Building the Future Therapies for Down Syndrome:The Third International Conference of the T21 Research Society

Research focused on Down syndrome has increased in the last several years to advance understanding of the consequences of trisomy 21 (T21) on molecular and cellular processes and, ultimately, on individuals with Down syndrome. The Trisomy 21 Research Society (T21RS) is the premier scientific organization for researchers and clinicians studying Down syndrome. The Third International Conference of T21RS, held June 6-9, 2019, in Barcelona, Spain, brought together 429 scientists, families, and industry representatives to share the latest discoveries on underlying cellular and molecular mechanisms of T21, define cognitive and behavioral challenges and better understand comorbidities associated with Down syndrome, including Alzheimer's disease and leukemia. Presentation of cutting-edge results in neuroscience, neurology, model systems, psychology, cancer, biomarkers and molecular and phar-ma-cological therapeutic approaches demonstrate the compelling interest and continuing advancement in all aspects of understanding and ameliorating conditions associated with T21

Ethanol-Induced Changes in Brain of Transgenic Mice Overexpressing DYRK1A

International audienceAlcoholism is a chronic relapsing disorder defined by loss of control over excessive consumption of ethanol despite damaging effects on the liver and brain. We previously showed that the overexpression in mice of Dyrk1A (TgDyrk1A, for dual-specificity tyrosine (Y) phosphorylation-regulated kinase 1A) reduces the severity of alcohol mediated liver injury. Ethanol consumption has also been associated with increased brain glutamate concentration that led to therapies targeting glutamatergic receptors and normalization of glutamatergic neurotransmission. Interestingly, mice overexpressing Dyrk1A (TgDyrk1A mice) present a reduction of glutamatergic brain transmission, which we propose could be protective against alcohol intake. To answer this question, we investigated the ethanol preference in TgDyrk1A mice using a two-bottle choice paradigm. TgDyrk1A mice showed a non-significant decrease of voluntary ethanol intake and ethanol preference compared with wild-type mice. At the peripheral level, mice overexpressing Dyrk1A show lower ethanol plasma levels, indicating a faster ethanol metabolism. At the end of the protocol, lasting 21 days, brains were extracted for protein analysis. Ethanol reduced levels of the synaptic protein PSD-95 and increased the glutamate decarboxylase GAD65, specifically in the cortex of TgDyrk1A mice. Our results suggest that overexpression of DYRK1A may cause different ethanol-induced changes in the brain

Erbb4 deletion from fast spiking interneurons causes schizophrenia-like phenotypes

Genetic variation in neuregulin and its ErbB4 receptor has been linked to schizophrenia, although little is known about how they contribute to the disease process. Here, we have examined conditional Erbb4 mouse mutants to study how disruption of specific inhibitory circuits in the cerebral cortex may cause large-scale functional deficits. We found that deletion of ErbB4 from the two main classes of fast-spiking interneurons, chandelier and basket cells, causes relatively subtle but consistent synaptic defects. Surprisingly, these relatively small wiring abnormalities boost cortical excitability, increase oscillatory activity, and disrupt synchrony across cortical regions. These functional deficits are associated with increased locomotor activity, abnormal emotional responses, and impaired social behavior and cognitive function. Our results reinforce the view that dysfunction of cortical fast-spiking interneurons might be central to the pathophysiology of schizophrenia.We thank D. Baeza and M. Fernandez-Otero for excellent technical assistance, A. Casillas, T. Gil, and M. Perez for general laboratory support, G. Fishell (New York University), K. Lloyd (University College Dublin), and N. Kessaris (University College London) for RCE, Erbb4, and Lhx6-Cre mouse strains, respectively, and J-M. Fritschy (University of Zurich) for GABA receptor antibodies. We are also grateful to members of the Borrell, Mann, and Rico laboratories for stimulating discussions and ideas. Supported by grants from the Spanish Government to B.R. (SAF2010-21723 and CONSOLIDER CSD2007-00023), O.M. (CSD2007-00023), M.D. (SAF2010-16427), and S.C. (CSD2007-00023, BFU2009-09938 and PIM2010ERN-00679, part of the ERANET NEURON TRANSALC project), from Fundacion Alicia Koplowitz to B.R., from the Lilly Research Awards Program to B.R. and O.M., and from Fundacio la Marato to O.M., B.R., and M.D. B.R. is an EMBO Young Investigator.Del Pino, I.; Garcia-Frigola, C.; Dehorter, N.; Brotons-Mas, JR.; Alvarez-Salvado, E.; Martinez De Lagran, M.; Ciceri, G.... (2013). Erbb4 deletion from fast spiking interneurons causes schizophrenia-like phenotypes. Neuron. 79(6):1152-1168. doi:10.1016/j.neuron.2013.07.010S1152116879