Comparative distribution of N‐Acetylaspartylglutamate and GAD67 in the cerebellum and precerebellar nuclei of the rat utilizing enhanced carbodiimide fixation and immunohistochemistry

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Abstract
The most prevalent peptide in the nervous system, N‐acetylaspartylglutamate (NAAG), specifically activates N‐methyl D‐aspartate (NMDA) receptors and a subclass of metabotropic glutamate receptors. One action of this peptide may be to modulate the release of other neurotransmitters, including gamma‐aminobutyric acid (GABA). The present study describes the cellular distribution of NAAG, relative to GABA, in the cerebellum and precerebellar nuclei as a foundation for further physiological investigations. Numerous cells of origin for mossy fibers, including many of the larger neurons of the pontine nuclei, lateral reticular nuclei, vestibular nuclei, reticulotegmental nuclei, and spinal grey, were moderately to strongly stained for NAAG. Many NAAG‐labeled fibers were clearly visible in the cerebellar peduncles and central white matter. Mossy fibers and mossy endings were among the most prominent NAAG‐immunoreactive elements in the cerebellar cortex. Most neurons in the inferior olive were not stained for NAAG, and only sparse, lightly immunoreactive, climbing fiber‐like endings could be identified in restricted regions of the cortical molecular layer. Purkinje neurons ranged from nonreactive to moderately positive, with the great majority being unstained. Cerebellar granule cells did not exhibit any NAAG immunoreactivity. A population of neurons in the deep cerebellar nuclei was highly immunoreactive for NAAG. Additionally, many neurons of the red nucleus were intensely stained for NAAG. Comparisons with staining for the 67 kD form of glutamic acid decarboxylase in serial sections revealed complementary distributions, with NAAG in excitatory pathways and cell groups, and glutamic acid decarboxylase in inhibitory systems. These findings suggest a significant functional involvement of NAAG in the excitatory afferent and efferent projection systems and provide an anatomical basis for investigations into the interactions of NAAG and GABA in the cerebellum.