Memantine Improves Spatial Learning in a Transgenic Mouse Model of Alzheimer's Disease

Abstract

Memantine, a low-to moderate-affinity uncompetitive N-methyl-D-aspartate receptor antagonist, has been shown to improve learning and memory in several pharmacological models of Alzheimer's disease (AD). In the present study, the effect of memantine on locomotor activity, social behavior, and spatial learning was assessed in a transgenic mouse model of AD. Eight-month-old male C57BL/6J mice carrying mutated human APP and PS1 genes (APP/PS1) and their nontransgenic (NT) litter mates were administered a therapeutic dose of memantine (30 mg/kg/day p.o.) for 2 to 3 weeks. At this age, APP/PS1 mice show elevated levels of ␤-amyloid peptides in several brain regions. APP/PS1 mice exhibited less exploratory rearing and increased aggressive behavior compared with NT mice. In the water maze test for spatial learning, APP/PS1 mice had longer escape latencies to both hidden and visible platforms, but they did not differ from NT mice in their swimming speed. Memantine significantly improved the acquisition of the water maze in APP/PS1 mice without affecting swimming speed. Memantine did not affect either locomotor activity or aggressive behavior in either genotype. These data indicate that memantine improves hippocampus-based spatial learning in a transgenic mouse model of AD without producing nonspecific effects on locomotion/exploratory activity.In the mammalian brain, NMDA receptors are involved in important physiological functions such as synaptic plasticity and synapse formation, which play important roles in memory, learning, and the formation of neural networks during development (Mayer and Westbrook, 1987). NMDA receptors are also thought to be involved in a variety of neuropathological states caused by excitotoxic neuronal injury such as ischemia, epilepsy, and several neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, and Huntington's disease). In fact, any central nervous system disorder in which neuronal loss is caused by glutamate-induced excitotoxicity has the potential to be treated by NMDA receptor antagonists. However, given the critical role of NMDA receptors in learning and memory (Morris, 1989;Tsien et al., 1996), it may appear counterintuitive that an NMDA receptor antagonist could improve the symptomatology of Alzheimer's disease (AD).Several NMDA receptor antagonists possessing high affinity for NMDA receptors [e.g., (ϩ)MK-801] have been found to cause neurobehavioral adverse effects such as hallucination and cognitive impairment (Benvenga and Spaulding, 1988;Abi-Saab et al., 1998). These adverse events have largely limited the clinical development of high-affinity NMDA receptor antagonists. An alternative approach to avoid such side effects is to produce a partial rather than complete blockade of the NMDA receptor. Partial receptor blockade can be achieved, for example, by low-affinity NMDA receptor antagonists, which typically possess a better therapeutic window than high-affinity NMDA receptor antagonists (Rogawski, 2000). Memantine, a low-to moderate-affinity NMDA r...

Effects of Memantine on Neuronal Structure and Conditioned Fear in the Tg2576 Mouse Model of Alzheimer's Disease

“…We were surprised to find no effect of memantine on contextual memory in a fear conditioning paradigm given that we used doses similar to those previously been reported to have beneficial behavioral effects in other transgenic mouse models of AD (Minkeviciene et al, 2004;Van Dam et al, 2005;Van Dam and De Deyn, 2006). The behavior deficits we observed in Tg + mice replicated earlier findings using Tg2576 mice (Hsiao et al, 1996;Corcoran et al, 2002;Arendash et al, 2004;Barnes and Good, 2005;Dong et al, 2005) and thus imply validity of the behavioral test employed here.…”

“…We selected three doses (5, 10, and 20 mg/ kg) for this study in an attempt to approach the therapeutic doses typically used in humans Parsons, 2003, Wenk et al, 2006). Previous studies in mice have reported that a 30 mg/kg oral dose of memantine in drinking water produces a steady-state plasma drug level of around 1 mM, which is thought to be therapeutic based on clinical studies (Kornhuber and Quack, 1995;Minkeviciene et al, 2004). However, it is difficult to select drug doses in animal studies that are equivalent to clinical doses because the composition and responses observed in the brains of rodents and humans differ (Wenk et al, 2006).…”

“…The behavior deficits we observed in Tg + mice replicated earlier findings using Tg2576 mice (Hsiao et al, 1996;Corcoran et al, 2002;Arendash et al, 2004;Barnes and Good, 2005;Dong et al, 2005) and thus imply validity of the behavioral test employed here. At present, the effects of memantine on behavior in transgenic mouse models of AD (Minkeviciene et al, 2004;Van Dam et al, 2005;Van Dam and De Deyn, 2006), as well as other models (Barnes et al, 1996;MiguelHidalgo et al, 2002;Lang et al, 2004;Woodruff-Pak et al, 2007; for review see Yuede et al, 2007) are inconsistent. Minkeviciene et al (2004) reported improved acquisition in water maze using APP/PS1 transgenic mice treated with 30 mg/kg memantine in drinking water for 3 weeks, whereas no effect was observed on retention.…”

“…At present, the effects of memantine on behavior in transgenic mouse models of AD (Minkeviciene et al, 2004;Van Dam et al, 2005;Van Dam and De Deyn, 2006), as well as other models (Barnes et al, 1996;MiguelHidalgo et al, 2002;Lang et al, 2004;Woodruff-Pak et al, 2007; for review see Yuede et al, 2007) are inconsistent. Minkeviciene et al (2004) reported improved acquisition in water maze using APP/PS1 transgenic mice treated with 30 mg/kg memantine in drinking water for 3 weeks, whereas no effect was observed on retention. Conversely, Van Dam et al (2005) reported beneficial effects of a much lower dose (2.0 mg/kg) of memantine while higher doses (10 mg/kg) demonstrated detrimental effects in the water maze.…”

What have we learned from the streptozotocin-induced animal model of sporadic Alzheimer’s disease, about the therapeutic strategies in Alzheimer’s research

“…Memantine treatment (30 mg/kg/day p.o.) for 2 to 3 weeks initiated at the age of 8 months also significantly improved the acquisition of the Morris Water Maze in APP/PS1 mice AD model without affecting swimming speed although it had no effects on locomotor activity or aggressive behaviour (Minkeviciene et al 2004).…”