Memantine normalizes several phenotypic features in the Ts65Dn mouse model of Down syndrome.
Ts65Dn (TS) mice exhibit several phenotypic characteristics of human Down syndrome, including an increased brain expression of amyloid-beta protein precursor (AbetaPP) and cognitive disturbances. Aberrant N-methyl-D-aspartate (NMDA) receptor signaling has been suspected in TS mice, due to an impaired generation of hippocampal long-term potentiation (LTP). Memantine, an uncompetitive NMDA receptor antagonist approved for the treatment of moderate to severe Alzheimer's disease, is known to normalize LTP and improve cognition in transgenic mice with high brain levels of AbetaPP and amyloid-beta protein. It has recently been demonstrated that acute injections of memantine rescue performance deficits of TS mice on a fear conditioning test. Here we show that oral treatment of aged TS mice with a clinically relevant dose of memantine (30 mg/kg/day for 9 weeks) improved spatial learning in the water maze task and slightly reduced brain AbetaPP levels. We also found that TS mice exhibited a significantly reduced granule cell count and vesicular glutamate transporter-1 (VGLUT1) labeling compared to disomic control mice. After memantine treatment, the levels of hippocampal VGLUT1 were significantly increased, reaching the levels observed in vehicle treated-control animals. Memantine did not significantly affect granule cell density. These data indicate that memantine may normalize several phenotypic abnormalities in TS mice, many of which--such as impaired cognition--are also associated with Down syndrome and Alzheimer's disease.
Rueda
Noemí
N
Department of Physiology and Pharmacology, Faculty of Medicine, University of Cantabria, Santander, Spain.
Llorens-Martín
María
M
Flórez
Jesús
J
Valdizán
Elsa
E
Banerjee
Pradeep
P
Trejo
Jose Luis
JL
Martínez-Cué
Carmen
C
D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D003463:Cues; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000150:complications* / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005106:Exploratory Behavior / Q000187:drug effects; D020233:Gait Disorders, Neurologic / Q000188:drug therapy / Q000209:etiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D018782:Maze Learning / Q000187:drug effects; D008559:Memantine / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype; D011597:Psychomotor Performance / Q000187:drug effects; D011930:Reaction Time / Q000187:drug effects; D045442:Rotarod Performance Test / Q000379:methods; D013028:Space Perception / Q000187:drug effects; D050598:Vesicular Glutamate Transport Protein 1 / Q000235:genetics / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000978:Antiparkinson Agents; D050598:Vesicular Glutamate Transport Protein 1; D008559:Memantine