Information processing in the nervous system involves neurons "talking" to each other or with target cells. Research in neurotransmission, including neurotransmitter turnover, release, and binding to receptor is central to our understanding of CNS aging. Chemical transmission requires a series of events (Box 3). One of the most studied aspects of aging of the nervous system involves neurotransmitter changes at the synapse. In the healthy elderly, neurotransmitter levels and number, and the affinity of their receptors, and the activity of their metabolic enzymes undergo modest changes circumscribed to specific brain structures and individual neurotransmitter systems. In some diseases, however, a definite relationship exists between loss of one (or several) neurotransmitter(s) and abnormal brain function. For example, dopamine (DA) deficit in the nigros-triatal pathway is associated with PD, and acetylcholine (ACh) deficit in the Meynert nucleus is associated with AD.
Many synapses are classified according to the major neurotransmitter released at their site. Examples of synaptic transmitters include ACh, norepinephrine (NE), DA, serotonin (5-hydroxy-tryptamine), and g-aminobutyric acid (GABA). Synthesis, storage, release, postsynaptic interactions, and inactivation of some neurotransmitters are summarized briefly (Fig. 11) (Box 3) (Table 2).
Several transmitters, often a classic neurotransmitter and a peptide, may coexist within the same neuron. Such
BOX 3 Chemical Classification of Synapses and Neurotransmitters
Known transmitters include amines, amino acids, peptides, and gases (Table 2). Of these, some may be viewed as classic, our knowledge of them extending back almost one century; they are acetylcholine, the catechol-amines—norepinephrine, epinephrine and dopamine—and serotonin.
Others include g-aminobutyric acid (GABA), certain amino acids such as glycine, glutamate, and aspartate. GABA transmits inhibitory impulses and aspartate and glutamate usually mediate excitatory synaptic transmission. Their role is crucial to several normal functions of the nervous system, including memory and long-term modification of synaptic transmission, perception of injurious stimuli, activation of membrane receptor, and transmembrane calcium and sodium fluxes (68).
Among the peptides, a few of the more extensively studied are enkephalin, substance P and hypothalamic neurohormones. Some peptides such as cholecystokinin and somatostatin are found both in the brain and the gastrointestinal tract.
The soluble gas nitric oxide (NO), viewed originally as a toxic molecule (in cigarette smoke and smog), is now considered to be a biologic messenger in mammals that acts by nonsynaptic intercellular signaling (69,70). NO is generated by the enzyme NO synthase (acting on arginine), sensitive to calcium and calmodulin modulation. Unlike other neurotransmitters, NO is not stored in or released from vesicles in the neuron, but rather diffuses out from the cell of origin. NO is also found in genitalia (where it is essential for penile erection) and in the gut (where it is involved in peristalsis). Carbon monoxide (CO), originally viewed as an exclusively toxic gas (70), and metals such as zinc (71,72) are now considered to be putative neurotransmitters in some specific neurons (in the olfactory bulb and hippocampus) often affected by aging.
A membrane-associated, synaptic vesicle protein, synapsin, may also influence neurotransmission by increasing the number of synapses, synaptic vesicles, and contacts (73). There are four synapsins, each with similar amino acid sequences, generated by two alternative gene splicings. All four are associated with the cell cytoskeleton and, like some of the other cytoskeletal proteins, they may undergo phosphorylation during synaptic transmission. Synaptic vesicles may be destabilized in the absence of synaptins and, during synaptic plasticity, upregulation of release may be defective.
TABLE 2 Neurotransmitters and Modulators in the Nervous System
Acetylcholine Glutamate Catecholamines Aspartate Norepinephrine Glycine Epinephrine Dopamine
Enkephalin Cholecystokinin Substance P VIPa
FIGURE 11 Diagrams of established CNS synapses illustrating presynaptic synthesis, storage, metabolism, synaptic release, and postsynaptic binding. (A) Cholinergic synapse. Choline is the precursor of the transmitter ACh through the actions of the synthesizing enzyme CAT ACh is free in the cytoplasm of the prejunctional axonal ending and is also contained in vesicles. Release of cytoplasmic ACh initiates transmembrane events. Several distinct pre- and postsynaptic ACh receptors have been described. Receptor-bound ACh is inactivated by the enzyme AChE. (B) Adrenergic synapse. NE precursor is tyrosine, and the enzymes involved in NE synthesis are TH, DOD, and DBH. The primary degrading enzyme is MAO. NE is stored in vesicles. Once released, transynaptic degradation is initiated by COMT Several pre-and postsynaptic adrenergic receptors have so far been identified. Released NE not degraded by COMT may be taken up by the presynaptic neuron and internalized. Note the simultaneous production of dopamine at its release at the synapse. (C) Serotonergic synapse. The precursor of serotonin is tryptophan, and the synthesizing enzyme is TrH; the degrading enzyme is MAO. Several different types of cell surface receptors are known. (D) GABAergic synapse. GABA is formed in the GABA-shunt pathway of the Krebs cycle. It is formed by the action of GAD from glutamate and is metabolized by deamination. At least two receptors for GABA have been identified in the CNS. Abbreviations: ACh, acetylcholine; CAT choline acetyltransferase; AChE, acetylcholinesterase; NE, norepinephrine; TH, tyrosine hydroxylase; DOD, dopa-decarboxylase; DBH, dopamine-p-hydroxylase; mAo, mitochondrial monamine oxidase; COMT catechol-o-methyltransferase; TrH, tryptophan hydroxylase; GABA, g-aminobutyric acid; GAD, glutamic acid decarboxylase; CNS, central nervous system; GABA-T GABA-transaminase.
"coexistence," resulting in "coutilization" of several transmitters, vastly expands the potential diversity of synaptic communications. Indeed, the peptide often "modulates" or "modifies" the action of the classic neurotransmitter. For example, serotonin coexists with substance P and thyrotropin-releasing hormone in neurons of the rat medulla and spinal cord, where the three neurotransmitters collaborate to regulate some motor and behavioral responses. Receptors may increase in number or affinity for the respective neurotransmitter and its agonists in response to a decrease in concentration of the
Nitric oxide Carbon monoxide Zinc
Synapsins Cell adhesion molecules Neurotropins Others aSerotonin, 5-hydroxytryptamine, or 5-HT.
Abbreviations: GABA, g-amino butyric acid; VIP, vasoactive intestinal polypeptide; TRH, thyrotropin-releasing hormone.
neurotransmitter, and vice versa (up- and down-regulation of receptors).
Synaptic diversification and multiplicity of neurotrans-mitters result in increasing complexity of neuronal communication and the need for a fine tuning of all chemical messengers, transmitters, and their modulators (Box 4) (Table 3). Neurotransmitters have excitatory or inhibitory actions, and it is most important to the function of the nervous system that these actions must remain in balance. With aging, alterations in function are more likely to occur as a consequence of imbalance among neurotransmitters, rather than as a consequence of a global alteration of a single neurotransmitter. Such imbalance could involve the classic neurotransmitters for which evidence is already available, or the neuropeptides, or both. In the human brain, knowledge and understanding of age differences in neurotransmitter levels, activities of their synthesizing and degrading enzymes, and receptor number and affinity are still fragmentary and await further clarification.
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