Neurodegeneration of purkinje cells. In a mouse model of neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disorder, accumulation of lipofuscin granules is followed by progressive neuronal cell death. Purkinje neurons in the cerebellum are severely affected as illustrated by loss of cell bodies and dendritic arbors. Massive lipofuscin deposits remain in the purkinje cell layer in the degenerating brain. The work by Tamaki et al. (pages 310–319) demonstrates that transplantation of human neural stem cells leads to neuroprotection of host cells in the NCL mouse brain. The cover image shows a section of cerebellum from a mouse with disease symptoms. Cover design by Monika Dohse.

Down syndrome (DS) can be modeled in mice segmentally trisomic for mouse chromosome 16. Ts65Dn and Ts1Cje mouse models have been used to study DS neurobiological phenotypes including changes in cognitive ability, induction of long-term potentiation (LTP) in the fascia dentata (FD), the density and size of dendritic spines, and the structure of synapses. To explore the genetic basis for these phenotypes, we examined Ts1Rhr mice that are trisomic for a small subset of the genes triplicated in Ts65Dn and Ts1Cje mice. The 33 trisomic genes in Ts1Rhr represent a “DS critical region” that was once predicted to be sufficient to produce most DS phenotypes. We discovered significant alterations in an open field test, a novel object recognition test and in a T-maze task. As in Ts65Dn and Ts1Cje mice, LTP in FD of Ts1Rhr could be induced only after blocking GABA_A-dependent inhibitory neurotransmission. In addition, widespread enlargement of dendritic spines and decreased density of spines in FD were preserved in Ts1Rhr. Twenty of 48 phenotypes showed significant differences between Ts1Rhr and 2N controls. We conclude that important neurobiological phenotypes characteristic of DS are conserved in Ts1Rhr mice. The data support the view that biologically significant trisomic phenotypes occur because of dosage effects of genes in the Ts1Rhr trisomic segment and that increased dosage is sufficient to produce these changes. The stage is now set for studies to decipher the gene(s) that play a conspicuous role in creating these phenotypes.

Down syndrome (DS) is a neurological disorder causing impaired learning and memory. Partial trisomy 16 mice (Ts65Dn) are a genetic model for DS. Previously, we demonstrated widespread alterations of pre- and postsynaptic elements and physiological abnormalities in Ts65Dn mice. The average diameter of presynaptic boutons and spines in the neocortex and hippocampus was enlarged. Failed induction of long-term potentiation (LTP) due to excessive inhibition was observed. In this paper we investigate the morphological substrate for excessive inhibition in Ts65Dn. We used electron microscopy (EM) to characterize synapses, confocal microscopy to analyze colocalization of the general marker for synaptic vesicle protein with specific protein markers for inhibitory and excitatory synapses, and densitometry to characterize the distribution of the receptor and several proteins essential for synaptic clustering of neurotransmitter receptors. EM analysis of synapses in the Ts65Dn vs. 2N showed that synaptic opposition lengths were significantly greater for symmetric synapses (approximately 18%), but not for asymmetric ones. Overall, a significant increase in colocalization coefficients of glutamic acid decarboxylase (GAD)65/p38 immunoreactivity (IR) (approximately 27%) and vesicular GABA transporter (VGAT)/p38 IR (approximately 41%) was found, but not in vesicular glutamate transporter 1 (VGLUT1)/p38 IR. A significant overall decrease of IR in the hippocampus of Ts65Dn mice compared with 2N mice for glutamate receptor 2 (GluR2; approximately 13%) and anti-gamma-aminobutyric acid (GABA_A) Continued on next page…

The most effective treatments for neurodegenerative disorders, including Alzheimer’s disease, will come from studies of the pathogenesis of age-related cognitive failure and understanding of the underlying mechanisms. Given the marked similarities in pathological and clinical phenotypes between Alzheimer’s disease and Down syndrome, studies of the pathogenesis of one can be expected to complement and support those in the other. Alzheimer’s disease and Down syndrome are characterized by dysfunction and loss of several biochemically and anatomically defined neuronal populations. The pathological involvement of hippocampus, in particular, is an early feature of both disorders, as is the degeneration of neurons whose axons innervate this region. Long, thin and poorly myelinated axons project from a number of subcortical and brain stem nuclei to modulate hippocampally mediated cognitive functions. In studies on mouse models of Down’s syndrome, we uncovered evidence for the involvement of a particular neuronal population heavily innervating the hippocampus. In an extensive series of experiments, we found evidence that failed retrograde transport of nerve growth factor signaling in cholinergic neurons of the basal forebrain is linked to their vulnerability and that these changes are caused by increased gene dose and overexpression of the gene for amyloid precursor protein. These findings raise the possibility that intracellular trafficking defects created by changes in amyloid precursor protein expression or processing make an important contribution to pathogenesis and set the stage for studies to explore the molecular mechanisms of degeneration Continued on next page…

Down syndrome (DS) is caused by trisomy of human chromosome 21. Because Ts65Dn and Ts1Cje mice are segmentally trisomic for a region of mouse chromosome 16, they genetically model DS and are used to study pathogenic mechanisms. Previously, we provided evidence for changes in both the structure and function of pre- and postsynaptic elements in the Ts65Dn mouse. Striking changes were evident in the size of the dendritic spines and in the ability to induce long-term potentiation (LTP) in the fascia dentata (FD). To explore the genetic basis for these changes, we examined Ts1Cje mice, which are trisomic for a completely overlapping but smaller segment of mouse chromosome 16. As in the Ts65Dn mouse, there was a regionally selective decrease in the density of dendritic spines (approximately 12%), an increase in the size of spine heads (approximately 26%), a decrease in the length of spine necks (approximately 26%), and reorganization of inhibitory inputs with a relative decrease in inputs to dendrite shafts and spine heads and a significant increase to the necks of spines (6.4%). Thus, all of the Ts65Dn phenotypes were present, but they were significantly less severe. In contrast, and just as was the case for the Ts65Dn mouse, LTP could not be induced unless the selective gamma-aminobutyric acid (GABA_A) receptor antagonist picrotoxin was applied. Therefore, there was conservation of important synaptic phenotypes in the Ts1Cje mice. The analysis of data from this and earlier studies points to genotype-phenotype linkages in DS whose complexity ranges from relatively simple to quite complex.

Down Syndrome (DS) caused by trisomy 21 is characterized by a variety of phenotypes and involves multiple organs. Sequencing of human chromosome 21 (HSA21) and subsequently of its orthologues on mouse chromosome 16 have created an unprecedented opportunity to explore the complex relationship between various DS phenotypes and the extra copy of approximately 300 genes on HSA21. Advances in genetics together with the ability to generate genetically well-defined mouse models have been instrumental in understanding the relationships between genotype and phenotype in DS. Indeed, elucidation of these relationships will play an important role in understanding the pathophysiological basis of this disorder and helping to develop therapeutic interventions. A successful example of using such a strategy is our recent studies exploring the relationship between failed nerve growth factor (NGF) transport and amyloid precursor protein (App) overexpression. We found that increased dosage of the gene for App is linked to failed NGF signaling and cholinergic neurodegeneration in a mouse model of DS. Herein, we discuss several mouse models of DS and explore the emergence of exciting new insights into genotype-phenotype relationships, particularly those related to nervous system abnormalities. An important conclusion is that uncovering these relationships is enhanced by working from carefully defined phenotypes to the genes responsible.

Neurotrophins play an important role in the survival, differentiation, and maintenance of neurons selectively involved in a number of disorders of the nervous system. Nerve growth factor (NGF) plays a vital role for basal forebrain cholinergic neurons (BFCNs), including the maintenance of the cholinergic phenotype in adults. Recognition of this role has suggested the use of NGF to ameliorate the loss of these neurons in Alzheimer’s disease (AD). While clinical studies directed at supplying NGF to patients continue to be pursued, fundamental questions remain as to the relationship between selective vulnerability of cholinergic neurons and the actions of NGF. In this chapter, we review the structure and function of the basal forebrain cholinergic system, its role in higher cognitive functions, and the importance of NGF actions on these cells. Studies that link changes in NGF signaling to the degeneration of BFCNs are then discussed, as are current approaches to NGF-related treatments. Finally, on the basis of recent findings in mouse models of AD and Down syndrome, we suggest that impaired retrograde axonal transport of NGF plays a significant role in pathogenesis. This insight may guide future studies of pathogenesis and innovative treatment for BFCNs and, perhaps, other neurons affected in AD.

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Down Syndrome (DS) caused by trisomy 21 is characterized by a variety of phenotypes and involves multiple organs. Sequencing of human chromosome 21 (HSA21) and subsequently of its orthologues on mouse chromosome 16 have created an unprecedented opportunity to explore the complex relationship between various DS phenotypes and the extra copy of 300 genes on HSA21. Advances in genetics together with the ability to generate genetically well-defined mouse models have been instrumental in understanding the relationships between genotype and phenotype in DS. Indeed, elucidation of these relationships will play an important role in understanding the pathophysiological basis of this disorder and helping to develop therapeutic interventions. Continued on next page…