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Section I:
Cellular and Molecular Neurobiology

7. Synaptic Plasticity
Part 2 of 2

Heterosynaptic Forms of Synaptic Plasticity. Just as there are two types of homosynaptic plasticity, there are two types of heterosynaptic plasticity. Before discussing heterosynaptic plasticity, it is useful to review the types of synapses that are present in the central nervous system. Three broad categories of synapses are found in the central nervous system. (See also Chapter 8, Part 7 NOTE: Selecting this link moves you forward. After viewing, you will need to press the browser's "Back" button to return to this page.)

Axosomatic synapses are synapses that are made onto the soma or cell body of a neuron.

Axodendritic synapses, probably the most prominent kind of synapses, are synapses that one neuron makes onto the dendrite of another neuron.

Axoaxonic synapses are synapses made by one neuron onto the synapse of another neuron. Axoaxonic synapses mediate presynaptic inhibition and presynaptic facilitation.

Figure 7.4

Figure 7.5

The figure at left illustrates the two major types of heterosynaptic plasticity; presynaptic inhibition and presynaptic facilitation. Presynaptic inhibition is not an esoteric phenomenon. It is very prominent in the spinal cord and regulates the propagation of information to higher brain centers. An action potential in the presynaptic cell produces an EPSP in the postsynaptic cell. The modulatory cell (M1) makes an axoaxonic synapse with the presynaptic cell. After firing cell M1, the EPSP in the postsynaptic cell is smaller. This phenomenon is called presynaptic inhibition, because cell M1 regulates the ability of the presynaptic cell to release transmitter. The modulatory transmitter engages metabotropic type receptors that then activate a second messenger system that phosphorylates Ca²⁺ channels in such a way that the Ca²⁺ channels open less readily. There are fewer Ca²⁺ channels to be opened, therefore there is less Ca²⁺ influx. Less Ca²⁺ influx leads to less transmitter release and a smaller EPSP.

The phenomenon complementary to presynaptic inhibition is presynaptic facilitation. The scheme is the same, but the mechanisms are different. M2 is capable of increasing the strength of the synaptic pathway. Whereas the mechanism for presynaptic inhibition is a decrease in Ca²⁺ influx produced by affecting calcium channels directly, the mechanism for presynaptic facilitation is not due to the direct modulation of a Ca²⁺ channel, but rather to an indirect effect on the Ca²⁺ channel brought about by modulation of a K⁺ channel. As a result of the activation of a second messenger cascade by M2, there are fewer K⁺ channels available to be opened in the presynaptic terminal. The action potential is broader and there is a greater amount of time for the Ca²⁺ influx to occur. The Ca²⁺ influx occurs for a longer time, therefore more transmitter can be released.

In both presynaptic inhibition and presynaptic facilitation, the Ca²⁺ current is modulated. But in one case the Ca²⁺ channel is modulated directly (presynaptic inhibition) and in the other case (presynaptic facilitation), the Ca²⁺ channel is modulated indirectly.

Long-Term Potentiation (LTP). A very enduring form of synaptic plasticity is called long-term potentiation (LTP). It can have both homosynaptic and heterosynaptic components. An electric shock to afferent fibers produces an EPSP. If the pathway is repeatedly stimulated (e.g., every minute), the amplitude of EPSP is constant. A tetanus produces post-tetanic potentiation (PTP) that dies away after several minutes. What is left is a very enduring enhancement of the EPSP. There is excitement about LTP because it is the kind of mechanism necessary to store memory.

Figure 7.6

Figure 7.7

Figure 7.8

Figure 7.9

The NMDA-type receptor is critical for some forms of LTP, in particular LTP at the CA3-CA1 synapse in the hippocampus. The postsynaptic spines of CA1 neurons have two types of glutamate receptors; NMDA-type glutamate receptors and the non-NMDA-type glutamate receptors (Figures 7.8 and 7.9). Both receptors are permeable to Na⁺ and K⁺, but the NMDA-type has two additional features.

First, in addition to being permeable to Na⁺, it also has a significant permeability to Ca²⁺.
Second, this channel is normally blocked by Mg²⁺.

Even if glutamate binds to the channel and produces a conformational change, there is no efflux of K⁺ or influx of Na⁺ or Ca ²⁺ because it is "plugged up" by the Mg²⁺. Thus, a weak stimulus will not open this channel because it is blocked by Mg²⁺. A weak stimulus will produce an EPSP, but that EPSP will be mediated by the non-NMDA receptor.

Now consider the consequences of a tetanus. Because of the tetanus, there will be spatial and temporal summation of the EPSPs produced by the multiple afferent synapses on the common postsynaptic cell. Consequently, the membrane potential of the postsynaptic neuron will become very depolarized. Since the inside of the cell becomes positive, the positively charged Mg²⁺ is "thrust" out of the channel (Figure 7.10). Ca²⁺ then enters the spine through the NMDA receptor. That Ca²⁺ activates various protein kinases, which then trigger long-term changes.

Figure 7.10

Summary

Figure 7.11

A given postsynaptic neuron receives synaptic input from a number of different sources. There are the traditional type of axosomatic and axodendritic synapses. These can be either excitatory or inhibitory. In addition, the synaptic responses can be mediated by both ionotropic and metabotropic receptors. The presynaptic cells can be modulated through presynaptic inhibition and presynaptic facilitation. Consider that any one postsynaptic cell makes and receives 10,000 connections with other cells and that this module can be recapitulated in each of the billions of cells in the nervous system. It is this enormous pattern of synaptic connections and the plasticity that occurs at each one of these synapses which makes the nervous system so extraordinary.

It is very difficult to overestimate the importance of synaptic transmission. It is critical to the basic functioning of the nervous system and appears to be critical in learning and memory. Also, changes in synaptic transmission seem to be central to understanding a number of neurological disorders such as myasthenia gravis and Parkinson's disease. Synaptic transmission is central to understanding mental diseases such as schizophrenia, anxiety, and depression. A major theme of neuroscience is to identify the specific transmitter systems involved in these brain diseases and design appropriate interventions. Finally, most of the psychoactive drugs function by affecting some aspects of synaptic transmission.

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