Systemic treatment with GPI 1046 improves spatial memory and reverses cholinergic neuron atrophy in the medial septal nucleus of aged mice.

Systemic treatment with GPI 1046, a non-immunosuppressive ligand of the immunophilin FKBP12 (FK-506-binding protein 12 kDa), has previously been shown to promote morphological recovery of the nigrostriatal dopaminergic projection after MPTP lesion in mice, and of lesioned sciatic nerve fibres after nerve crush in rats. In the present study, we investigated whether chronic systemic treatment with GPI 1046 could affect the decline of spatial learning and memory, and the atrophy of medial septal cholinergic neurons, associated with late senescence in C57 black mice. Three-month old (young) and 18-19-month old (aged) male C57BL/6N-Nia mice were first trained in a place learning task in the Morris water maze. Based on their performance relative to young controls, aged animals were then allocated to treatment groups (10 mg/kg GPI 1046, or vehicle). Retention of the spatial platform location was assessed after 3 weeks of dosing. We found that aged animals that had been dosed with GPI 1046 now performed at a significantly better level than their vehicle control group. Aged animals that had shown the greatest degree of impairment during training in the place learning task showed the greatest relative degree of improvement under treatment and were statistically indistinguishable from young, or aged unimpaired control animals. Cell volumes of cholinergic cells in the medial septal nucleus were assessed after an additional 10 months of dosing at 30 months of age, using stereological methods. We found that aged animals displayed a significant 34% decrease in volume of these cells relative to young controls. This atrophy was significantly reversed in aged GPI 1046-treated animals (13% shrinkage). We conclude that chronic systemic treatment with GPI 1046 positively affects memory mechanisms in the aged mouse, possibly by acting on the septohippocampal cholinergic system.