Working memory: performance in Y-maze.

<p>A. The baseline rate of spontaneous alternations in Y-maze was lower in the vehicle-treated Ts65Dn vs. 2N mice, reflecting an impairment of working memory. JZL184-treatment had no effect on the performance of both 2N and Ts65Dn mice suggesting no effect on working memory. B. The number of ‘arm entries’ during the Y-maze test was greater in vehicle-treated Ts65Dn vs. 2N mice reflecting increased locomotion of Ts65Dn mice. JZL184-treatment reduced this parameter to the levels seen in 2N animals.</p

Levels of Aβ species in brain samples of mice treated with JZL184 or vehicle.

<p>A: Levels of Aβ40 were significantly increased in the vehicle-treated Ts65Dn vs. 2N mice. JZL184-treatment reduced the levels of Aβ40 in both Ts65Dn and 2N samples. B: Levels of Aβ42 were also greater in Ts65Dn vs 2N samples and were reduced by the JZL184-treatment.</p

Long-term memory: Novel object recognition with the retention period of 24 hours.

<p>A: Time of object exploration during acquisition. There was no difference between the groups, and no effect of JZL184-treatment on the exploration time. B: Testing phase. Left: Time of object exploration during testing was smaller in vehicle-treated Ts65Dn vs. 2N mice. There was no such difference between the JZL184-treated Ts65Dn and 2N groups. Right: Discrimination index was smaller in the vehicle-treated Ts65Dn vs. 2N mice. JZL184-treatment significantly increased the discrimination index in Ts65Dn mice, but had no effect on the performance of their 2N littermates.</p

Long-term potentiation in the CA1 region of hippocampal slices of Ts65Dn and 2N mice.

<p>A: In the vehicle-treated animals, LTP was smaller in Ts65Dn vs. 2N slices. Scale bars: 1 mV; 2 ms. B: In the JZL184-treated mice, there was no difference between the Ts65Dn vs. 2N slices. C: Quantification of the data. JZL184-treatment increased LTP in Ts65Dn mice.</p

Short-term memory: Novel place recognition with the retention period of 10 min.

<p>A: Time spent investigating objects during acquisition. There was no difference between the groups. B: Testing phase. Left: Time spent investigating objects during testing. Vehicle-treated Ts65Dn mice spent less time investigating the objects than their littermate 2N controls. There was no such difference in the JZL-treated groups. Right: Discrimination index was smaller in both vehicle- and JZL-treated Ts65Dn vs. 2N groups. Thus, short-term memory was not affected by the JZL184-treatment.</p

Effect of chronic JZL184 treatment on the brain levels of endocannabinoids and their metabolites.

<p>The values are given in percents of the ‘2N Veh’ group.</p>a)<p>p<0.001. Significant difference vs. ‘2N Veh’ group.</p>b)<p>p<0.001. Significant difference vs. ‘Ts65Dn Veh’ group.</p><p>Effect of chronic JZL184 treatment on the brain levels of endocannabinoids and their metabolites.</p

Effects of ZL184-treatment on locomotor activity (A-C) and thigmotactic behavior (D-F).

<p>In the vehicle-treated animals, locomotor activity was significantly increased in Ts65Dn vs. 2N mice. This can be seen from the increased ambulatory distance (A) and ambulatory time (B) and decreased resting time (C) of Ts Veh vs. 2N Veh group. Treatment with JZL184 (8 mg/kg) restored these locomotion parameters to control levels. In addition, Ts65Dn mice exhibited increased thigmotactic behavior which can be seen from an increased percentage of ambulatory distance (D), ambulatory time (E), and resting time (F) on the arena periphery. JZL184 treatment had no effect on these parameters.</p