NEUROCHEMISTRY

None of the billions of nerve cells, or neurons, in the human brain functions alone. To process information, neurons must form circuits and must communicate with each other rapidly and with great precision. Within a neuron, the electrical impulses that carry information are propagated by rapid changes in membrane potential that arise from the controlled opening and closing of ion channels. These pores in the cell membrane permit the controlled passage of positive or negative ions between the interior and exterior of the cell, and thereby the conduction of electrical impulses along the cell's processes. Additional mechanisms are required at synapses (neuron junctions) to pass signals from one neuron to another. Although a few neurons form electrical synapses, where electrical signals are conducted directly from one neuron to the other through specialized ion channels (gap junctions), most neurons in the mature nervous system communicate via chemical synapses. At chemical synapses, electrical activity in a presynaptic neuron causes the release of a chemical messenger, a neurotransmitter, which diffuses across the narrow synaptic cleft to bind to neurotransmitter receptors on the postsynaptic neuron and elicit changes in the electrical activity of that neuron.

Neurochemistry of synaptic transmission

Multiple neurochemical processes are involved in the synthesis, packaging, and release of neurotransmitters, and in the production and function of neurotransmitter receptors. Significantly, each of these biochemical steps represents a point of potential regulation of synaptic function and a site of possible age-related changes.

Most neurons produce and release one of several small molecules that serve as neurotransmitters, including acetylcholine, biogenic amines (dopamine, norepinephrine, epinephrine, histamine, or serotonin), or amino acids (glutamate, glycine, or gamma-aminobutyric acid). Many neurons also release one or more neuroactive peptides (neuropeptides), which provide additional modulation of signal transmission. Low levels of neuronal activity often result in release of only the small-molecule transmitter, whereas higher levels of activity result in the co-release of neuropeptides. Release of the neuropeptides may cease at very high levels of activity, however, since peptides must be delivered from the cell body and are replenished slowly. In contrast, synthesis and packaging of other neurotransmitters occurs more rapidly because the necessary synthetic enzymes are present within the cytoplasm in the region of the synapse. The release of neurotransmitters depends upon an increase in intracellular calcium that occurs with the depolarization (decrease in membrane potential) associated with the arrival of action potentials, regenerative waves of electrical activity that are the basis for signaling along neronal processes. Increased calcium leads to modification of vesicle-binding proteins, which facilitate the fusion of vesicles, membrane-bound packages in the cytoplasm, with the cell membrane and subsequent release of the vesicles' contents into the extracellular space.

After release, all neurotransmitters bind to neurotransmitter receptors and initiate changes in the postsynaptic neuron. It is the biochemical properties of the receptor protein, rather than that of the neurotransmitter itself, that determine the response of the postsynaptic cell. Each neurotransmitter binds to a different receptor, although multiple receptor types exist for several neurotransmitters, with each receptor initiating a different response in the target neuron. Functionally, neurotransmitter receptors fall into two groups, based on the mechanisms by which they alter the electrical activity of a neuron. Ionotropic receptors include an ion channel as part of their structure, and binding of the neurotransmitter results in immediate opening of that ion channel. Metabotropic receptors influence ion channels indirectly through activation of one of several second-messenger pathways. The three second-messenger systems that have been identified so far are similarly organized in that each includes a ligand-binding receptor domain coupled to a transducer that regulates the activity of an effector enzyme. The enzyme produces a second messenger that acts directly on one or more target proteins or activates additional, secondary effector enzymes. In addition to regulating ion channels, second-messenger systems may influence a variety of intracellular processes and elicit long-lasting changes in stimulated neurons.

Once a neurotransmitter has activated its receptors, it must be removed or destroyed rapidly in order to permit transmission of subsequent signals. Some neurotransmitters, regardless of type, simply diffuse from the synaptic cleft. Small-molecule neurotransmitters are also taken back up by presynaptic and postsynaptic neurons and by neighboring cells. One neurotransmitter, acetylcholine (ACh), is broken down rapidly by a membrane-bound enzyme in the region of the synapse. Neuroactive peptides are eliminated only by diffusion from the synaptic cleft and by proteolysis (degradation) by extracellular enzymes; thus they tend to have more sustained effects than small-molecule neurotransmitters.

Effects of age on the neurochemistry of synapses

Normal aging appears to result in significant but restricted neurochemical changes in synapses. Each of the many steps involved in neurotransmission may be altered in some neurons, but it does not appear that there are global changes in the neurochemistry of all synapses. Studies of neurotransmitter synthesis are difficult because most of the synthetic enzymes are unstable and difficult to measure; however, synthesis of ACh has been demonstrated to diminish with age in some brain regions, including the cerebral cortex. Levels of other neurotransmitters (e.g., dopamine) also appear to decline late in life, also in a regionally specific manner. Age-related changes in neurotransmitter receptors have been studied by direct assay of the proteins and by analysis of the binding of labeled neurotransmitters to sections of the brain. Receptors for the neuropeptides and for some amino acid neurotransmitters appear to be relatively resistant to age-related changes. In contrast, ACh, dopamine, and serotonin receptors decline with age in several regions of the brain. Even for synapses at which both neurotransmitter levels and neurotransmitter receptors are maintained, changes in second-messenger systems may produce age-related declines in synaptic function. Such changes may account for an age-dependent loss of plasticity —that is, a decline in the ability of synaptic stimulation to produce the sustained biochemical changes in postsynaptic neurons that underlie learning and memory.

Functional consequences of age-related neurochemical changes

It is difficult to link age-related changes in the neurochemistry of synapses to specific changes in cognitive function. Neurochemical studies of experimental animals are easier to perform and better controlled than those using postmortem human brain tissue, but they are not readily related to cognitive changes in humans. Despite such difficulties, however, there is accumulating evidence that age-related declines in transmission at cholinergic, serotonergic, and dopaminergic synapses contribute to changes in motor function, mood, and memory, respectively. Recent developments in functional brain imaging have provided significant advances in studies of the neurochemistry of synapses, changes in the aging brain, and their relationship to cognitive function. Radioactive ligands for specific neurotransmitter receptors, which can be imaged in living subjects using positron emission tomography (PET), permit investigators to visualize the activity of specific types of synapses in discrete regions of the brain. This approach permits direct comparisons of synaptic function in the brains of individuals of different ages and allows investigators to link neurochemical differences to differences in cognitive function.

David R. Riddle

See also Brain; Neurodegenerative Diseases; Neurotransmitters; Plasticity.

BIBLIOGRAPHY

DeKosky, S. T., and Palmer, A. M. "Neurochemistry of Aging." In Clinical Neurology of Aging. Edited by M. L. Albert and J. E. Knoefel. New York: Oxford, University Press. 1994. Pages 79–101.

Meltzer, C. C. "Neuropharmacology and Receptor Studies in the Elderly." Journal of Geriatric Psychiatry and Neurology 12 (1999): 137–149.

Schwartz, J. H. "Neurotransmitters." In Principles of Neural Science. Edited by E. R. Kandel, J. H. Schwartz, and T. M. Jessell. New York: McGraw-Hill, 2000. Pages 280–297.

Strong, R. "Neurochemical Changes in the Aging Human Brain: Implications for Behavioral Impairment and Neurodegenerative Disease." Geriatrics 53 (1998): S9–S12.

Neurochemistry

Neurochemistry refers to the chemical processes that occur in the brain and nervous system. The fact that one can read this text, remember what has been read, and even breathe during the entire time that these events take place relies on the amazing chemistry that occurs in the human brain and the nerve cells with which it communicates.

There are two broad categories of chemistry in nerve systems that are important. The first is the chemistry that generates electrical signals which propagate along nerve cells. The key chemicals involved in these signals are sodium and potassium ions. To see how they give rise to a signal, one must first look at a nerve cell that is at rest.

Like any other cell, a nerve cell has a membrane as its outer "wall." On the outside of the membrane, the concentration of sodium ions will be relatively high and that of potassium ions will be relatively low. The membrane maintains this concentration gradient by using channels and enzymes.

The channels are pores that may be opened or closed by enzymes which are associated with them. Some ion channels allow the movement of sodium ions and others allow potassium ions to cross the membrane. They are also called "gated" channels because they can open and close much like a gate in a fence. The voltage they experience dictates whether the gate is open or closed. Thus, for example, a gated sodium ion channel in a membrane opens at certain voltages to allow sodium ions to pass from regions of high concentration to regions of low concentration.

Active transport mechanisms are also present. Enzymes that span the membrane can actively pump sodium and potassium ions from one side of the membrane to another. When the nerve cell is at rest, these mechanisms maintain a high potassium and low sodium environment inside the cell.

Even when it is at rest, a nerve cell is in contact with many other nerve cells. When a neighboring cell passes on a signal to the resting cell (by a mechanism to be discussed shortly), a dramatic change occurs in the ion concentrations. Once the nerve cell at rest has received a sufficient signal from a neighbor to surpass a threshold level, some of the sodium ion channels near the connection point open and sodium ions flow into the cell. This flow of charge results in an electrical potential that is called the action potential. The action potential does not stay localized, however. Farther down the nerve cell, more sodium ion channels surpass their threshold and open so that the sodium ions flow into them as well. Thus, the action potential moves down the nerve. After the sodium ion gates open, the potassium ion gates also open and potassium ions flow out of the cell. This flow of ions offsets the charge from sodium ions flowing into the cell and the signal has receded in that region (and has moved on).

Once the cell propagates a signal, how does that cell send its signal to a neighbor? This question leads to the second broad category of neurochemistry: the chemistry at the synapse. Nerve cells do not actually touch their neighbors, but rather form a small gap called the synapse. The signal is transferred across this gap by chemicals called neurotransmitters.

The communication that occurs across the synapse may either excite or inhibit the action of the neighboring nerve cell. Thus, synapses are further categorized as either excitatory synapses or inhibitory synapses. The cell that is propagating the signal is called the presynaptic cell, and the cell that receives the signal is the postsynaptic cell.

The end of the presynaptic cell contains small vesicles , spherical collections of the same lipid molecules that make up the cell membrane. Inside these vesicles, neurotransmitters exist in high concentrations. When the action potential reaches the end of the presynaptic cell, some of the vesicles merge with the cell membrane and release their contents (a process called exocytosis). The released neurotransmitters experience an immediate concentration gradient. They diffuse away from the release point to counteract the gradient, and in doing this, they cross the synapse and arrive at the neighboring cell.

On the postsynaptic cell, there are receptors that are capable of interacting with the neurotransmitters. Once these messenger molecules cross the synapse, they connect with the receptors and the two cells have successfully communicated. The proteins of the receptors are capable of opening sodium gated ion channels, and a new action potential is engaged in the postsynaptic cell.

The remaining step in the process is also a critical one. Somehow the action of the neurotransmitters must cease. If they continue to cross the synapse, or are not removed from the receptors of the postsynaptic cell, they will continue to activate that cell. An overexcited or inhibited nerve cell is not capable of proper function. For example, schizophrenia is a mental disease that is caused by the brain's inability to eliminate excitatory neurotransmitters. The nerve cells continue firing, even when they need not, and the incorrect brain chemistry results in debilitating symptoms such as auditory hallucinations—hearing voices that are not actually there.

see also Enzymes; Neurotoxins; Neurotransmitters; Stimulants.

Thomas A. Holme

Bibliography

Bloch, K. (1999). Blondes in Venetian Paintings, the Nine Banded Armadillo and Other Essays in Biochemistry. New Haven, CT: Yale University Press.

Bradford, H. F. (1986). Chemical Neurobiology. New York: W.H. Freeman.

Darnell, J.; Lodish, H.; and Baltimore, D. (1990). Molecular Cell Biology. New York: Scientific American Books.