Glutamate and aspartate are the two major excitatory amino acids in the CNS and are present in high concentrations (Nestler et al. 2001; Squire et al. 2003). As the principal mediators of excitatory synaptic transmission in the mammalian brain, they participate in wide-ranging aspects of both normal and abnormal CNS function. Physiologically, glutamate appears to play a prominent role in synaptic plasticity, learning, and memory. However, glutamate can also be a potent neuronal excitotoxin under a variety of experimental conditions, triggering either rapid or delayed neuronal death. Unlike the monoamines, which require transport of amino acids through the blood-brain barrier, glutamate and aspartate cannot adequately penetrate into the brain from the periphery and are produced locally by specialized brain machinery. The metabolic and synthetic enzymes responsible for the formation of these nonessential amino acids are located in glial cells as well as neurons (Squire et al. 2003).
The major metabolic pathway in the production of glutamate is derived from glucose and the transamination of Ct-ketoglutarate; however, a small proportion of glutamate is formed directly from glutamine. The latter is actually synthesized in glia, via an active process (requiring adenosine triphosphate [ATP]), and is then transported to neurons where glutaminase is able to convert this precursor to glutamate (Figure 1-7). Following release, the concentration of glutamate in the extracellular space is highly regulated and controlled, primarily by a Na+-dependent reuptake mechanism involving several transporter proteins.
FIGURE 1-7. The glutamatergic system.
This figure depicts the various regulatory processes involved in glutamatergic neurotransmission. The biosynthetic pathway for glutamate involves synthesis from glucose and the transamination of a-ketoglutarate; however, a small proportion of glutamate is formed more directly from glutamine by glutamine synthetase. The latter is actually synthesized in glia and, via an active process (requiring ATP), is transported to neurons, where in the mitochondria glutaminase is able to convert this precursor to glutamate. Furthermore, in astrocytes glutamine can undergo oxidation to yield a-ketoglutarate, which can also be transported to neurons and participate in glutamate synthesis. Glutamate is either metabolized or sequestered and stored in secretory vesicles by vesicle glutamate transporters (VGluTs). Glutamate can then be released by a calcium-dependent excitotoxic process. Once released from the presynaptic terminal, glutamate is able to bind to numerous excitatory amino acid (EAA) receptors, including both ionotropic (e.g., NMDA [N-methyl-D-aspartate]) and metabotropic (mGluR) receptors. Presynaptic regulation of glutamate release occurs through metabotropic glutamate receptors (mGluR2 and mGluR3), which subserve the function of autoreceptors; however, these receptors are also located on the postsynaptic element. Glutamate has its action terminated in the synapse by reuptake mechanisms utilizing distinct glutamate transporters (labeled VGT in figure) that exist on not only presynaptic nerve terminals but also astrocytes; indeed, current data suggest that astrocytic glutamate uptake may be more important for clearing excess glutamate, raising the possibility that astrocytic loss (as has been documented in mood disorders) may contribute to deleterious glutamate signaling, but more so by astrocytes. It is now known that a number of important intracellular proteins are able to alter the function of glutamate receptors (see diagram). Also, growth factors such as glial-derived neurotrophic factor (GDNF) and S100Í3 secreted from glia have been demonstrated to exert a tremendous influence on glutamatergic neurons and synapse formation. Of note, serotoniniA (5-HTia) receptors have been documented to be regulated by antidepressant agents; this receptor is also able to modulate the release of SIOOB. AKAP = A kinase anchoring protein; CaMKII = Ca2+/calmodulin-dependent protein kinase II; ERK = extracellular response kinase; GKAP = guanylate kinase-associated protein; Glu = glutamate; Gly = glycine; GTg = glutamate transporter glial; GTn = glutamate transporter neuronal; Hsp70 = heat shock protein 70; MEK = mitogen-activated protein kinase/ERK; mGluR = metabotropic glutamate receptor; MyoV = myosin V; NMDAR = NMDA receptor; nNOS = neuronal nitric oxide synthase; PKA = phosphokinase A; PKC = phosphokinase C; PP-1, PP-2A, PP-2B = protein phosphatases; RSK = ribosomal S6 kinase; SHP2 = src homology 2 domain-containing tyrosine phosphatase.
Source. Adapted from Cooper JR, Bloom FE, Roth RH: The Biochemical Basis of Neuropharmacology, 7th Edition. New York, Oxford University Press, 2001. Copyright 1970, 1974, 1978, 1982, 1986, 1991, 1996, 2001 by Oxford University Press, Inc. Used by permission of Oxford University Press, Inc. Modified from Nicholls 1994.
The major glutamate transporter proteins found in the CNS include the excitatory amino acid transporters (EAATs) EAAT1 (or GLAST-1), EAAT2 (or GLT-1), and EAAT3 (or EAAC1), with EAAT2 being the most predominantly expressed form in the forebrain. Additionally, these transporters are differentially expressed in specific cell types, with EAAT1 and EAAT2 being found primarily in glial cells and EAAT3 being localized in neurons. EAAT4 is mainly localized in cerebellum. The physiological events regulating the activity of the glutamate transporters are not well understood, although there is evidence that phosphorylation of the transporters by protein kinases may differentially regulate glutamate transporters and therefore glutamate reuptake (Casado et al.
1993; Conradt and Stoffel 1997; Pisano et al. 1996). Glutamate concentrations have been shown to rise to excitotoxic levels within minutes following traumatic or ischemic injury, and there is evidence that the function of the glutamate transporters becomes impaired under these excitotoxic conditions (Faden et al. 1989). It is surprising that the glutamatergic system has only recently undergone extensive investigation with regard to its possible involvement in the pathophysiology of mood disorders, since it is the major excitatory neurotransmitter in the CNS and known to play a role in regulating the threshold for excitation of most other neurotransmitter systems. Although direct evidence for glutamatergic excitotoxicity in bipolar disorder is lacking and the precise mechanisms underlying the cell atrophy and death that occur in recurrent mood disorders are unknown, considerable data have shown that impairments of the glutamatergic system play a major role in the morphometric changes observed with severe stresses (McEwen 1999; Sapolsky 2000).
It is now clear that modification of the levels of synaptic AMPA-type glutamate receptors—in particular by receptor subunit trafficking, insertion, and internalization—is a critically important mechanism for regulating various forms of synaptic plasticity and behavior. Recent studies have identified region-specific alterations in expression levels of AMPA and NMDA glutamate receptor subunits in subjects with mood disorders (Beneyto et al. 2007). Supporting the suggestion that abnormalities in glutamate signaling may be involved in mood pathophysiology, AMPA receptors have been shown to regulate affective-like behaviors in rodents. AMPA antagonists have been demonstrated to attenuate amphetamine- and cocaine-induced hyperactivity and psychostimulant-induced sensitization and hedonic behavior (Goodwin and Jamison 2007).
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