Functions of N-acetyl-L-aspartate and N-acetyl-L-aspartylglutamate in the vertebrate brain: Role in glial cell-specific signaling

N-Acetyl-L-aspartate (NAA) and its derivative N-acetylaspartylglutamate (NA AG) are major osmolytes present in the vertebrate brain. Although they are synthesized primarily in neurons, their function in these cells is unclear. In the brain, these substances undergo intercompartmental cycles in which they are released by neurons in a regulated fashion and are then rapidly hy drolyzed by catabolic enzymes associated with glial cells. Recently, the ca tabolic enzyme for NAA hydrolysis has been found to be expressed only in ol igodendrocytes, and the catabolic enzyme for NAAG expressed only in astrocy tes. These results indicate an unusual tricellular metabolic sequence for t he synthesis and hydrolysis of NAAG wherein it is synthesized in neurons fr om NAA and L-glutamate, hydrolyzed to NAA and L-glutamate by astrocytes, an d further hydrolyzed to L-aspartate and acetate by oligodendrocytes. Since the discovery that the NAA and NAAG anabolic products of neurons are specif ically targeted to oligodendrocytes and astrocytes, respectively, this uniq ue metabolic compartmentalization also suggests that these substances may p lay an important role in cell-specific glial signaling. In this review, it is hypothesized that a key function of NAA and NAAG in the vertebrate brain is in cell signaling and that these substances are important in the regula tion of interactions of brain cells and in the establishment and maintenanc e of the nervous system.