Reversing excitatory GABAAR signaling restores synaptic plasticity and memory in a mouse model of Down syndrome

被引:197
作者
Deidda, Gabriele [1 ]
Parrini, Martina [1 ]
Naskar, Shovan [1 ]
Bozarth, Ignacio F. [1 ]
Contestabile, Andrea [1 ]
Cancedda, Laura [1 ]
机构
[1] Ist Italiano Tecnol, Neurosci & Brain Technol Dept, Genoa, Italy
关键词
CATION-CHLORIDE COTRANSPORTERS; TS65DN MOUSE; MEDIATED NEUROTRANSMISSION; HIPPOCAMPAL INTERNEURONS; DIURETIC BUMETANIDE; ALZHEIMERS-DISEASE; SYNDROME MICE; DEFICITS; INHIBITION; NKCC1;
D O I
10.1038/nm.3827
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Down syndrome (DS) is the most frequent genetic cause of intellectual disability, and altered GABAergic transmission through Cl- permeable GABA(A) receptors (GABA(A)Rs) contributes considerably to learning and memory deficits in DS mouse models. However, the efficacy of GABAergic transmission has never been directly assessed in DS. Here GABA(A)R signaling was found to be excitatory rather than inhibitory, and the reversal potential for GABA(A)R-driven Cl- currents (E-Cl) was shifted toward more positive potentials in the hippocampi of adult DS mice. Accordingly, hippocampal expression of the cation Cl-cotransporter NKCC1 was increased in both trisomic mice and individuals with DS. Notably, NKCC1 inhibition by the FDA-approved drug bumetanide restored ECl, synaptic plasticity and hippocampus-dependent memory in adult DS mice. Our findings demonstrate that GABA is excitatory in adult DS mice and identify a new therapeutic approach for the potential rescue of cognitive disabilities in individuals with DS.
引用
收藏
页码:318 / +
页数:12
相关论文
共 68 条
[1]  
ALGER BE, 1991, ANN NY ACAD SCI, V627, P249
[2]   Dysfunctional hippocampal inhibition in the Ts65Dn mouse model of Down syndrome [J].
Best, Tyler K. ;
Cramer, Nathan P. ;
Chakrabarti, Lina ;
Haydar, Tarik F. ;
Galdzicki, Zygmunt .
EXPERIMENTAL NEUROLOGY, 2012, 233 (02) :749-757
[3]   Disease-Modifying Effects of Phenobarbital and the NKCC1 Inhibitor Bumetanide in the Pilocarpine Model of Temporal Lobe Epilepsy [J].
Brandt, Claudia ;
Nozadze, Maia ;
Heuchert, Nina ;
Rattka, Marta ;
Loescher, Wolfgang .
JOURNAL OF NEUROSCIENCE, 2010, 30 (25) :8602-8612
[4]   Specific targeting of the GABA-A receptor α5 subtype by a selective inverse agonist restores cognitive deficits in Down syndrome mice [J].
Braudeau, J. ;
Delatour, B. ;
Duchon, A. ;
Pereira, P. Lopes ;
Dauphinot, L. ;
de Chaumont, F. ;
Olivo-Marin, J-C ;
Dodd, R. H. ;
Herault, Y. ;
Potier, M-C .
JOURNAL OF PSYCHOPHARMACOLOGY, 2011, 25 (08) :1030-1042
[5]   The MIQE Guidelines: Minimum Information for Publication of Quantitative Real-Time PCR Experiments [J].
Bustin, Stephen A. ;
Benes, Vladimir ;
Garson, Jeremy A. ;
Hellemans, Jan ;
Huggett, Jim ;
Kubista, Mikael ;
Mueller, Reinhold ;
Nolan, Tania ;
Pfaffl, Michael W. ;
Shipley, Gregory L. ;
Vandesompele, Jo ;
Wittwer, Carl T. .
CLINICAL CHEMISTRY, 2009, 55 (04) :611-622
[6]   Excitatory GABA action is essential for morphological maturation of cortical neurons in vivo [J].
Cancedda, Laura ;
Fiumelli, Hubert ;
Chen, Karen ;
Poo, Mu-ming .
JOURNAL OF NEUROSCIENCE, 2007, 27 (19) :5224-5235
[7]   Treatment of Neurodevelopmental Disorders in Adulthood [J].
Castren, Eero ;
Elgersma, Ype ;
Maffei, Lamberto ;
Hagerman, Randi .
JOURNAL OF NEUROSCIENCE, 2012, 32 (41) :14074-14079
[8]   Olig1 and Olig2 triplication causes developmental brain defects in Down syndrome [J].
Chakrabarti, Lina ;
Best, Tyler K. ;
Cramer, Nathan P. ;
Carney, Rosalind S. E. ;
Isaac, John T. R. ;
Galdzicki, Zygmunt ;
Haydar, Tarik F. .
NATURE NEUROSCIENCE, 2010, 13 (08) :927-U39
[9]   Bumetanide Enhances Phenobarbital Efficacy in a Rat Model of Hypoxic Neonatal Seizures [J].
Cleary, Ryan T. ;
Sun, Hongyu ;
Thanhthao Huynh ;
Manning, Simon M. ;
Li, Yijun ;
Rotenberg, Alexander ;
Talos, Delia M. ;
Kahle, Kristopher T. ;
Jackson, Michele ;
Rakhade, Sanjay N. ;
Berry, Gerard ;
Jensen, Frances E. .
PLOS ONE, 2013, 8 (03)
[10]   Lithium rescues synaptic plasticity and memory in Down syndrome mice [J].
Contestabile, Andrea ;
Greco, Barbara ;
Ghezzi, Diego ;
Tucci, Valter ;
Benfenati, Fabio ;
Gasparini, Laura .
JOURNAL OF CLINICAL INVESTIGATION, 2013, 123 (01) :348-361