Modification of ion channels and calcium homeostasis of basal forebrain neurons during aging

Abstract

In this paper we review the last several years of work from our lab with attention to changes in the properties of basal forebrain neurons during aging. These neurons play a central role in behavioral functions, such as: attention, arousal, cognition and autonomic activity, and these functions can be adversely affected during aging. Therefore, it is fundamental to define the cellular mechanisms of aging in order to understand the basal forebrain and to correct deficits associated with aging. We have examined changes in the physiological properties of basal forebrain neurons during aging with whole-cell and single-channel patch-clamp, as well as, microfluorimetric measurements of intracellular calcium concentrations. These studies contribute to the understanding of integration within the basal forebrain and to the identification of age-related changes within central mammalian neurons. Although extensive functional/behavioral decline is often assumed to occur during aging, our data support an interpretation of compensatory increases in function for excitatory amino acid receptors, GABA_A receptors, voltage-gated calcium currents and calcium homeostatic mechanisms. We believe that these changes occur to compensate for decrements accruing with age, such as decreased synaptic contacts, ion imbalances or neuronal loss. The basal forebrain must retain functionality into late aging if senescence is to be productive. Thus, it is critical to recognize the potential cellular and subcellular targets for therapeutic interventions intended to correct age-related behavioral deficits.

Introduction

The basal forebrain has been implicated in control of cortical activity and behavioral states, with the importance of the cholinergic basal forebrain system particularly emphasized [36]. Whereas reviews elsewhere in this issue discuss this control and some postulate a ‘final common pathway’ through the basal forebrain for regulation of cortical activity, our focus will be on the components of the basal forebrain and those homeostatic mechanisms regulating the physiology of individual neurons during aging. Recently, we have begun to understand the physiology and pharmacology of both cholinergic and non-cholinergic basal forebrain neurons, and to elucidate some age-related changes within these cells. Neither the intracellular mechanisms involved in coordination of the basal forebrain projecting systems, nor the changes that cause age-related cognitive dysfunctions are well defined. The profound age-related cognitive deficits and neurodegenerative diseases associated with basal forebrain dysfunction highlight the importance of investigating the aging basal forebrain.

Those time-dependent processes that ultimately result in the ‘nonpathological’ demise of individual cells and organisms are conveniently termed ‘aging’. There is no doubt that an impressive number of molecular, cellular and systemic changes occur in all organisms during their normal lifespan. A wide variety of age-dependent physiological and molecular changes have been described in mammalian central nervous systems. As the complex links between physiological and molecular mechanisms are becoming widely apparent, it is clear that an understanding of the mechanisms of neuronal aging will be possible only when these relationships are discovered. It seems likely that many of the age-related changes that are known to occur in mammalian neurons are linked by cause-and-effect compensatory feedback mechanisms that attempt to maintain homeostasis. However, researchers have found that these putative compensatory mechanisms are difficult to assign with certainty, since coincidental interference from other age-related mechanisms often cannot be ruled out. Even when a link seems clear there may be a 'chicken or egg' dilemma of precedence. Nevertheless, it is important that such compensatory linkages be determined in order to effectively design clinical approaches that might ameliorate age-related declines in mental function.

In this review, we describe some of the age-related changes in the basic physiology of neurons from the rat basal forebrain, and propose that many of these changes could represent compensatory mechanisms. Neurons of the medial septum (MS), nuclei of the diagonal band (nDB) and nucleus basalis (NB) are located in the basal forebrain and innervate the hippocampus, olfactory cortex and cerebral cortex [37], [81]. As stated above, these cells have been implicated in cognitive processes such as attention and some forms of memory [8], [33], [100] and changes in these cells occur in age and Alzheimer's disease [26], [28], [33], [39], [78]. MS/nDB neurons have proven to be a valuable model for investigation of age-related changes in individual central mammalian neurons. This is one of the few preparations from which neurons from aged animals can be acutely dissociated and electrophysiologically characterized. We have used this model system for the study of age-related plasticity and possible compensatory mechanisms. Our data suggest that the aging brain in general, and basal forebrain specifically, undergo subtle, but specific, changes to compensate for physiological alterations associated with aging. The ultimate goal is to understand how age-related neurophysiological changes produce the cognitive and behavioral dysfunctions characteristic of normal aging and how to correct these deficits pharmacologically.