Preserved fronto-striatal plasticity and enhanced procedural learning in a transgenic mouse model of Alzheimer's disease overexpressing mutant hAPPswe

Abstract

Mutations in the amyloid precursor protein (APP) gene inducing abnormal processing and deposition of beta-amyloid protein in the brain have been implicated in the pathogenesis of Alzheimer's disease (AD). Although Tg2576 mice with the Swedish mutation (hAPPswe) exhibit age-related Abeta-plaque formation in brain regions like the hippocampus, the amygdala, and the cortex, these mice show a rather specific deficit in hippocampal-dependent learning and memory tasks. In view of recent findings showing that neural systems subserving different forms of learning are not simply independent but that depressing or enhancing one system affects learning in another system, we decided to investigate fronto-striatal synaptic plasticity and related procedural learning in these mutants. Fronto-striatal long-term depression (LTD) induced by tetanic stimulation of the cortico-striatal input was similar in Tg2576 and wild-type control mice. Behavioral data, however, pointed to an enhancement of procedural learning in the mutants that showed robust motor-based learning in the cross maze and higher active avoidance scores. Thus, in this mouse model of AD, an intact striatal function associated with an impaired hippocampal function seems to provide neural conditions favorable to procedural learning. Our results suggest that focusing on preserved or enhanced forms of learning in AD patients might be of interest to describe the functional reorganization of the brain when one memory system is selectively compromised by neurological disease.

Figure 1

(Experiment 1) Tg2576 mice do not differ from wild-type mice in the number of arm entries but exhibit a lower rate of spontaneous alternation. (A) Mean number ± SEM of arm entries and (B) mean percentage ± SEM of spontaneous alternation rate, during a 5-min session of exploration in the Y maze. (tg) Tg2576 mice; (wt) wild-type mice; (^*) P < 0.05.

Figure 2

(Experiment 2) Tg2576 mice show superior cross maze training performance. Mean number ± SEM of correct runs made during six daily four-run trials (top) and mean time ± SEM to complete each trial (bottom). (tg) Tg2576 mice; (wt) wild-type mice.

Figure 3

(Experiment 2) All Tg2576 mice showed response learning on the cross maze probe trial, whereas wild-type mice were predominantly place learners. Number of choices corresponding to place (solid open bar) or response (solid filled bars) learning. (tg) Tg2576 mice; (wt) wild-type mice; (^*) P < 0.05; (^**) P < 0.01.

Figure 4

(Experiment 3) Tg2576 mice show superior active avoidance scores on the last training trial. Mean number of conditioned responses ± SEM during three consecutive daily sessions involving 90 US-CS pairings each. (tg) Tg2576 mice; (wt) wild-type mice; (^*) P < 0.05.

Figure 5

(Experiment 4) Field potentials induced in the striatum following stimulation of the fronto-striatal pathway are similar in Tg2576 and wild-type mice (p > 0.10). (A) Tetanic stimulation (arrow) of fronto-cortical fibers induced LTD in both wild-type (left) and in Tg2576 mice (right). The top traces are averages of six successive responses obtained immediately before and 50 min after the tetanic train. (B) Pooled data showing the normalized changes in field potential amplitude ± SEM induced by the tetanic stimulation (arrow) in Tg2576 (n = 9 slices from 5 mice) and wild-type (n = 5 slices from 4 mice). The degree of depression measured 10-60 min after the tetanic stimulation in both groups did not differ significantly (F_(1,48) = 0.50, p > 0.10).