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NAAG and NAA have different distributions in the nervous system, and this disparity is most apparent in cortical areas of the CNS. NAA has a ubiquitous presence in most neurons in the nervous system, and yet NAA levels in different cell groups can vary

Figure 6. NAAG expression in rhesus monkey motor cortex. NAAG is expressed in all layers of neocortex in the monkey (A). In superficial cortical layers, NAAG was expressed in many small neurons, and in the apical dendrites of pyramidal cells (B). Unlike the rat, NAAG expression was highest in layer V, where it is present in pyramidal cells, and a dense plexus of fibers and synapses in the neuropil (C). In deeper layers, many small neurons expressed high levels of NAAG, as did axons entering the white matter and corpus callosum (D). Bar = 200^m A; 60^m C, D and E.

Figure 6. NAAG expression in rhesus monkey motor cortex. NAAG is expressed in all layers of neocortex in the monkey (A). In superficial cortical layers, NAAG was expressed in many small neurons, and in the apical dendrites of pyramidal cells (B). Unlike the rat, NAAG expression was highest in layer V, where it is present in pyramidal cells, and a dense plexus of fibers and synapses in the neuropil (C). In deeper layers, many small neurons expressed high levels of NAAG, as did axons entering the white matter and corpus callosum (D). Bar = 200^m A; 60^m C, D and E.

substantially (Figures 1B, 4B, 9B, D and F). NAAG has a more restricted distribution, and exhibits an increasing concentration gradient from the rostral to the caudal CNS (see Fig 3). NAAG-IR in vivo is only expressed in neurons, but it has been reported that oligodendrocytes and microglia can express low levels of NAAG in vitro}2 In addition to being localized in most neurons, NAA was observed at low levels in oligodendrocytes (Figure 5B). Some brain capillary endothelial cells were also stained moderately to strongly for NAA, but only a small percentage of the total endothelial population of the CNS was NAA-positive (data not shown).

NAA has been shown to have a more ubiquitous distribution in the CNS as compared with NAAG, but both compounds are present in most or all regions of the brain and spinal cord of the rat.8,11,20 Several broad generalizations can be made concerning their comparative localization, to which there are exceptions. First, both compounds are expressed at high levels primarily in neurons, although NAA is found in other cell types in the brain. Astrocytes and microglia did not stain for either compound in any species examined. NAA-IR is present in most neurons to a greater or lesser degree, and is particularly prominent in cortical pyramidal cells, and in granule cell layers in many brain regions, including hippocampus, retrosplenial cortex and cerebellar cortex. The distribution in NAAG in forebrain is also widespread, but only a relatively small percentage of neurons are NAAG-positive in many areas of the telencephalon. While cortical areas have relatively low numbers of NAAG immunoreactive neurons, NAAG is expressed in the majority of neurons in many brainstem and spinal cord regions. For example, virtually all the neurons of the deep cerebellar nuclei are strongly stained for NAAG, whereas a much lower density of stained neurons is seen throughout neocortex.

NAAG is colocalized extensively with GABA in GABAergic projection systems such as the globus pallidus, lateral hypothalamus, thalamic reticular nucleus (Figure 8) and the reticular region of the substantia nigra, but it is only partially colocalized with GABAergic interneurons in cortical brain areas. NAAG is known to be colocalized with other neurotransmitters, including acetylcholine, dopamine, norepinephrine and serotonin (see Figure 9). NAAG is also localized extensively in the retinal projections and retinorecipient terminals areas, which are known to be glutamatergic, perhaps to provide a means of preventing excitotoxicity associated with prolonged glutamate release.22

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