p25, a degradation product of p35, has been reported to accumulate in the forebrain of patients with Alzheimer's disease. p25 as well as p35 are activators of cyclin-dependent kinase 5 (Cdk5) although p25/Cdk5 and p35/Cdk5 complexes have distinct properties. Several mouse models with high levels of p25 expression exhibit signs of neurodegeneration. On the contrary, we have shown that low levels of p25 expression do not cause neurodegeneration and are even beneficial for particular types of learning and memory [Angelo et al., (2003) Eur J. Neurosci., 18, 423-431]. Here, we have studied the influence of low-level p25 expression in hippocampal synaptic plasticity and in learning and memory for each sex separately in two different genetic backgrounds (129B6F1 and C57BL/6). Surprisingly, we found that low-level p25 expression had different consequences in male and female mutants. In the two genetic backgrounds LTP induced by a strong stimulation of the Schaffer's collaterals (four trains, 1-s duration, 5-min interval) was severely impaired in male, but not in female, p25 mutants. Furthermore, in the two genetic backgrounds spatial learning in the Morris water maze was faster in female p25 mutants than in male transgenic mice. These results suggest that, in women, the production of p25 in Alzheimer's disease could be a compensation for some early learning and memory deficits.