Age-related alterations in neurotransmitter receptors: An electrophysiological and biochemical analysis

Abstract

The difficulties involved in understanding the complex phenomena of geriatric cognitive dysfunction clearly call for an interdisciplinary approach. We have initiated multi-laboratory studies in order to assess the utility of the aged Fisher 344 rat as a potential animal model. Prior behavioral experiments have demonstrated that these aged animals suffer from age-related memory impairments conceptually similar to those which occur in humans. Neurophysiological and biochemical studies have focused on the task of assessing hippocampal functioning in this potential animal model. The hippocampus was chosen for these studies because changes in hippocampal function may contribute to the memory impairments associated with old age. The overall firing rate of single hippocampal pyramidal cells was reduced in OLD (26–28 months) rats when compared to YOUNG rats (6–8 months). This effect was due to a selective decrease in the simple spike firing rate. Since burst firing was relatively intact, these results argue against a generalized non-specific decrease in neuronal activity. This interpretation is supported by the observation that microiontophoretic application of glutamate stimulated the firing of hippocampal pyramidal cells to the same extent in both young and old animals. However, microiontophoretic application of GABA inhibited hippocampal pyramidal cell firing to a greater extent in old rats. This effect was not accompanied by any age-related alterations in 3H-muscimol binding in the dorsal hippocampi obtained from these same animals. The pyramidal cell stimulation produced by microiontophoretic application of acetylcholine was reduced in OLD rats. The number of muscarinic receptors (as measured by the binding of 3H-agonists and antagonists) in the dorsal hippocampi was reduced approximately 20% in the aged rats. All of these results have generated the following conclusions: (1) The neuronal activity of hippocampal pyramidal cells is reduced in aged rats, an effect which might contribute to the mnemonic disturbances observed in these animals. (2) Age-related alterations in the functional consequences of GABA receptor activation occurred independent of any change in the binding parameters of 3-muscimol. (3) The decrease in muscarinic binding sites is reminiscent of the decreases observed in aged human brain. Together with the decreased functional response to acetylcholine, these results provide strong evidence for a cholinergic hypothesis of geriatric cognitive dysfunction.