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Biology 202
1998 Second Web Reports
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Neuromodulation and Neural Plasticity

Daniel Casasanto

Neuromodulatory synaptic transmission differs from classical chemical synaptic transmission in both mechanism and function. The function of a classical synapse is to convey information rapidly from the presynaptic neuron to its target cell, producing a short-term effect. The neuromodulatory synapse may do the same initially, but its primary function is to transmit information that will have long-lasting effects on the postsynaptic neuron's metabolic activity, and on its response to subsequent input. These effects are fundamental to the development and adaptation of the nervous system, and are believed to be the basis of such higher functions as learning and memory.

Neurotransmitters released from a classical presynaptic neuron bind to specific receptor proteins in the postsynaptic cell membrane, causing ion channels in the membrane to open or close. If the resulting flow of ions depolarizes the membrane relative to its resting potential, the probability that an action potential will be generated increases, and the synapse is considered excitatory. If the ion flow results in a net hyperpolarization of the membrane, the probability that an action potential will be generated decreases, and the synapse is considered inhibitory. Neuromodulatory synapses can be either excitatory or inhibitory. A neurotransmitter released from the presynaptic neuron may cause the postsynaptic membrane to depolarize or to hyperpolarize by the same mechanism used in classical synapses, but the resulting postsynaptic potential will be relatively weak and slow. Whereas a neurotransmitter in a classical synapse may induce postsynaptic effects lasting from ten to one hundred milliseconds, a neuromodulator's postsynaptic effects may persist from several hundred milliseconds to several hours.

Neuromodulation of the postsynaptic neuron depends not so much on the neurotransmitter as on the receptor to which it binds, called a metabotropic receptor. Whereas classical ionotropic receptors affect postsynaptic membrane permeability directly, metabotropic receptors effect changes in the postsynaptic neuron via intracellular molecules called a second messengers. When a neurotransmitter binds to a metabotropic receptor, a protein inside the postsynaptic cell initiates a cascade of biochemical events that influence the neuron's future response to stimuli. Although the neurotransmitter, or "first messenger," becomes inactivated rapidly, the effects of the second messenger may last several days. One way in which the second messenger induces prolonged effects is by initiating the synthesis of new proteins, which remain in the cytoplasm of the postsynaptic neuron, influencing its activity. Certain proteins can affect the genome of a postsynaptic cell, permanently altering the cell's activities.

Neural plasticity is the ability of neural circuits to undergo changes in function or organization due to previous activity. The simplest example of neural plasticity is facilitation: the increase in amplitude of a postsynaptic potential due to rapid repeated activation. The facilitated neuron returns to its resting potential between activations, and its enhanced postsynaptic response is fleeting. Potentiation, in contrast, is a special type of facilitation in which an increased postsynaptic potential persists after the facilitating stimulus has subsided. A high frequency burst of presynaptic impulses lasting several seconds, called a tetanic stimulus, can cause a posttetanic potentiation, (PTP) lasting several minutes. Extended tetanization engenders long-term potentiation, (LTP) which can result in elevated postsynaptic activity for hours or days. LTP is sustained, in part, by molecules called retrograde messengers. These molecules are synthesized in the postsynaptic cell as a result of presynaptic events. Retrograde messengers diffuse back into the presynaptic cell, where they stimulate neurotransmitter release. Although homosynaptic potentiation is possible, LTP usually results from heterosynaptic potentiation: the convergence of two or more inputs on a neuron which bears the appropriate type of receptor, called an NMDA receptor. Although this receptor is ionotropic, LTP is a neuromodulatory process, in which serotonin commonly serves as the neuromodulator, and cAMP is the second messenger.

Although early neural development is largely gene-dependent, neural plasticity is necessary for the functioning of activity-dependent circuits: systems which only develop if properly stimulated by neuronal activity resulting from an organism's exposure to its environment. Studies conducted on kittens in which one eye was occluded during the developmental critical period suggest that processes associated with binocular vision depend upon a kind of LTP, mediated by NMDA receptors. Extrinsic stimuli that cause activation of the developing pathways must accompany intrinsic developmental mechanisms.

Developmental plasticity is observed commonly in maturing organisms, but is also evident in adults. Experiments involving two groups of rats, one raised in a "simple" environment with few stimuli, the other raised in a "complex" environment with many stimuli, evince activity-dependent development. Predictably, the rats raised in the complex environment demonstrated enhanced neural development relative to those raised in the simple environment. Surprisingly, rats raised in a common environment until adulthood showed developmental differences upon separation into simple and complex environments. Rats placed in a complex environment after the critical period showed enhancements similar to those demonstrated by rats raised in the complex environment: increased cortical mass, increased dendritic branching and complexity, and an increased number of synapses per neuron. Enhancements appeared within a week of the rats' placement in the complex environment. Although not all developmental effects seen in young rats were observed in adults, these experiments show that structural changes occur in the nervous systems of adult organisms when they experience new stimuli.

Learning, a change in an animal's behavior as a consequence of its experience, may be considered at the neuronal level to be an extension of previously described neuromodulatory processes. Habituation, the simplest form of learning, is the decline and eventual cessation of a neuron's response to a repeated stimulus. It is closely related to facilitation. Whereas facilitation is an increase in postsynaptic activity accompanied by increased neuromodulator transmission, habituation is a reduction in postsynaptic response accompanied by reduced neurotransmitter release from the presynaptic neuron. Also related are dishabituation, the recovery of a habituated neuron's responsiveness upon the introduction of a novel strong stimulus, and sensitization, the strengthening of a neuronal response due to some strong stimulus other than the stimulus that usually activates a given neuron. A somewhat more sophisticated type of sensitization is associative conditioning, most memorably demonstrated by Pavlov's dog. The conditioned animal forms an association between two different stimuli which are repeatedly presented in rapid succession. Eventually, the animal begins to exhibit behavior appropriately elicited by one stimulus, even when presented with the other stimulus alone.

A progression from facilitation to these incrementally more complicated processes should be evident. It is not surprising, therefore, that they have a common neuromodulatory mechanism. In invertebrates, sensory neurons connect with motor neurons via facilitating interneurons. Serotonin is released from the interneurons, triggering the cAMP second messenger to initiate biochemical events whose outcome is observable as a "learned" response. If results of neural plastic adaptations persist, becoming long-lasting changes in neuronal structure or activity, they can be described as memory. There are significantly different types of memory, but all types can be seen as the prolongation of alterations in the nervous system brought about by neuromodulatory processes such as habituation and sensitization. One way in which transient neuromodulation can become memory is through the regulation of protein synthesis in the postsynaptic cell. A neurotransmitter activates a cAMP second messenger, which leads to the binding of a regulatory protein to a DNA strand, which controls the transcription of a gene responsible for protein synthesis. A new protein may help to perpetuate the cells activity, or may induce structural changes such as those giving rise to new synapses. Although these processes involved in memory formation are well understood, many questions remain regarding the storage and retreival of what organisms learn. Perhaps what is known about the neuromodulatory events underlying learning and memory will help neuroscientists to continue learning about their mysteries.

Selected Bibliography

Delcomyn, Fred. Foudations of Neurobiology, W.H. Freeman, New York, 1997

Schacher, S. et al. Pathway-Specific Synaptic Plasticity.

Varela, J. et al. A Quantitative Description of Short-Term Plasticity at Excitatory Synapses in Layer 2/3 of Rat Visual Cortex

Basic Motor Pathways Somatosensory Pathways from the Body Basal Ganglia and Cerebellum


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