Glutamate, a neurotransmitter found in all cells, plays a crucial role in multiple metabolic pathways and serves as a precursor to GABA, the primary inhibitory neurotransmitter. Despite its universal presence, identifying glutamatergic neurons proved challenging initially. However, experimental evidence now confirms glutamate as the major excitatory neurotransmitter in the central nervous system (CNS). When applied to cells, glutamate induces depolarization and is released from neurons. Specific receptors and transporters for glutamate have been identified.

Aside from its role as the main excitatory neurotransmitter, glutamate can also act as a potent neurotoxin at high concentrations. Hence, strict regulation of glutamate's activity following its release from the presynaptic terminal is necessary. This regulation not only allows normal synaptic transmission but also prevents cell death. Specialized membrane transporter proteins accomplish this task.

GABA and glycine, on the other hand, function as inhibitory neurotransmitters. GABA is the primary inhibitory transmitter throughout the nervous system. It is derived from glutamate through the action of a specific enzyme called glutamic acid decarboxylase, which is exclusive to GABAergic neurons. Immunolabeling with antibodies against this enzyme allows for the identification of inhibitory GABAergic cells. Many local interneurons are GABAergic, and numerous GABAergic projection neurons are found in various brain regions, including the striatum and the cerebellar cortex.

Glycine acts as an inhibitory neurotransmitter within a more limited territory. Glycinergic synapses are primarily located in the spinal cord, where they account for approximately half of the inhibitory synapses. They are also present in significant numbers in the lower brainstem, cerebellum, and retina. Interestingly, glycine serves another synaptic function. It is required to bind to excitatory NMDA-type glutamate receptors for the ion channel to open. Thus, it acts as a cotransmitter at these synapses. While it was generally believed that the extracellular glycine concentration is sufficiently high under normal conditions to saturate the glycine binding sites on the NMDA channel, recent findings suggest that this may not always be the case. This implies that fluctuations in glycine levels might also play a crucial role in modulating NMDA-mediated synaptic transmission.
Glutamate is the neurotransmitter at the overwhelming majority of excitatory synapses throughout the CNS. Despite its ubiquity, it was initially difficult to identify specific neurons as glutamatergic because glutamate is present in all cells; it has a key role in multiple metabolic pathways, and it is a precursor to GABA, the major inhibitory neurotransmitter. Nevertheless, experimental results have now clearly established glutamate as the major excitatory CNS neurotransmitter. When applied to cells, it causes depolarization and is released from neurons, and specific receptors and transporters for it have been identified.
In addition to being the main excitatory neurotransmitter, glutamate is a potent neurotoxin at high concentrations. Thus, strict limitation of glutamate’s activity after its release from the presynaptic terminal is necessary, not only to allow normal synaptic transmission but also to prevent cell death. This task is accomplished by specialized membrane transporter proteins (
Fig. 6.11
At the Cellular Level box).
GABA and glycine act as inhibitory neurotransmitters. GABA is the major inhibitory transmitter throughout the nervous system. GABA is produced from glutamate by a specific enzyme (glutamic acid decarboxylase) that is present only in neurons that use GABA as a transmitter. Thus, experimentally, it is possible to identify cells as inhibitory GABAergic neurons by using antibodies to this enzyme to mark them (immunolabeling, see
Fig. 6.1B ). Many local interneurons are GABAergic. In addition, several brain regions contain large numbers of GABAergic projection neurons. The most notable are the spiny neurons of the striatum and the Purkinje cells of the cerebellar cortex. The inhibitory nature of Purkinje cells was especially surprising because they represent the entire output of the cerebellar cortex, and thus cerebellar cortical activity basically functions to suppress the activity of its downstream targets (cerebellar and vestibular nuclei).
Glycine functions as an inhibitory neurotransmitter in a much more restricted territory. Glycinergic synapses are predominantly found in the spinal cord, where they represent approximately half of the inhibitory synapses. They are likewise present in the lower brainstem, cerebellum, and retina in significant numbers. Interestingly, glycine also has another synaptic function. At excitatory NMDA-type glutamate receptors, glycine must also be bound for the ion channel to open. Thus, it acts as a cotransmitter at these synapses. It was generally thought that under physiological conditions the extracellular glycine concentration was high enough that the glycine binding sites of the NMDA channel were always saturated, but recent results suggest that this may not always be true, which implies that fluctuations in glycine levels may also be an important modulator of NMDA-mediated synaptic transmission.