Affiliations: [a] Department of Physiology and Pharmacology, Faculty of Medicine, University of Cantabria, Santander, Spain | [b] Cajal Institute, CSIC, Madrid, Spain | [c] Institute of Biomedicine and Biotechnology (IBBITEC, UC-CSIC-IDICAN), Santander, Spain | [d] CIBERSAN Instituto de Salud Carlos III, Madrid, Spain | [e] Forest Research Institute, Jersey City, NJ, USA
Correspondence:
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Correspondence to: Carmen Martínez-Cué, Laboratory of Neurobiology of Learning, Department of Physiology and Pharmacology, Faculty of Medicine, University of Cantabria, c/ Cardenal Herrera Oria, s/n, Santander, 39011, Spain. Tel.: +34 942201966; Fax: +34 942201903; E-mail: martinec@unican.es.
Abstract: Ts65Dn (TS) mice exhibit several phenotypic characteristics of human Down syndrome, including an increased brain expression of amyloid-β protein precursor (AβPP) 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 AβPP and amyloid-β 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 AβPP 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.
Keywords: Alzheimer's disease, amyloid-β protein precursor, Down syndrome, memantine, Morris water maze, NMDA, spatial learning, Ts65Dn mice, vesicular glutamate transporter-1
