Glutamatergic transmission aberration: a major cause of behavioral deficits in a murine model of Down's syndrome.
Trisomy 21, or Down's syndrome (DS), is the most common genetic cause of intellectual disability. Altered neurotransmission in the brains of DS patients leads to hippocampus-dependent learning and memory deficiency. Although genetic mouse models have provided important insights into the genes and mechanisms responsible for DS-specific changes, the molecular mechanisms leading to memory deficits are not clear. We investigated whether the segmental trisomy model of DS, Ts[Rb(12.1716)]2Cje (Ts2), exhibits hippocampal glutamatergic transmission abnormalities and whether these alterations cause behavioral deficits. Behavioral assays demonstrated that Ts2 mice display a deficit in nest building behavior, a measure of hippocampus-dependent nonlearned behavior, as well as dysfunctional hippocampus-dependent spatial memory tested in the object-placement and the Y-maze spontaneous alternation tasks. Magnetic resonance spectra measured in the hippocampi revealed a significantly lower glutamate concentration in Ts2 as compared with normal disomic (2N) littermates. The glutamate deficit accompanied hippocampal NMDA receptor1 (NMDA-R1) mRNA and protein expression level downregulation in Ts2 compared with 2N mice. In concert with these alterations, paired-pulse analyses suggested enhanced synaptic inhibition and/or lack of facilitation in the dentate gyrus of Ts2 compared with 2N mice. Ts2 mice also exhibited disrupted synaptic plasticity in slice recordings of the hippocampal CA1 region. Collectively, these findings imply that deficits in glutamate and NMDA-R1 may be responsible for impairments in synaptic plasticity in the hippocampus associated with behavioral dysfunctions in Ts2 mice. Thus, these findings suggest that glutamatergic deficits have a significant role in causing intellectual disabilities in DS.
Nathan S. Kline Institute, Orangeburg, New York, 10962, Department of Child and Adolescent Psychiatry, Department of Psychiatry, Department of Biochemistry and Molecular Pharmacology, and Department of Physiology and Neuroscience, NYU Langone School of Medicine, New York, New York, 10016, and Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York 10032.
Gurjinder
G
Kaur
Ajay
A
Sharma
Wenjin
W
Xu
Scott
S
Gerum
Melissa J
MJ
Alldred
Shivakumar
S
Subbanna
Balapal S
BS
Basavarajappa
Monika
M
Pawlik
Masuo
M
Ohno
Stephen D
SD
Ginsberg
Donald A
DA
Wilson
David N
DN
Guilfoyle
Efrat
E
Levy
D000818:Animals; D056547:CA1 Region, Hippocampal / Q000378:metabolism / Q000503:physiopathology; D018891:Dentate Gyrus / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D017774:Long-Term Potentiation; D008297:Male; D018782:Maze Learning; D008568:Memory; D051379:Mice; D009425:Nesting Behavior; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism; D013569:Synapses / Q000378:metabolism / Q000502:physiology
D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid
Down's syndrome; LTP; NMDA receptors; glutamate; spatial memory