Autism is characterized by a broad spectrum of clinical manifestations including qualitative impairments in social interactions and communication, and repetitive and stereotyped patterns of behavior. Abnormal acceleration of brain growth in early childhood, signs of slower growth of neurons, and minicolumn developmental abnormalities suggest multiregional alterations. The aim of this study was to detect the patterns of focal qualitative developmental defects and to identify brain regions that are prone to developmental alterations in autism. Formalin-fixed brain hemispheres of 13 autistic (4–60 years of age) and 14 age-matched control subjects were embedded in celloidin and cut into 200-μm-thick coronal sections, which were stained with cresyl violet and used for neuropathological evaluation. Thickening of the subependymal cell layer in two brains and subependymal nodular dysplasia in one brain is indicative of active neurogenesis in two autistic children. Subcortical, periventricular, hippocampal and cerebellar heterotopias detected in the brains of four autistic subjects (31%) reflect abnormal neuronal migration. Multifocal cerebral dysplasia resulted in local distortion of the cytoarchitecture of the neocortex in four brains (31%), of the entorhinal cortex in two brains (15%), of the cornu Ammonis in four brains and of the dentate gyrus in two brains. Cerebellar flocculonodular dysplasia detected in six subjects (46%), focal dysplasia in the vermis in one case, and hypoplasia in one subject indicate local failure of cerebellar development in 62% of autistic subjects. Detection of flocculonodular dysplasia in only one control subject and of a broad spectrum of focal qualitative neuropathological developmental changes in 12 of 13 examined brains of autistic subjects (92%) reflects multiregional dysregulation of neurogenesis, neuronal migration and maturation in autism, which may contribute to the heterogeneity of the clinical phenotype.

Down syndrome (DS) is the most common genetic disorder associated with mental retardation (MR).It is believed that many of the phenotypic features of DS stem from enhanced expression of a set of genes located within the triplicated region on chromosome 21. Among those genes is DYRK1A encoding dual -specificity proline-directed serine/treonine kinase, which, as documented by animal studies, can potentially contribute to cognitive deficits in DS. Whether this contribution can be exerted through elevated levels of DYRK1A protein in the brain of DS subjects was the main goal of the present study. The levels of DYRK1A protein were measured by Western blotting in six brain structures that included cerebral and cerebellar cortices and white matter. The study involved large cohorts of DS subjects and age-matched controls representing infants and adults of different age, gender and ethnicity. Trisomic Ts65Dn mice, an animal model of DS, were also included in the study. Both in trisomic mice and in DS subjects, the brain levels of DYRK1A protein were increased approximately 1.5-fold, indicating that this protein is overexpressed in gene dosage-dependent manner. The exception was an infant group, in which there was no enhancement suggesting the existence of a developmentally regulated mechanism. We found DYRK1A to be present in every analyzed structure irrespective of age. This widespread occurrence and constitutive expression of DYRK1A in adult brain suggest an important, but diverse from developmental, role played by this kinase in adult central nervous system. It also implies that overexpression of DYRK1A in DS may be potentially relevant to MR status of these individuals during their entire life span. KeywordsMinibrain DYRK1A kinase; Down syndrome (DS); Chromosome 21 trisomy; Down Syndrome Critical Region (DSCR) Down syndrome (DS) is the most frequent genetic cause of mental retardation. It is assumed that many of the phenotypic features of DS stem from enhanced expression of a set of genes Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. [14]. Among genes cloned from this region was a human homologue of the Drosophila minibrain/rat DYRK gene, which encodes a dual-specificity tyrosine phosphorylation-regulated kinase; DYRK1A [11,22,23]. This gene is highly expressed in the brain [12,13,19] and seems to play a role during brain development by regulating neurogenesis and neuronal differentiation [13,23,27]. That it also plays an important role in adult central nervous system was deduced from its expression patterns in the brain [9,16] and the diverse learning and memory d...

IntroductionA total of 38 brain cytoarchitectonic subdivisions, representing subcortical and cortical structures, cerebellum, and brainstem, were examined in 4- to 60-year-old subjects diagnosed with autism and control subjects (a) to detect a global pattern of developmental abnormalities and (b) to establish whether the function of developmentally modified structures matches the behavioral alterations that are diagnostic for autism. The volume of cytoarchitectonic subdivisions, neuronal numerical density, and total number of neurons per region of interest were determined in 14 subjects with autism and 14 age-matched controls by using unbiased stereological methods.ResultsThe study revealed that significant differences between the group of subjects with autism and control groups are limited to a few brain regions, including the cerebellum and some striatum and amygdala subdivisions. In the group of individuals with autism, the total number and numerical density of Purkinje cells in the cerebellum were reduced by 25% and 24%, respectively. In the amygdala, significant reduction of neuronal density was limited to the lateral nucleus (by 12%). Another sign of the topographic selectivity of developmental alterations in the brain of individuals with autism was an increase in the volumes of the caudate nucleus and nucleus accumbens by 22% and 34%, respectively, and the reduced numerical density of neurons in the nucleus accumbens and putamen by 15% and 13%, respectively.ConclusionsThe observed pattern of developmental alterations in the cerebellum, amygdala and striatum is consistent with the results of magnetic resonance imaging studies and their clinical correlations, and of some morphometric studies that indicate that detected abnormalities may contribute to the social and communication deficits, and repetitive and stereotypical behaviors observed in individuals with autism.

The gene encoding the minibrain kinase/dualspeciWcity tyrosine phosphorylated and regulated kinase 1A (DYRK1A) is located in the Down syndrome (DS) critical region of chromosome 21. The third copy of DYRK1A is believed to contribute to abnormal brain development in patients with DS. In vitro studies showing that DYRK1A phosphorylates tau protein suggest that this kinase is also involved in tau protein phosphorylation in the human brain and contributes to neuroWbrillary degeneration, and that this contribution might be enhanced in patients with DS. To explore this hypothesis, the brain tissue from 57 subjects including 16 control subjects, 21 patients with DS, and 20 patients with sporadic Alzheimer's disease (AD) was examined with two antibodies to the amino-terminus of DYRK1A (7F3 and G-19), as well as two polyclonal antibodies to its carboxy-terminus (X1079 and 324446). Western blots demonstrated higher levels of full-length DYRK1A in the brains of patients with DS when compared to control brains. Immunocytochemistry revealed that DYRK1A accumulates in neuroWbrillary tangles (NFTs) in subjects with sporadic AD and in subjects with DS/AD. Overexpression of DYRK1A in patients with DS was associated with an increase in DYRK1A-positive NFTs in a gene dosage-dependent manner. Results support the hypothesis that overexpressed DYRK1A contributes to neuroWbrillary degeneration in DS more signiWcantly than in subjects with two copies of the DYRK1A gene and sporadic AD. Immunoreactivity with antibodies against DYRK1A not only in NFTs but also in granules in granulovacuolar degeneration and in corpora amylacea suggests that DYRK1A is involved in all three forms of degeneration and that overexpression of this kinase may contribute to the early onset of these pathologies in DS.

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