Pictorial Review of Glutamate Excitotoxicity: Fundamental Concepts for Neuroimaging

A, Glutamine. This closely related amino acid is formed from glutamate with the addition of an amino group at the γ carboxyl of the side chain.

B, This formation of an amide linkage at the γ carboxyl group requires the enzyme glutamine synthetase and the process is adenosine triphosphate (ATP)-dependent. This reaction is also a major mechanism for the detoxification of cerebral ammonia.

Neuronal glutamate processing and transport. Glutamate is processed by the endoplasmic reticulum and Golgi apparatus in preparation for fast axonal transport, which also requires other transport proteins and mitochondria. When glutamate emerges from the “trans” face of the Golgi apparatus, it is encapsulated inside a neurosecretory vesicle, which consists of a bilipid membrane. These vesicles are transported down the axon along microtubule tracks to be deposited at the tip of the axon near the presynaptic membrane. Waves of axonal membrane depolarization would trigger the release of the glutamate into the synaptic space by exocytosis, which is exhibited by the merging of the neurosecretory vesicles with the postsynaptic membrane to free the packaged glutamate. The empty vesicle would then be recycled back to the neuronal body by retrograde transport along the microtubular tracks (adapted from [32])

A–C, Electron micrographs show neurosecretory vesicles releasing neurotransmitter molecules by exocytosis on the presynaptic membrane. Numerous small neurotransmitter substances can be seen in the synaptic space (open arrows). These neurotransmitters will then settle on and activate receptors on the postsynaptic membrane. Dark circles by straight solid arrows represent vesicles filled with neurotransmitters. Light partial circles by curved solid arrows represent the vesicle merging with the presynaptic membrane and releasing neurotransmitter into the synaptic space (adapted from [32])

Pictorial display of the neurotransmitter glutamate (orange) released into the synaptic space and docking with the glutamate receptor site on the postsynaptic membrane. The activation of the glutamate receptor then opens the ion channel coupled to the receptor, allowing the passage of extracellular calcium (yellow) into the intracellular cytosol, which in turn triggers a series of biochemical events (adapted from Schornak S, BNI Q 11:1995)

fig 7. Ionotropic and metabotropic receptors. The ionotropic receptors NMDA (purple) and AMPA (red) are directly coupled to ion channels. The metabotropic receptors (blue and orange) activate intermediary molecules such as G protein affecting multiple cytoplasmic enzymes to produce molecules, such as IP₃, that increase cytosol calcium concentrations. Also depicted are modulatory substances, such as spermine, which facilitate calcium influx, and receptor complex inhibitors, such as zinc, magnesium, and PCP. L-2-amino-4-phosphonopriopionic acid (L-AP4) and aminocyclopentyl dicarboxylic acid (ACPD) receptors are classified as metabotropic, as they are coupled to intermediary G proteins (G) that activate phosphodiesterase (PDE) for L-AP4 receptors and form inositol 1,4,5-trisphosphate (IP₃) and diacylglycerol (DAG) from phosphatidylinositol 4,5-bisphosphate (PIP₃) for the ACPD receptors via phospholipase C. 2-amino-3-phosphonopriopionic acid (AP3) and quinoxaline-2,3-dione (NBQX) are antagonists for ACPD and AMPA receptors, respectively.

Schematic representation of NMDA, AMPA, and kainate receptors as receptor–channel complexes. Glutamate docks with the receptor, which opens the coupled channel to allow the intracellular influx of extracellular calcium. Other molecules (such as magnesium, zinc, and PCP) can influence receptor function by interacting with several receptor and channel modulatory sites

Membrane channels and transporters. The ion channels are pathways to allow the diffusion of ions across the cell membrane. These channels can be opened or closed by changes in membrane voltage, associated ligands, and so on. Excessive intracellular calcium is detrimental to neuronal health, and a calcium gradient is maintained across the neuronal membrane mostly by three main types of transporters. The antiporters use an existing ion gradient (usually established by active or ATP-dependent transport) to transport calcium ions (green) in the opposite direction of the energizing ion (ie, sodium). Symporters transport calcium in the same direction of the energizing ion (blue). Both antiporter and symporters are considered secondary transporters because they derive energy from an existing gradient. The ATP-coupled active transporter is considered a primary transporter that uses ATP to affect the transmembrane movement of calcium to establish its gradient (adapted from [32])

Calcium homeostasis. Membrane transporter (antiporter and ATP-dependent transporter) maintain a much higher extracellular calcium (small circles) concentration than the cytosol. The endoplasmic reticulum and mitochondria are important sources of intracellular extracytosolic calcium. These internal sources of calcium can be released into the cytosol when provoked by specific agents, such as the second messenger (IP₃) actions on the endoplasmic reticulum (adapted from [32])

Excessive accumulation of intracellular calcium caused by overactivation of the glutamate receptor sites stimulates multiple enzymes, which are involved in normal neuronal development and function, resulting in damage to the cell membrane, cytoskeleton, and DNA.

fig 12. Abnormally increased activation of some enzymes, such as phospholipase A, can cause an intracellular feedback cycle of events, leading to cell death.

Neuronal glutamate that is released into the synaptic space is normally removed from the synaptic space by adjacent glial cells, in which the glutamate is converted to the closely related glutamine, which can then readily diffuse back into the neuron. Glutamine is converted back to glutamate in the neuron.

fig 14. Diagram shows sequence of events occurring in cerebral ischemia leading to neuronal death. (Free radical formation and lipase activation are also related to the increased intracellular calcium, although the two processes are not directly connected to the increased calcium by arrows in this schematic.)

MR spectrum of a normal frontal lobe obtained at 1.5 T with a single-voxel point-resolved spectroscopy (PRESS) technique at 1500/41 (TR/TE).

fig 16. MR spectrum of the same frontal lobe as in figure 15 obtained at 0.5 T with a single-voxel PRESS technique at 1500/41. Note the more conspicuous glx peak.

A, Coronal T2-weighted MR image of a patient with right mesial temporal sclerosis.

B, MR spectrum obtained from a voxel (indicated in A) centered in the region of the patient's right hippocampal formation shows an elevated glx peak.