Fig. 5

Overview of the NAA cycle. NAA is synthetized from acetyl-CoA and aspartate in the mitochondria of neurons by the enzyme aspartate N-acetyltransferase (ANAT), and subsequently transported to the cytosol by unknown transporters. NAA might either be released from neurons or converted into N-acetyl-aspartyl glutamate (NAAG) catalyzed by NAAG synthetase I or II (NAAGS). NAA release likely occurs through ABCC5 as well as other uncharacterized transporters. Upon its release, NAA may be taken up by astrocytes or oligodendrocytes through the sodium-dependent dicarboxylate cotransporter 3 (NADC3) or exchanged through gap junctions. Within oligodendrocytes, ASPA hydrolyzes NAA to aspartate and acetate, which can be utilized by the cell. A fraction of NAA may also end up in the bloodstream. NAAG can be released from postsynaptic dendrites in response to stimulation of ionotropic glutamate receptors. NAAG then acts on presynaptic metabotropic glutamate receptor 3 (mGluR3) to inhibit further presynaptic glutamate release. Additionally, NAAG acts on mGluR3 on astrocytes to induce cyclooxygenase (COX1) activation, which in turn leads to release of prostaglandins to the vascular system. This in turn increased cerebral blood flow (CBF) to the area. Lastly, glutamate carboxypeptidase II/III (GCPII/III), catalyse the hydrolysis of NAAG to NAA and glutamate