Conclusions

Based on their cellular localization and known actions, several conclusions can be drawn concerning the roles played by these two compounds in brain function. In general, the distribution of NAA is consistent with it having a metabolic or housekeeping role in the nervous system, whereas the distribution of NAAG is more consistent with a role in neurotransmitter release modulation.

Because NAA is present at high concentrations in most neurons, and because it is not released from neurons in a calcium dependent manner after depolarization, it can not be acting as a classical neurotransmitter. The high concentration, lack of electrophysiological actions, and ubiquitous distribution all argue in favor of a metabolic role. These facts have led some researchers to propose that NAA acts to counter the "anion deficit" in neurons, 28 or acts as a "molecular water pump" to extrude metabolic water

Figure 10. NAA (A, C and E) and NAAG (B, D and F) in goldfish brain. Both NAA and NAAG are phylogenetically conserved brain molecules found in the brains of teleost fish. NAA is expressed strongly throughout the goldfish brain, including cortex (A), hypothalamus (B) and hindbrain (C). NAAG, in contrast, has a very limited expression, with only scattered neurons being strongly stained in cortex (B, rotated 90 degrees compared with A), hypothalamus (D) and hindbrain (F). Bar = 100 ^m

Figure 10. NAA (A, C and E) and NAAG (B, D and F) in goldfish brain. Both NAA and NAAG are phylogenetically conserved brain molecules found in the brains of teleost fish. NAA is expressed strongly throughout the goldfish brain, including cortex (A), hypothalamus (B) and hindbrain (C). NAAG, in contrast, has a very limited expression, with only scattered neurons being strongly stained in cortex (B, rotated 90 degrees compared with A), hypothalamus (D) and hindbrain (F). Bar = 100 ^m from neurons.29'30 Recent findings clearly demonstrate that NAA provides a significant source of acetate for myelin lipid synthesis during CNS development,31 and that NAA possibly plays a significant role in neuronal energy metabolism.32

The evidence for NAAG acting as a neurotransmitter or neuromodulator is convincing. NAAG meets all the criteria of a classical neurotransmitter except for one. It is released in a calcium dependent manner after neuronal depolarization, it is broken down extracellularly by a specific enzyme (carboxypeptidase II) and it is known to act at postsynaptic NMDA receptors at high concentrations. However, NAAG application fails the test of eliciting the same postsynaptic actions as are elicited by stimulation of the afferent fibers to various brain regions receiving NAAG input (e.g., the lateral geniculate). Indeed, NAAG application often results in mixed actions on postsynaptic neurons. Electrophysiological studies have shown that different neurons in various brain regions could be depolarized, hyperpolarized, or not respond at all to exogenous NAAG

application.33,34

The most compelling reason to think that NAAG is a peptide involved in neurotransmitter release modulation, rather than being a classical neurotransmitter, is that it is extensively colocalized with every major neurotransmitter known. Further, the specific and potent action at certain metabotropic glutamate receptors (mGluR3) which are linked to neurotransmitter release modulation35,36 argues strongly in favor of a modulatory role for NAAG. Finally, the extensive colocalization with both glutamatergic and GABAergic systems implicates NAAG in the regulation of the balance between excitatory and inhibitory neurotransmission in the nervous system.

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