Neuroscience Online

Section I: Cellular and Molecular Neurobiology 13. Amino Acid Neurotransmitters Part 1 of 5 Neal Waxham, Ph.D.

Introduction and Review

Amino acid transmitters provide the majority of excitatory and inhibitory neurotransmission in the nervous system. The sensory-to-motor neuron connection in the spinal cord that controls the knee-jerk reflex is an excellent starting point for illustration. Figure 13.1 shows a monosynaptic connection in the spinal cord between the sensory neuron (in green) and the motor neuron innervating the extensor muscle (in blue).

Spatial and Morphological Distinctions between Excitatory and Inhibitory Inputs Neurons receive many thousands of synaptic inputs some excitatory, some inhibitory, and some modulatory. Excitatory synaptic connections are typically found on the major receiving area of the neuron, the dendrite, and most often on spines that project from the dendrite (Figure 13.2). These excitatory synapses have identifiable morphological characteristics and are referred to as Type I (Figure 13.2, box labeled Dendrites). A distinct zone frequently exists in the pre-synaptic terminal of Type I synapses responsible for the release of vesicles containing glutamate and a corresponding zone under the postsynaptic membrane that serves to anchor the receptors for glutamate (click on the box for details). In addition, vesicles that contain glutamate are small (~50 nm in diameter) and tend to have a spherical appearance.

Figure 13.2

Inhibitory synapses (like those utilizing glycine and GABA) tend to be localized near the neuronal soma and are referred to as Type II (Figure 13.2, box labeled Axosomatic synapse). Morphologically, the synapses again have specializations for release of vesicles and for anchoring receptors. However, the zones of contact tend to be smaller than for excitatory synapses (click on the box for more details). For unknown reasons, the vesicles containing glycine or GABA are often elliptical in shape.

Functionally, the location of these synaptic contacts has profound influences on the postsynaptic neuron. In general, the further from the cell body, the more the EPSP is attenuated by the passive properties of the membrane (these potentials are not propagating action potentials; they are synaptic potentials). Therefore, for neurons lacking regenerative processes in their dendrites, EPSPs that are far from the point of action potential generation (the cell soma and axon hillock) attenuate to a greater degree than IPSPs which are generated closer to the neuron's soma. Due to this spatial arrangement and the relatively small size of each EPSP (1 mV), many distant EPSPs must summate to cause the initiation of an action potential. In contrast, fewer local IPSPs on the cell soma are required to inhibit production of action potentials. On a typical cortical neuron, one might find 10,000 axodendritic excitatory synapses and only 10-50 axosomatic inhibitory synapses.

Structure of Amino Acid Transmitters

Initially, amino acids were not considered viable candidates for neurotransmitters since they are ubiquitous cellular constituents and are required for protein synthesis. Also, unlike the specific enzymes in neurons that synthesize ACh and catecholamines, enzymes that synthesize glutamate, aspartate and glycine are not unique to neurons. Whereas antibodies to choline acetyltransferase can be used to identify neurons as cholinergic, no such markers are available for neurons that use the amino acids as transmitters. Nevertheless, it is now known that amino acids constitute the major group of substances used for generating excitatory and inhibitory synaptic potentials in the CNS. Amino acids used for synaptic transmission are compartmentalized. For example, glutamate to be used as a neurotransmitter is compartmentalized from metabolic glutamate used for protein synthesis by packaging the transmitter into synaptic vesicles for subsequent Ca²⁺-dependent release.

Figure 13.3

Figure 13.3 illustrates the structure of four key amino acid neurotransmitters. Note that the excitatory amino acids carry two negative charges from the two carboxylate groups (COO-, red balls) as opposed to one for the inhibitory amino acids. Recognize that N-methyl-D-Aspartate is a synthetic compound not found in the brain and is technically not a neurotransmitter. It is a highly useful agonist that can mimic the actions of glutamate on a particular subset of glutamate receptors.