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Down syndrome (DS) is caused by triplication of chromosome 21 (HSA21). It is characterised by intellectual disability and impaired motor coordination that arise from changes in brain volume, structure and function. However, the contribution of each HSA21 gene to these various phenotypes and to the causal alterations in neuronal and synaptic structure and function are largely unknown. Here we have investigated the effect of overexpression of the HSA21 gene DSCAM (Down syndrome cell adhesion molecule), on glutamatergic synaptic transmission and motor coordination, using Drosophila expressing three copies of Dscam1. Electrophysiological recordings of miniature and evoked excitatory junction potentials at the glutamatergic neuromuscular junction of Drosophila larvae showed that the extra copy of Dscam1 changed the properties of spontaneous and electrically-evoked transmitter release and strengthened short-term synaptic depression during high-frequency firing of the motor nerve. Behavioural analyses uncovered impaired locomotor coordination despite preserved gross motor function. This work identifies DSCAM as a candidate causative gene in DS that is sufficient to modify synaptic transmission and synaptic plasticity and cause a DS behavioural phenotype., Highlights • Drosophila expressing a third copy of Dscam have altered neuromuscular transmission. • Drosophila expressing a third copy of Dscam have deficits in locomotor coordination. • Drosophila are a powerful system for studying single-gene effects in Down syndrome.

The highly conserved dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A) plays crucial roles during central nervous system development and homeostasis. Furthermore, its hyperactivity is considered responsible for some neurological defects in individuals with Down syndrome. We set out to establish a zebrafish model expressing human Dyrk1A that could be further used to characterize the interaction between Dyrk1A and neurological phenotypes. First, we revealed the prominent expression of dyrk1a homologs in cerebellar neurons in the zebrafish larval and adult brains. Overexpression of human dyrk1a in postmitotic cerebellar Purkinje neurons resulted in a structural misorganization of the Purkinje cells in cerebellar hemispheres and a compaction of this cell population. This impaired Purkinje cell organization was progressive, leading to an age-dependent dispersal of Purkinje neurons throughout the cerebellar molecular layer with larval swim deficits resulting in miscoordination of swimming and reduced exploratory behavior in aged adults. We also found that the structural misorganization of the larval Purkinje cell layer could be rescued by pharmacological treatment with Dyrk1A inhibitors. We further reveal the in vivo efficiency of a novel selective Dyrk1A inhibitor, KuFal194. These findings demonstrate that the zebrafish is a well-suited vertebrate organism to genetically model severe neurological diseases with single cell type specificity. Such models can be used to relate molecular malfunction to cellular deficits, impaired tissue formation, and organismal behavior and can also be used for pharmacological compound testing and validation.

Nearly all individuals with Down Syndrome (DS) display pathology associated with Alzheimer's disease (AD) beginning as early as age 30. Previous research in typically developed adults suggests that increased moderate-to-vigorous physical activity (MVPA) may improve cognitive function and protect against age-related structural and functional changes in the brain; however, the potential impact of increased MVPA on the development of AD in adults with DS has not been evaluated. Despite the potential positive impact of MVPA on cognition and AD risk, participation in MVPA among young adults with DS is low. The limited research evaluating strategies for increasing MVPA in adults with DS has been unsuccessful in increasing MVPA. Results from our preliminary investigation where we remotely delivered real-time MVPA, led by a trained health educator, to groups of adults with DS in their homes via video conferencing on a tablet computer demonstrated high attendance, increased MVPA during group sessions, and improvements in cognitive function. However, the sustainability, impact on total daily MVPA, optimal session frequency, and potential impacts on cognitive function and brain health of remotely delivered group MVPA sessions in adults with DS are unknown. Therefore, we will conduct a trial in 80 non-demented adults with DS to determine the feasibility and potential efficacy of remotely delivered group MVPA sessions to increase daily MVPA, relative to a usual care control. Secondarily we will assess the impact of MVPA on cardiovascular fitness, quality of life, cognitive function and brain parameters related to AD. NCT registration NCT04048759.

People with Down syndrome (DS) develop Alzheimer's disease (AD) at higher rates and a younger age of onset compared to the general population. As the average lifespan of people with DS is increasing, AD is becoming an important health concern in this group. Neuroimaging is becoming an increasingly useful tool in understanding the pathogenesis of dementia development in relation to clinical symptoms. Furthermore, neuroimaging has the potential to play a role in AD diagnosis and monitoring of therapeutics. This review describes major recent findings from in vivo neuroimaging studies analysing DS and AD via ligand-based positron emission tomography (PET), [18F] fluorodeoxyglucose (FDG)-PET, structural magnetic resonance imaging (sMRI), and diffusion tensor imaging (DTI). Electroencephalography (EEG) and retinal imaging are also discussed as emerging modalities. The review is organized by neuroimaging method and assesses the relationship between cognitive decline and neuroimaging changes. We find that amyloid accumulation seen on PET occurs prior to dementia onset, possibly as a precursor to the atrophy and white matter changes seen in MRI studies. Future PET studies relating tau distribution to clinical symptoms will provide further insight into the role this protein plays in dementia development. Brain activity changes demonstrated by EEG and metabolic changes seen via FDG-PET may also follow predictable patterns that can help track dementia progression. Finally, newer approaches such as retinal imaging will hopefully overcome some of the limitations of neuroimaging and allow for detection of dementia at an earlier stage., Highlights • We review recent neuroimaging findings in the field of Down syndrome and Alzheimer's disease. • Review is organized by neuroimaging methodology. • Correlation between cognitive decline and imaging findings is considered. • Neuroimaging is a useful tool for studying and monitoring Alzheimer's disease in the Down syndrome population.

Down syndrome (DS) mouse models exhibit cognitive deficits, and are used for studying the neuronal basis of DS pathology. To understand the differences in the physiology of DS model neurons, we used dissociated neuronal cultures from the hippocampi of Ts65Dn and Tc1 DS mice. Imaging of [Ca2+]i and whole cell patch clamp recordings were used to analyze network activity and single neuron properties, respectively. We found a decrease of ~ 30% in both fast (A-type) and slow (delayed rectifier) outward potassium currents. Depolarization of Ts65Dn and Tc1 cells produced fewer spikes than diploid cells. Their network bursts were smaller and slower than diploids, displaying a 40% reduction in Δf / f0 of the calcium signals, and a 30% reduction in propagation velocity. Additionally, Ts65Dn and Tc1 neurons exhibited changes in the action potential shape compared to diploid neurons, with an increase in the amplitude of the action potential, a lower threshold for spiking, and a sharp decrease of about 65% in the after-hyperpolarization amplitude. Numerical simulations reproduced the DS measured phenotype by variations in the conductance of the delayed rectifier and A-type, but necessitated also changes in inward rectifying and M-type potassium channels and in the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. We therefore conducted whole cell patch clamp measurements of M-type potassium currents, which showed a ~ 90% decrease in Ts65Dn neurons, while HCN measurements displayed an increase of ~ 65% in Ts65Dn cells. Quantitative real-time PCR analysis indicates overexpression of 40% of KCNJ15, an inward rectifying potassium channel, contributing to the increased inhibition. We thus find that changes in several types of potassium channels dominate the observed DS model phenotype., Highlights • Down syndrome model neurons display altered action potential shape, are less excitable and have decreased potassium currents. • The data is accurately described by a numerical simulation that changes conductance of four potassium and the HCN currents. • Measurements of the currents related to these four channels, and RT-pcr for a fifth (KCNJ15), confirm the numerical model. In Down syndrome (DS) cognitive function is impaired, leading us to use cultured hippocampal neuronal networks to investigate the cellular basis of its pathology. DS mouse model neurons are less excitable, produce fewer spikes and generate less network activity. Alterations in several types of potassium currents were detected in these neurons. Numerical simulation of a DS neuron successfully reproduced the experimental results. Beyond extending our understanding of neuronal function and pathology, the alterations in channel conductance can now be targeted with specific drugs so as to point to new directions in therapy of cognitive disabilities of DS.

Down syndrome (DS) is characterized by intellectual disability and impaired motor control. Lack of coordinated movement, poor balance, and unclear speech imply dysfunction of the cerebellum, which is known to be reduced in volume in DS. The principal cause of the smaller cerebellum is a diminished number of granule cells (GCs). These neurons form the ‘input layer’ of the cerebellar cortex, where sensorimotor information carried by incoming mossy fibers is transformed before it is conveyed to Purkinje cells and inhibitory interneurons. However, it is not known how processing of this information is affected in the hypogranular cerebellum that characterizes DS. Here we explore the possibility that the electrical properties of the surviving GCs are changed. We find that in the Ts65Dn mouse model of DS, GCs have a higher input resistance at voltages approaching the threshold for firing, which causes them to be more excitable. In addition, they fire narrower and larger amplitude action potentials. These subtly modified electrical properties may result in atypical transfer of information at the input layer of the cerebellum., Highlights ► Granule neurons in the cerebellum of the Ts65Dn mouse model of Down syndrome. ► Action potential firing is evoked with smaller current injections. ► Action potentials are narrower and have larger amplitudes.

DS (Down syndrome), resulting from trisomy of chromosome 21, is the most common cause of genetic mental retardation; however, the molecular mechanisms underlying the cognitive deficits are poorly understood. Growing data indicate that changes in abundance or type of CSPGs (chondroitin sulfate proteoglycans) in the ECM (extracellular matrix) can influence synaptic structure and plasticity. The purpose of this study was to identify changes in synaptic structure in the hippocampus in a model of DS, the Ts65Dn mouse, and to determine the relationship to proteoglycan abundance and/or cleavage and cognitive disability. We measured synaptic proteins by ELISA and changes in lectican expression and processing in the hippocampus of young and old Ts65Dn mice and LMCs (littermate controls). In young (5 months old) Ts65Dn hippocampal extracts, we found a significant increase in the postsynaptic protein PSD-95 (postsynaptic density 95) compared with LMCs. In aged (20 months old) Ts65Dn hippocampus, this increase was localized to hippocampal stratum oriens extracts compared with LMCs. Aged Ts65Dn mice exhibited impaired hippocampal-dependent spatial learning and memory in the RAWM (radial-arm water maze) and a marked increase in levels of the lectican versican V2 in stratum oriens that correlated with the number of errors made in the final RAWM block. Ts65Dn stratum oriens PNNs (perineuronal nets), an extension of the ECM enveloping mostly inhibitory interneurons, were dispersed over a larger area compared with LMC mice. Taken together, these data suggest a possible association with alterations in the ECM and inhibitory neurotransmission in the Ts65Dn hippocampus which could contribute to cognitive deficits.

© 2015. Alterations in cerebral cortex connectivity lead to intellectual disability and in Down syndrome, this is associated with a deficit in cortical neurons that arises during prenatal development. However, the pathogenic mechanisms that cause this deficit have not yet been defined. Here we show that the human DYRK1A kinase on chromosome 21 tightly regulates the nuclear levels of Cyclin D1 in embryonic cortical stem (radial glia) cells, and that a modest increase in DYRK1A protein in transgenic embryos lengthens the G1 phase in these progenitors. These alterations promote asymmetric proliferative divisions at the expense of neurogenic divisions, producing a deficit in cortical projection neurons that persists in postnatal stages. Moreover, radial glial progenitors in the Ts65Dn mouse model of Down syndrome have less Cyclin D1, and Dyrk1a is the triplicated gene that causes both early cortical neurogenic defects and decreased nuclear Cyclin D1 levels in this model. These data provide insights into the mechanisms that couple cell cycle regulation and neuron production in cortical neural stem cells, emphasizing that the deleterious effect of DYRK1A triplication in the formation of the cerebral cortex begins at the onset of neurogenesis, which is relevant to the search for early therapeutic interventions in Down syndrome., This work was supported by the Spanish Ministry of Economy and Competitiveness (MINECO) [Grant numbers SAF-2010-17004, SAF2013-46676-P and CSIC-201020I003], the Jérôme Lejeune Foundation, and the Generalitat de Catalunya [Grant number 2009SGR1464]. S.N. was supported by a FI fellowship from the Generalitat de Catalunya [Fellowship number 2011B1-OG242] and by a FPU fellowship from the MINECO [Fellowship number AP2012-3064]. M.J.B. is supported by the program JAE DOC-CSIC/European Social Fund and JA by a FPI fellowship from the MINECO [Fellowship number BES2011-047472]. S.J.C and D.O. were supported by a strategic grant from the Biotechnology and Biological Sciences Research Council (BBSRC). A.L.A. was supported by a BBSRC CASE PhD studentship with AstraZeneca and P.A.L by a grant form the Association for International Cancer Research