Enriched early experiences of mice underexpressing the beta-amyloid precursor protein restore spatial learning capabilities but not normal openfield behavior of adult animals.
We have previously reported severely impaired spatial learning in mutant mice underexpressing a shortened variant of the beta-amyloid precursor protein (beta-APPtheta/theta). This targeted mutation is functionally equivalent to a null mutation. It also disturbs behavioral and neurological maturation with deficits emerging mainly between postnatal day (pd) 11 and 19. Such early tested mice exhibited almost no genotype-related difference in Morris water maze learning, raising the possibility that early handling might have compensated for genetic deficits. To verify this effect, we compared watermaze learning and open field behavior of 66 adult mutant and wildtype mice having been handled during pd 3-27 with that of 70 non-handled mutant and wildtype mice. Neurological testing during pd 3-27 markedly reduced time near wall and improved spatial retention of adult mutants, restoring their learning capabilities to wildtype levels. Early handling did not cure the mutation associated activity deficit in the open field, but mainly increased center field exploration in both mutants and wildtypes. In a follow-up experiment we analyzed whether an early (pd 3-10, n = 22) or middle (pd 11-19, n = 24) period of handling in form of neurological testing had differential effects on adult behavior. Mice handled during pd 11-19 had slightly shorter escape times than mice handled during pd 3-10 but were not significantly different in other behavioral measures. There were no sex related differences. Correlational and factor analysis showed that both the mutation and early handling had pleiotropic behavioral effects, resulting in differentially impaired mutants depending on the test situation. Likewise, early handling affected not only thigmotactic tendencies but also, more subtly, other behavioral components underlying water maze learning. We conclude that early postnatal stimulation can prevent mutation induced learning deficits in adult mice, but probably through other developmental mechanisms than those affected by the mutation. This implies that some behavioral impairments related to beta-APP malfunction may be corrected through simple treatments.
Tremml
P
P
Institute of Anatomy, University of Zürich-Irchel, Zürich, Switzerland.
Lipp
H P
HP
Müller
U
U
Wolfer
D P
DP
D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D005091:Exons; D018782:Maze Learning / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics*; D012016:Reference Values; D017384:Sequence Deletion
D016564:Amyloid beta-Protein Precursor