 34:227234.[ISI][Medline]
Rorke LB (1994) A perspective: the role of disordered genetic control of neurogenesis in the pathogenesis of migration disorders. J Neuropathol Exp Neurol 53:105117.[ISI][Medline]
Rubinstein JH, Taybi H (1963) Broad thumbs and toes and facial abnormalities. A possible mental retardation syndrome. Am J Dis Child 105:88108.
Rudelli RD, Brown WT, Wisniewski K, Jenkins EC, Laure-Kamionowska M, Connell F, Wisniewski HM (1985) Adult fragile X syndrome. Clinico-neuropathologic findings. Acta Neuropathol (Berl) 67: 289295.[ISI][Medline]
Schulz E, Scholz B (1992) Neurohistological findings in the parietal cortex of children with chromosome aberrations. J Hirnforsch 33:3762.[ISI][Medline]
Sener RN (1995) Rubinstein-Taybi syndrome: cranial MR imaging findings. Comput Med Imag Graph 19:417418.[ISI][Medline]
Stevens CA, Carey JC, Blackburn BL (1990) Rubinstein-Taybi syndrome: a natural history study. Am J Med Genet Suppl 6:3037.[Medline]
Steward O, Bakker CE, Willems PJ, Oostra BA (1998) No evidence for disruption of normal patterns of mRNA localization in dendrites or dendritic transport of recently synthesized mRNA in FMR1 knockout mice, a model for human fragile-X mental retardation syndrome. NeuroReport 9:477481.[ISI][Medline]
Stratling WH, Yu F (1999) Origin and roles of nuclear matrix proteins. Specific functions of the MAR-binding protein MeCP2/ARBP. Crit Rev Euk Gene Expr 9:311318.[ISI][Medline]
Suetsugu M, Mehraein P (1980) Spine distribution along the apical dendrites of the pyramidal neurons in Down's syndrome. A quantitative Golgi study. Acta Neuropathol 50:207210.[ISI][Medline]
Takashima S, Becker LE, Armstrong DL, Chan F (1981) Abnormal neuronal development in the visual cortex of the human fetus and infant with Down's syndrome. A quantitative and qualitative Golgi study. Brain Res 225:121.[ISI][Medline]
Takashima S, Becker LE, Chan F-W, Augustin R (1985) Golgi and computer morphometric analysis of cortical dendrites in metabolic storage disease. Exp Neurol 88:652672.[ISI][Medline]
Takashima S, Ieshima A, Nakamura H, Becker LE (1989) Dendrites, dementia and the Down syndrome. Brain Dev 11:131133.[ISI][Medline]
Takashima S, Iida K, Mito T, Arima M (1994) Dendritic and histochemical development and ageing in patients with Down's syndrome. J Intellect Disabil Res 38:265273.[ISI][Medline]
Teller JK, Russo C, DeBusk LM, Angelini G, Zaccheo D, Dagna-Bricarelli F, Scartezzini P, Bertolini S, Mann DM, Tabaton M, Gambetti P (1996) Presence of soluble amyloid beta-peptide precedes amyloid plaque formation in Down's syndrome. Nature Med 2:9395.[ISI][Medline]
von Bossanyi P, Becher M (1990) Quantitative study of the dendritic spins of lamina V pyramidal neurons of the frontal lobe in children with severe mental retardation. J Hirnforsch 31:181192.[ISI][Medline]
Wan M, Lee SS, Zhang X, Houwink-Manville I, Song HR, Amir RE, Budden S, Naidu S, Pereira JL, Lo IF, Zoghbi HY, Schanen NC, Francke U (1999) Rett syndrome and beyond: recurrent spontaneous and familial MECP2 mutations at CpG hotspots. Am J Hum Genet 65:15201529.[ISI][Medline]
Williams RS, Lott IT, Ferrante RJ (1977) The cellular pathology of neuronal ceroid-lipofuscinosis. A Golgi-electronmicroscopic study. Arch Neurol 34:298305.[Abstract]
Williams RS, Ferrante RJ, Caviness VS (1978) The Golgi rapid method in clinical neuropathology: the morphologic consequences of suboptimal fixation. J Neuropathol Exp Neurol 37:1333.[ISI][Medline]
Williams RS, Hauser SL, Purpura DP, De Long GR, Swisher CN (1980) Autism and mental retardation. Neuropathologic studies performed in four retarded persons with autistic behavior. Arch Neurol 37: 749753.[Abstract]
Wisniewski KE (1990) Down syndrome children often have brain with maturation delay, retardation of growth, and cortical dysgenesis. Am J Med Genet Suppl 7:274281.[Medline]
Wisniewski KE, Kida E (1994) Abnormal neurogenesis and synaptogenesis in Down syndrome brain. Devl Brain Dysfunc 7:289301.
Wisniewski KE, Laure-Kamionowska M, Connell F, Wisniewski HM (1985) Quantitative determination of synaptic density and their morphology during the postnatal development in visual cortex of Down syndrome brain. J Neuropathol Exp Neurol 44:342 (abstract).
Yan Y, Guan C, Leng L, Li J (1989) Quantitative histology study on brain nervous cells of neurological endemic cretins. In: Iodine and the brain (DeLong GR, Robbins J, Condliffe PG, eds), p. 359. New York: Plenum.