The traditional view of the synapse is that it functions like a valve, transmitting information in one direction. However, it is now clear that the synapse can generate signals that feed back onto the presynaptic terminal to modify transmitter release. Endocannabinoids are the best documented example of such retrograde signaling (see below). Postsynaptic activity leads to the synthesis and release of endocannabinoids, which then bind to receptors on the presynaptic terminal. Although the gas nitric oxide (NO) has long been proposed as a retrograde messenger, its physiologic role in the CNS is still not well understood.
The selectivity of CNS drug action is based on two primary factors. First, with a few exceptions, different neurotransmitters are released by different groups of neurons. These transmitters are often segregated into neuronal systems that subserve broadly different CNS functions. That this segregation occurs has provided neuroscientists with a powerful pharmacologic approach for analyzing CNS function and treating pathologic conditions. Second, there is a multiplicity of receptors for each neurotransmitter. For example, there are at least 14 different serotonin receptors encoded by different genes. These receptors often have differential cellular distributions throughout the CNS, allowing for the development of drugs that selectively target particular receptors and CNS functions.
Most of the neuronal systems in the CNS can be divided into two broad categories: hierarchical systems and nonspecific or diffuse neuronal systems.
Hierarchical systems include all the pathways directly involved in sensory perception and motor control. These pathways are generally clearly delineated, being composed of large myelinated fibers that can often conduct action potentials at a rate of more than 50 m/s. The information is typically phasic and occurs in bursts of action potentials. In sensory systems, the information is processed sequentially by successive integrations at each relay nucleus on its way to the cortex. A lesion at any link incapacitates the system.
Within each nucleus and in the cortex, there are two types of cells: relay or projection neurons and local circuit neurons (Figure 21–5A). The projection neurons form the interconnecting pathways that transmit signals over long distances. Their cell bodies are relatively large, and their axons can project long distances but also emit small collaterals that synapse onto local interneurons. These neurons are excitatory, and their synaptic influences, which involve ionotropic receptors, are very short-lived. The excitatory transmitter released from these cells is, in most instances, glutamate.
Local circuit neurons are typically smaller than projection neurons, and their axons arborize in the immediate vicinity of the cell body. Most of these neurons are inhibitory, and they release either GABA or glycine. They synapse primarily on the cell body of the projection neurons but can also synapse on the dendrites of projection neurons as well as with each other. Two common types of pathways for these neurons (Figure 21–5A) include recurrent feedback pathways and feed-forward pathways. A special class of local circuit neurons in the spinal cord forms axoaxonic synapses
FIGURE 21–5 Hierarchical pathways in the CNS. A shows parts of three excitatory relay neurons (blue) and two types of local inhibitory interneuron pathways, recurrent and feed-forward. The inhibitory neurons are shown in gray. B shows the pathway responsible for axoaxonic presynaptic inhibition in which the axon of an inhibitory neuron (gray) synapses onto the presynaptic axon terminal of an excitatory fiber (blue) to inhibit its neurotransmitter release.