MINI-REVIEW Molecular changes in fetal Down syndrome brain Ephrem Engidawork and Gert Lubec Department of Pediatrics, University of Vienna, Vienna, Austria Abstract Trisomy of human chromosome 21 is a major cause of mental retardation and other phenotypic abnormalities collectively known as Down syndrome. Down syndrome is associated with developmental failure followed by processes of neurodegen- eration that are known to supervene later in life. Despite a widespread interest in Down syndrome, the cause of devel- opmental failure is unclear. The brain of a child with Down syndrome develops differently from that of a normal one, although characteristic morphological differences have not been noted in prenatal life. On the other hand, a review of the existing literature indicates that there are a series of bio- chemical alterations occurring in fetal Down syndrome brain that could serve as substrate for morphological changes. We propose that these biochemical alterations represent and/or precede morphological changes. This review attempts to dissect these molecular changes and to explain how they may lead to mental retardation. Keywords: brain, cytoskeleton, fetal Down syndrome, mental retardation, signalling. J. Neurochem. (2003) 84, 895–904. Chromosome abnormality is the most commonly recognized cause of fetal death in our species. Around 50% of spontaneous abortions before 15 weeks of gestation are chromosomally aneuploid and trisomies account for about 50% of the abnormal abortions. Trisomy 21 is one of the trisomies that occur with a higher incidence in newborns, and has large individual and socioeconomic consequences (Nicolaidis and Petersen 1998). The clinical entity of trisomy 21 is known as Down syndrome (DS) and perhaps is the oldest condition associated with mental retardation and the most common genetic cause of developmental disability. In addition to developmental failure, DS is also characterized by Alzheimer’s disease-like neuropathology [b-amyloid (Ab) plaque, neurofibrillary tangles and neuronal loss] known to supervene later in life. Mental retardation represents a condition characterized by subnormal intellectual functioning and impaired adaptive behaviour that become manifest during developmental years. The relationship between mental retardation and the trisomic condition of DS is unclear and probably complex. With the Golgi method, fetal DS brains were reported to have the same neuronal morphology and spine counts as brain from normal fetuses (Takashima et al. 1981; Becker et al. 1986). Gross and light microscopical analyses also failed to uncover any difference in development between DS and normal brain in terms of shape, weight, configuration and myelination (Wisniewski and Schmidt-Sidor 1989; Schmidt-Sidor et al. 1990). Stereological cell counting techniques, however, revealed that the second phase of cortical development and the emergence of lamination are both delayed and disorgan- ized in fetal DS brain (Golden and Hyman 1994) (Fig. 1). In addition, although the emergence and morphology of microglial cells appear not to differ from those in normal fetuses, microglial cells outnumber astroglial cells in fetal DS brain (Wierzba-Bobrowicz et al. 1999). Conspicuous morphological abnormalities start to be apparent in brains of newborns and older infants with DS. They have shortened basilar dendrites, a decreased number of spines with altered morphology and defective cortical layering (Marin-Padilla 1976; Takashima et al. 1981; Becker et al. 1986; Schmidt-Sidor et al. 1990). In addition, other studies have revealed relatively delayed myelination, fewer neurones, lower neuronal density and distribution, and abnormal synaptic density and length, caused probably by Received September 17, 2002; accepted October 31, 2002. Address correspondence and reprint requests to Professor Gert Lubec, CChem, FRSC (UK), Department of Pediatrics, University of Vienna, Wa ¨hringer Gu ¨rtel 18–20, A-1090, Vienna, Austria. E-mail: Gert.Lubec@akh-wien.ac.at Abbreviations used:Ab, b-amyloid; APP, b-amyloid precursor pro- tein; DS, Down syndrome; DSCR-1, Down syndrome critical region-1; GDI, GDP-dissociation inhibitor; 5-HT, serotonin; NDK, nucleoside diphosphate kinase; RACK, receptor for activated C kinase; REST, repressor element-silencing transcription factor; SH, Src homology; SNAP, synaptosome-associated protein; SOD, superoxide dismutase [Cu–Zn]. Journal of Neurochemistry , 2003, 84, 895–904 doi:10.1046/j.1471-4159.2003.01614.x Ó 2003 International Society for Neurochemistry, J. Neurochem. (2003) 84, 895–904 895