Fig. 4. mGluR1-positive allosteric modulator ameliorates defects in learning and memory in BACE1-null mice.

A, B BACE1-null mice treated with Ro0711401 were first tested on the Y-maze task in comparison to mock-treated controls. Total numbers of arm entry were shown in A, and changes in percentage of spontaneous alternation were not obvious among three groups shown in B. BACE1-null mice exhibited high numbers of entry. This increase was reverted by Ro0711401 treatment. C–E BACE1-null mice with or without Ro0711401 were tested in an open field. Significant reversions in the total distance covered (C) and average speed (D) were observed in BACE1-null mice treated with Ro0711401 compared to mock treatment. E Heat maps showing that mice treated with Ro0711401 explored both the corners and the center of the open-field arena similar to WT, while BACE1-null mice spent more time in the corners. The anxiety seen in BACE1-null mice was mitigated by PAM treatment. F–J Mice were tested in the Morris water maze. In the habitation (F) and training (G), BACE1-null mice showed defects in learning, taking much longer time compared to WT and BACE1-null treated with Ro0711401. H On day 9 in the Morris water maze test, the number of entries made to the platform quadrant looking for the hidden platform were visibly increased when BACE1-null mice were treated with Ro0711401, and this is more obvious in the representative track plots (I). N = 12 each in WT and BACE1^−/− group and 10 in BACE1^−/− with Ro0711401 treatment; **P < 0.01; ***P < 0.01; Student’s t test. Values are expressed as mean ± SEM. J LTP was recorded on horizontal hippocampal slices from 16-month-old mice as described above after treatment with Ro0711401 for ~50 days. The LTP in the Ro0711401 treatment group was comparable to WT in this age group and both were significantly higher than BACE1-null mice at 16 months (N = 7 for BACE1^−/−, and N = 10 for BACE1^−/− + Ro0711401, N = 8 for WT; **P < 0.01, unpaired Student’s t test).