INCREASED EXPRESSION OF HIPPOCAMPAL CHOLINERGIC NEUROSTIMULATING PEPTIDE-RELATED COMPONENTS AND THEIR MESSENGER-RNAS IN THE HIPPOCAMPUS OF AGED SENESCENCE-ACCELERATED MICE

Hippocampal cholinergic neurostimulating peptide stimulates cholinergi c phenotype development by inducing choline acetyltransferase in the r at medial septal nucleus in vitro. Adult senescence-accelerated-prone mice/8, a substrain of the senescence-accelerated-prone mouse, show a remarkable age-accelerated deterioration in learning and memory. We cl oned mouse hippocampal cholinergic neurostimulating peptide precursor protein complementary DNA. The deduced amino acid sequence showed that the neurostimulating peptide itself is the same as that found in the rat. In situ hybridization revealed that the highest expression of the precursor protein messenger RNA was in hippocampal pyramidal neurons. Compared with a strain of senescence-accelerated-resistant mouse (con trol mouse), adult senescence-accelerated-prone mice/8 showed increase d expression of both the precursor messenger RNA and the neurostimulat ing peptide-related immunodeposits in the hippocampal CAI field. The d eposits were intensely and diffusely precipitated in neuropils through out the strata oriens and radiatum in senescence-accelerated-prone mic e/8, but not in control mice. The neurostimulating peptide content in the hippocampus was higher in senescence-accelerated-prone mice/8 than in control mice, while its precursor protein itself was not different between the two strains. Furthermore, our previous and present data s how that the medial septal and hippocampal choline acetyltransferase a ctivity was significantly lower in senescence-accelerated-prone mice/8 than in control mice. The data suggest that, in hippocampal neurons i n adult senescence-accelerated-prone mice/8, the production of hippoca mpal cholinergic neurostimulating peptide precursor protein in neurona l somata, which is associated with an increased expression of its mess enger RNA in the CA1 held, occurs as a consequence of low activity in their presynaptic cholinergic neurons. This is followed by accelerated processing to generate bioactive peptide and transport to its functio nal fields. However, certain mechanisms reduce the release of the pept ide and lead to its accumulation in the neuropil. These disturbances o f the septohippocampal cholinergic system might be the biochemical mec hanism underlying the characteristic deterioration of senescence-accel erated-prone mice/8. (C) 1998 IBRO. Published by Elsevier Science Ltd.