Overview of glutamatergic neurotransmission in the nervous system

Abstract

This introductory article to the special edition on glutamate neurotransmission in neuropsychiatric disorders provides an overview of glutamate neurotransmitter system physiology and pharmacology. Glutamate was only relatively recently recognized as the major excitatory neurotransmitter in the mammalian brain, in part due to its ubiquitous nature and diverse metabolic roles within the CNS. The extremely high concentration of glutamate in brain tissue paired with its excitotoxic potential requires tight physiological regulation of extracellular glutamate levels and receptor signaling in order to assure optimal excitatory neurotransmission but limits excitotoxic damage. In order to achieve this high level of control, the system has developed a complex physiology with multiple regulatory processes modulating glutamate metabolism, release, receptor signaling, and uptake. The basic physiology of the various regulatory components of the system including the rich receptor pharmacology is briefly reviewed. Potential contributions from each of the system's components to the pathophysiology of neuropsychiatric illnesses are briefly discussed, as are the many new pharmacological targets for drug development provided by the system, especially as they pertain to the proceeding preclinical and clinical articles in this issue.

Figure 1. Glutamatergic Neurotransmission

Due to the risk of excitotoxic damage in the wake of excessive glutamatergic stimulation, precise physiological control of glutamate must be maintained in the mammalian CNS. Glutamine (Gln) is converted to glutamate (Glu) by glutaminase [though glutamate may also be derived from the TCA cycle (not shown)]. Glu is packaged into presynaptic vesicles by vesicular Glu transporter (VGLUT) proteins and synaptically released in an voltage-dependent manner through vesicular interactions with SNARE proteins. Synaptically-released Glu is recycled from the extracellular space by excitatory amino acid transporters (EAATs) expressed predominantly on astroglia. In astrocytes, Glu is converted to Gln by Gln synthetase and exported extracellularly to be taken up again by neurons. Additionally, system x-C is a cystine/glutamate antiporter expressed on glia that also contributes to Glu recycling. Glu receptors are present on presynaptic and postsynaptic neurons as well as on glial cells. These include both ionotropic receptors (NMDA, AMPA/KA) and metabotropic receptors (mGluRs). The effect of Glu is determined by the receptor subtype, localization (synaptic, perisynaptic and extrasynaptic), and interactions with various scaffolding and signaling proteins (not shown) in the postynaptic density. Glu receptor stimulation results not only in rapid ionotropic effects but also synaptic plasticity, e.g. long-term potentiation (LTP) and long-term depression (LTD), via cognate signal transduction cascades.

Figure 2