Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04

    • integrin inhibitors br Author Contributions br Conflict of I

    2018-10-25


    Author Contributions
    Conflict of Interest
    Acknowledgments We thank Dr. Jennifer Darnell for valuable comments, Dr. Maurice Swanson for the mice, Matthew Bancone for assistance with muscle fiber CSA assessment and Dr. Glenn Morris, Dr. Ian Holt and the Muscular Dystrophy Association Monoclonal Antibody Resource (http://www.glennmorris.org.uk/mabs.htm) for the MB2a monoclonal antibodies. Research reported in this publication was supported by NIH/NINDS award number NS060839 (SR) and NIH/NIAMS award numbers AR047664, AR54816, and AR041802 (JLV). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
    Introduction Down syndrome (DS) is the most abundant chromosomal abnormality in humans, affecting between 1:800 and 1:1200 of the population. People with DS have an extra copy (all or part) of chromosome 21 (trisomy 21). This presents severe health problems (Roizen and Patterson, 2003), with a moderate to severe intellectual disability. Several neurological differences characterize the DS brain, for example a smaller integrin inhibitors and hippocampus (Pinter et al., 2001; Aylward et al., 1997) and a higher incidence of hyperactivity and epilepsy (Goldberg-Stern et al., 2001; Arya et al., 2011). The full neurological aspects of DS are not yet fully understood but are apparent at the behavioral, morphological and single neuron levels. We used the Ts65Dn and Tc1 mouse models (Herault et al., 2012). The orthologous genes of human chromosome 21 reside in the mouse on segments of chromosomes 10, 16 and 17 (Hattori et al., 2000). The Ts65Dn mouse model (Davisson et al., 1993) contains a small reciprocal translocation chromosome with genes from chromosomes 16 and 17 (Reinholdt et al., 2011; Akeson et al., 2001), a total of about 50% of the DS genes. The Tc1 mouse model (O\'Doherty et al., 2005) contains a freely segregating human chromosome 21 with about 83% of the known genes on Hsa21. This more recent “transchromosomal” mouse model is 50% mosaic, and it has been less thoroughly investigated. At the behavioral level, developmental delays and hyperactivity were shown in Ts65Dn mice (Davisson et al., 1993), as well as several forms of learning deficits (Rueda et al., 2012; Wenger et al., 2004; Hyde et al., 2001; Demas et al., 1996; Martinez-Cue et al., 2002), for example impaired performance in the Morris water maze (Reeves et al., 1995). The Tc1 mice show decreased performance in cognitive and locomotive tasks (O\'Doherty et al., 2005) along with impaired short term memory (Morice et al., 2008) and reduced exploratory behavior (Salehi et al., 2007). At the cellular level, Ts65Dn exhibits a change in the balance of excitatory to inhibitory neurons in the neocortex, abnormal synapse morphology in the neocortex, hippocampus and dentate gyrus (Reeves, 2006; Best et al., 2012; Garner and Wetmore, 2012; Cramer and Galdzicki, 2012), developmental disruption of inhibitory synaptic transmission (Mitra et al., 2012) and hippocampal hypocellularity (Lorenzi and Reeves, 2006). GABA has been recently reported to be excitatory rather than inhibitory in the hippocampus of Ts65Dn (Deidda et al., 2015). A significant reduction in granule cell density in the DS cerebellum was reported by Baxter et al. (2000). In the Tc1 model a reduction in cerebellar volume was reported (O\'Doherty et al., 2005), and altered protein profiles in the hippocampus (Ahmed et al., 2013). Previous work identified a clear effect of enhanced GABAB inhibition at the single-cell level in the Ts65Dn mice. Elevated expression of GIRK2 channels using RT-PCR was reported (Harashima et al., 2006) in adult hippocampus, frontal cortex and substantia nigra of Ts65Dn mouse. This was linked to GABAB–GIRK2 attenuation of synaptic plasticity as well as to reduced long term potentiation (LTP) and increased long term depression (LTD). A 2-fold increase in GABAB mediated currents in primary cultured hippocampal neurons was reported in Best et al. (2007). In the Tc1 model deficits in synaptic plasticity and learning along with reduced LTP in the dentate gyrus of the hippocampus were observed (O\'Doherty et al., 2005).