Increased expression of type 1 insulin-like growth factor receptor messenger RNA in rat hippocampal formation is associated with aging and behavioral impairment.

Abstract

Insulin-like growth factor messenger RNAs are expressed in adult rat brain. However, little is known about the effects of aging on the expression of the insulin-like growth factors, their receptors, and their binding proteins in different regions of rat brain. The goal of the current study was to assess whether there is altered expression of the insulin-like growth factor system during normal aging in the hippocampal formation, a region particularly vulnerable to the aging process. A spatial learning task in the Morris water maze was used to assess the cognitive status of young (7-8-month-old) and aged (28-29-month-old) male Long-Evans rats. Sites of expression and abundance of insulin-like growth factor-I, type 1 insulin-like growth factor receptor, and insulin-like growth factor binding protein-4 messenger RNAs were then examined by in situ hybridization histochemistry and solution or northern blot hybridization assays. In situ hybridization histochemistry revealed no qualitative differences in the regional distribution of insulin-like growth factor-I, type 1 receptor, and insulin-like growth factor binding protein-4 messenger RNAs within the hippocampal formation of young and aged rats. However, quantitative analysis of messenger RNA abundance in hippocampal tissue homogenates showed a significant age-related increase in type 1 receptor messenger RNA (n = 25; t = -2.5; P < 0.02). Furthermore, linear regression analysis indicated that type 1 receptor messenger RNA abundance was significantly correlated with spatial learning impairment in the water maze (r = 0.44; P < 0.03) such that greater behavioral impairment was associated with higher type 1 receptor messenger RNA levels in the hippocampal formation. Neither insulin-like growth factor-I nor insulin-like growth factor binding protein-4 messenger RNA abundance was related to age or behavior. However, linear regression revealed a negative correlation between insulin-like growth factor-I messenger RNA abundance and type 1 receptor messenger RNA abundance in aged hippocampus (r = -0.72, P < 0.01). These data indicate that increased hippocampal expression of type 1 receptor messenger 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 insulin-like growth factor availability may influence type 1 receptor expression. However, because no overall age difference was found in the amount of insulin-like growth factor-I messenger RNA in the hippocampal formation, decreased insulin-like growth factor from other sources such as the cerebrospinal fluid and the peripheral circulation may be involved in up-regulating type 1 receptor messenger RNA. Alternatively, type 1 receptor messenger RNA regulation may be part of a trophic response to the degenerative and regenerative events that occur within the hippocampal formation during aging.