INCREASED EXPRESSION OF TYPE-1 INSULIN-LIKE GROWTH-FACTOR RECEPTOR MESSENGER-RNA IN RAT HIPPOCAMPAL-FORMATION IS ASSOCIATED WITH AGING AND BEHAVIORAL IMPAIRMENT

Insulin-like growth factor messenger RNAs are expressed in adult rat b rain. However, little is known about the effects of aging on the expre ssion of the insulin-like growth Factors, their receptors, and their b inding proteins in different regions of rat brain. The goal of the cur rent study was to assess whether there is altered expression of the in sulin-like growth factor system during normal aging in the hippocampal formation, a region particularly vulnerable to the aging process. A s patial learning task in the Morris water maze was used to assess the c ognitive status of young (7-8-month-old) and aged (28-29-month-old) ma le Long-Evans rats. Sites of expression and abundance of insulin-like growth factor-I, type 1 insulin-like growth factor receptor, and insul in-like growth factor binding protein-4 messenger RNAs were then exami ned by in situ hybridization histochemistry and solution or northern b lot hybridization assays. In situ hybridization histochemistry reveale d no qualitative differences in the regional distribution of insulin-l ike growth factor-I, type 1 receptor, and insulin-like growth factor b inding protein-4 messenger RNAs within the hippocampal formation of yo ung and aged rats. However, quantitative analysis of messenger RNA abu ndance in hippocampal tissue homogenates showed a significant age-rela ted increase in type 1 receptor messenger RNA (n = 25; t = -2.5; P < 0 .02). Furthermore, linear regression analysis indicated that type 1 re ceptor messenger RNA abundance was significantly correlated with spati al learning impairment in the water maze (r = 0.44; P < 0.03) such tha t greater behavioral impairment was associated with higher type 1 rece ptor messenger RNA levels in the hippocampal formation. Neither insuli n-like growth factor-I nor insulin-like growth factor binding protein- 4 messenger RNA abundance was related to age or behavior. However, lin ear regression revealed a negative correlation between insulin-like gr owth factor-I messenger RNA abundance and type 1 receptor messenger RN A abundance in aged hippocampus (r = -0.72, P < 0.01). These data indi cate that increased hippocampal expression of type 1 receptor messenge r RNA is associated with aging and cognitive decline. The correlation between type 1 receptor and insulin-like growth factor-I messenger RNA abundance in the hippocampal formation of aged rats suggests that ins ulin-like growth factor availability may influence type 1 receptor exp ression. However, because no overall age difference was found in the a mount of insulin-like growth factor-I messenger RNA in the hippocampal formation, decreased insulin-like growth factor from other sources su ch as the cerebrospinal fluid and the peripheral circulation may be in volved in up-regulating type 1 receptor messenger RNA. Alternatively, type 1 receptor messenger RNA regulation may be part of a trophic resp onse to the degenerative and regenerative events that occur within the hippocampal formation during aging.