Galantamine improves olfactory learning in the Ts65Dn mouse model of Down syndrome

Abstract

Down syndrome (DS) is the most common form of congenital intellectual disability. Although DS involves multiple disturbances in various tissues, there is little doubt that in terms of quality of life cognitive impairment is the most serious facet and there is no effective treatment for this aspect of the syndrome. The Ts65Dn mouse model of DS recapitulates multiple aspects of DS including cognitive impairment. Here the Ts65Dn mouse model of DS was evaluated in an associative learning paradigm based on olfactory cues. In contrast to disomic controls, trisomic mice exhibited significant deficits in olfactory learning. Treatment of trisomic mice with the acetylcholinesterase inhibitor galantamine resulted in a significant improvement in olfactory learning. Collectively, our study indicates that olfactory learning can be a sensitive tool for evaluating deficits in associative learning in mouse models of DS and that galantamine has therapeutic potential for improving cognitive abilities.

Figure 1. A and B. Examples of olfactory learning behavior of trisomic and disomic mice exposed to odor pairs A and B.

Bold lines represent disomic mice, and dashed lines the trisomic mice. (A) Representative responses of a single trisomic (dashed line with circle markers) and disomic mice (continuous line with square markers) on the first test-day on odor pair A. (B) Same as A, but for the second test-day. (C) Mean correct responses for all blocks within each section on the first and second days for odor pair A. (D) Same as C, but for odor pair B. Note that these mice do not achieve learning in day 1. This indicates that mice of the C3H background take two days in achieving learning in this task. Mean (circle or square markers) and standard error bars are shown for each case. Significant differences are marked with one (P<0.05) or two asterisks (P<0.01). The y-axis shows the percent of correct responses.

Figure 2. Olfactory learning behavior of odor pairs A and B by disomic and trisomic mice on chronic treatment with galantamine or saline.

Olfactory learning behavior of disomic (continuous lines) and trisomic (dashed lines) mice under chronic treatment with galantamine (square markers) or saline (circle markers), and exposed to odor pairs A and B. (A) Mean number of correct responses of disomic mice on galantamine and saline for all blocks on odor pair A. (B) Same as A, but for trisomic mice. (C) Same as A, but for odor pair B. (D) Same as B, but for odor pair B. Mean (circle or square markers) and standard error bars are shown for each case. Significant differences are marked with one (P<0.05) or two asterisks (P<0.01). The y-axis shows the percent of correct responses.