NEUROTRANSMITTERS

The idea that nerve cells function as independent units and form a physical contact to facilitate intercellular communication was first proposed by neurobiologists at the turn of the twentieth century. This concept, termed the neuron theory of brain function, is based on the knowledge that the nervous system is not made up of a contiguous labyrinth of intertwining processes but instead represents a collection of neurons, together with their axons and dendrites, that form close functional contacts to permit the transfer of information from one cell to another. The site at which the contact between two neurons is made is called the synapse; and the chemical signal that is used for mediating communication between neurons is the neurotransmitter.

For both the central and peripheral nervous system there are a relatively small number of molecules that fulfill the criteria of a neurotransmitter. These include dopamine (DA), norepinephrine (NE), epinephrine, serotonin, histamine, acetylcholine (Ach), gamma-amino butyric acid (GABA), glycine, and glutamate. During development the nervous system takes on the responsibility for controlling a variety of body functions including movement, consciousness, learning and memory, and sensory processing. A fully competent nervous system is essential for maintaining the integrity of body functions in adulthood while an aging nervous system has often been coupled with an irreversible loss of global function. However, this oversimplified picture of brain aging is far from the truth. Research conducted since the early 1980s has indicated that an age-related decline in neurotransmitter function is not a global phenomenon. Instead, studies have reported that just as organisms age at different rates, so do the different neurotransmitter systems in their bodies; and that wide differences in neurotransmitter levels exist in the brain between individuals of like age. This divergence between biological and chronological old age is most obvious in the human population but is also found in aged rodents and nonhuman primates. Functional variability with age is tied closely to the variability in the biochemical and anatomical changes found in different neurotransmitter systems of the brain and is unquestionably linked to genetic and environmental factors that influence the "rate" at which we age. Thus, the degree to which age-related anatomical and biochemical changes occur in neurotransmitter systems of the brain can be described as variable at best.

When investigating age-related alterations in neurotransmitter function it is important to realize that a decline of a particular neurotransmitter does not always equate with a loss in physiological function. Previous studies have reported that age-related changes in the brain cannot be represented by simple cell loss that leads to functional decline. Rather, it is understood that the aging brain represents a composite of various adaptive and compensatory responses, which work together to maintain and repair the brain's neural networks in response to naturally occurring cell loss or neurochemical deficits that are brain region, cell type, and species specific. In addition, it is important to distinguish between changes in neurotransmitter systems that are seen in normal aging with that characteristic of the diseased state. While it was once believed that neurodegenerative diseases such as Alzheimer's and Parkinson's disease were part of an accelerated aging process it is now known that the neuropathology of the diseased brain represents extensive neuronal degeneration and cell death that goes beyond normal aging. In fact anatomical studies with sophisticated neuronal counting techniques indicate that the degree of neuron loss in the aged brain is quite low and age-related changes ascribed to neurotransmitter neurons may not affect our activities of daily living until we are well into our late seventies or eighties.

If global neurodegeneration and cell death are not characteristic of neurotransmitter neurons then what are the changes seen in neurotransmitter neurons with increased age? To answer this question we must consider that changes can occur in either the presynaptic or postsynaptic components involved in information transfer. Age-related changes in the presynaptic components can include changes in neurotransmitter synthesis, storage, synaptic release, and neurotransmitter re-uptake. Changes in postsynaptic components include changes in neurotransmitter receptors (protein complexes that bind neurotransmitters), secondary messenger systems (responsible for transfer of information into neurons), and enzymes involved in neurotransmitter degradation. The following is a brief overview of the age-related changes that have been described for the four most common neurotransmitters found in the central and peripheral nervous system.

Acetylcholine

The neurotransmitter acetylcholine is important for communication in a number of brain regions, particularly the hippocampus, striatum, and cerebral cortex. It is also the neurotransmitter used to transmit information at the neuromuscular junction. Acetylcholine is synthesized presynaptically by the enzyme choline acetyltransferase (CAT). Absolute levels of CAT and its activity decline with age, ranging from a 20 to 30 percent decline in the hippocampus and striatum and about a 10 percent decline in the cerebral cortex. Within these same anatomical regions there is evidence of some neuron cell loss, but it does not necessarily account for total decline in neurotransmitter production. It is interesting that the loss of CAT activity can be reversed or attenuated. For example, increased production of neurotrophic factors (which themselves are regulated by exercise and diet) influence CAT activity and acetylcholine production. In addition to these presynaptic changes, postsynaptic alterations have also been documented. For example, the muscarinic acetylcholine receptor, the synaptic receptor protein that binds acetylcholine, has been shown to decline by similar degrees in areas where CAT activity is also diminished. However, it remains to be determined whether this is the cause of the neurotransmitter deficiency or a consequence in response to presynaptic changes. Despite the fact that global neuron cell death may not underlie specificity of neurotransmitter system decline, some studies, but not all, have suggested that altered cholinergic neurotransmission may also be accompanied by a decline in the number or size (atrophy) of cholinergic neurons, including those in the nucleus basalis. The best example of a neurodegenerative disease associated with the loss of cholinergic neurons is Alzheimer's disease.

Dopamine

Dopamine is the primary neurotransmitter in the basal ganglia (i.e., striatum, substantia nigra) and to a lesser extent in the cerebral cortex. In normal aging there are presynaptic alterations including decline of dopamine in the striatum, decreased dopamine metabolites (indicated by decreased dopamine biosynthesis), as well as postsynaptic alterations including decreased dopamine receptors. As summarized in the review by Morgan and Finch, the decline in the DA content and TH activity of the substantia nigra and striatum of aged rodents is not a consistent finding across rodent species and is generally smaller than that reported for nonhuman primate and postmortem human brains. Similarly, for dopamine cell loss, while it has been reported that normal aging is not associated with a significant decline in the total number of DA neurons of the substantia nigra in aged mice, controversy exists as to the degree DA cell loss occurs in the substantia nigra of nonhuman primates and man. It is interesting that despite the fact that there are presently five different classes of dopamine receptors, the decline in the D2 receptor is the only one that has been reported to show an age-related decline across species. The reasons for this variability are yet unclear. Other age changes seen in the dopaminergic system included decreased dopamine transporter (responsible for uptake of dopamine from the synapse) and increased monoamine oxidase B (an enzyme that breaks down dopamine resulting in reduced effective synaptic levels of dopamine). The prime example of a neurogenerative disease associated with the loss of dopamine neurons is Parkinson's disease.

GABA and glutamate

GABA and glutamate are both metabolic intermediates and neurotransmitters. GABA is considered the major inhibitory neurotransmitter in the brain, whereas glutamate is considered an excitatory neurotransmitter that promotes a postsynaptic stimulatory response. In the aged brain glutamic acid decarboxylase (GAD), the enzyme that converts glutamate into GABA, falls 20–30 percent in the cortex and thalamus of postmortem human brain, and there is a decrease in GABA receptor binding sites and GAD mRNA levels in the aged rodent brain. Similarly, previous studies have reported an age-related decrease in glutamate receptors in the hippocampus of aged rats, mice, and nonhuman primates while no change in glutamate receptor binding sites has been found in postmortem human brains. Huntington's disease is the classic example of a neurodegenerative disease linked to the loss of GABA neurons in the striatum.

To summarize, while there is little doubt that degenerative changes occur in neurons of the aged brain the severity of these changes vary from person to person, and the question of cause and effect remains elusive. In addition, previous studies have shown that age-related changes in the neurotransmitter systems of the brain are not a global phenomenon of normal aging but are brain region, cell type, and species specific. Species variability is well documented in the gerontologic literature, and we must be cautious in our interpretations when comparing data across animal species or when comparing cellular changes in animals and human aging. Lastly, it is no longer possible to associate brain aging with the loss of function and structure without taking into consideration the compensatory or plastic nature of the nervous system. Rather, it is understood that the aging brain represents a composite of various adaptive and compensatory responses, which work together to maintain neurotransmitter levels in the brain and repair the brain's neural networks in response to naturally occurring cell loss or neurochemical changes that are brain region specific.

Thomas H. McNeill Michael Jakowec

See also Neurochemistry.

BIBLIOGRAPHY

Collier, T. J., and Coleman, P. D. "Divergence of Biological and Chronological Aging: Evidence from Rodent Studies." Neurobiology of Aging 12 (1991): 685–693.

Finch, C. E., and Roth, George S. "Biochemistry of Aging." In Basic Neurochemistry: Molecular, Cellular and Medical Aspects. Edited by G. J. Siegel, B. W. Agranoff, R. W. Albers, S. K. Fisher, and M. D. Uhler. Philadelphia: Lippincott-Raven, 1999. Pages 614–633.

Morgan, D. G., and Finch, C. E. "Dopaminergic Changes in Basal Ganglia: A Generalized Phenomenon of Aging in Mammals." Annals of the New Academy of Science 515 (1988): 145–160.

Wang, E., and Snyder, D. S. Handbook of the Aging Brain, San Diego, Calif.: Academic Press, 1998.

NORMAL AGING

See Physiological changes