Acute Injections of the NMDA Receptor Antagonist Memantine Rescue Performance Deficits of the Ts65Dn Mouse Model of Down Syndrome on a Fear Conditioning Test

Abstract

Individuals with Down syndrome (DS) and Ts65Dn mice (a major animal model of DS) carry an extra copy of the DSCR1 (Down Syndrome Critical Region 1) gene, which encodes for a protein that inhibits calcineurin. Calcineurin itself has been shown to modulate N-methyl-D-aspartate (NMDA) receptor (NMDAR) activation kinetics by decreasing channel mean open time and opening probability. We hypothesize that the overexpression of DSCR1 in persons with DS and Ts65Dn mice would inhibit normal calcineurin activity and produce pathological increases in NMDAR mean open time and opening probability. These kinetic changes should in turn produce an increase in inhibition of NMDAR-mediated currents by open channel blockers. To test this hypothesis, we investigated the locomotor-stimulating effects of MK-801 on Ts65Dn mice and have found that these mice display an increased sensitivity to this compound. Furthermore, we have found that acute injections (5 mg/kg, i.p.) of the uncompetitive NMDAR antagonist memantine rescue performance deficits of Ts65Dn mice on a fear conditioning test. Because the actions of memantine on NMDAR kinetics had been shown by others to mimic somewhat the actions of calcineurin, we attributed this positive effect of memantine on Ts65Dn mice to a drug-mediated 'normalization' of NMDAR function. To our knowledge, this is the first instance in which the acute injection of a pharmacological agent has improved the behavioral performance of Ts65Dn mice in a test of learning and memory. These results are very promising from a potential therapeutic perspective, given memantine's current status as a Food and Drug Administration (FDA)-approved drug.