Long-term effects of cysteamine on cognitive and locomotor behavior in rats: relationship to hippocampal glial pathology and somatostatin levels.

Peroxidase-positive astrocytic inclusions, derived from effete, iron-laden mitochondria, accumulate in the rat hippocampus, striatum and other subcortical brain regions as a function of advancing age. The sulfhydryl agent, cysteamine (CSH), accelerates the appearance of this senescent glial phenotype both in primary astrocyte cultures and in the aging subcortical brain in situ. Earlier experiments have shown that short-term administration of CSH results in reversible depletion of brain somatostatin (SS) levels, cognitive deficits and decreases in locomotor activity. In the present study, we tested spatial learning/memory and motor functioning in rats at 4-5 weeks following cessation of chronic (6 week) CSH treatment to determine whether behavioral deficits may be associated with gliopathic changes within the dorsal hippocampus distinct from the behavioral abnormalities accruing to the immediate effects of the drug. CSH-treated rats displayed significantly impaired performance in the Morris water maze 4-5 weeks following termination of prolonged CSH treatment. In contrast, locomotor activity was not affected in this experimental paradigm. CSH-treated animals exhibited significantly higher numbers of peroxidase-positive astrocyte granules as well as total numbers of GFAP-positive astrocytes in the CA1 sector of the dorsal hippocampus relative to saline-treated controls. In the hilus of the dentate gyrus, numbers of both peroxidase-positive glial inclusions and astrocytes were unaffected by CSH exposure. At 5 weeks following cessation of CSH treatment, SS levels in the hippocampus and hypothalamus (but not cerebral cortex) were elevated relative to those of saline-treated controls. Our results indicate that chronic CSH exposure induces senescence-like changes in CA1 astrocytes which are associated with deficits in cognitive, but not locomotor, behavior and elevated levels of hippocampal and hypothalamic SS. Pathological glial-neuronal interactions within the hippocampus and other subcortical brain regions may play an important role in the cognitive decline observed during normal senescence and in aging-related neurodegenerative disorders.