Evidence that N-acetyaspartylglutamate is the astrocyte-targeted neurovascular coupling agent that regulates slow tonic control of brain blood flow

Abstract

N-acetylaspartylglutamate (NAAG) is the highest concentration dipeptide present in brain. It is found primarily in neurons but its function is unclear. NAAG is synthesized by neurons from N-acetylaspartate and glutamate (Glu), maintained at mM concentrations and is released non-synaptically to extracellular fluid (ECF). NAAG is a non-excitatory form of Glu, and is targeted to the metabotropic group II Glu receptor 3 (mGluR3) on the surface of astrocytes. After docking with the receptor, Glu is released by the action of NAAG peptidase.Previously, it was shown for the first time that an NAAG-peptidase inhibitor reduced global cerebral blood flow (CBF) in mouse brain but did not affect their physical performance. Recently, it has been demonstrated that there are two separate systems involved in neurovascular coupling by astrocytes, one is a rapid focal phasic response providing energy for stimulation-induced neuronal activity, and the other a slower global tonic response providing energy for ongoing metabolic activities. Many neurovascular coupling mechanisms are known that regulate phasic changes in CBF, but how the brain accomplishes tonic control is unknown. In this paper we bring together two separate lines of inquiry, the decades' long search for the function of NAAG, and the more recent search for the mechanism of tonic neurovascular control. Herein, we present evidence that NAAG is the neurovascular coupling agent that regulates tonic changes in CBF via the astrocyte mGluR3-NAAG peptidase connection.

Separate N‐acetyl aspartyl glutamate, N‐acetyl aspartate, aspartate, and glutamate quantification after pediatric mild traumatic brain injury in the acute phase

“…Therefore, reduced intracellular NAAG concentrations might be associated with increased consumption of NAAG for the subsequent realization of neuroprotective functions. Moreover, NAAG’s activation of astrocytic mGluR3 initiates Ca 2+ oscillations in astrocytes and releases second messengers to capillary endothelial cells, resulting in a local hyperaemic response 60 . This response increases the supply of neurons with the necessary high‐energy compounds for energy metabolism activation 61 as well as excretion of the products of ATP reactions, thereby enabling the neuroreparative function of NAAG.…”

“…Moreover, NAAG's activation of astrocytic mGluR3 initiates Ca 2+ oscillations in astrocytes and releases second messengers to capillary endothelial cells, resulting in a local hyperaemic response. 60 This response increases the supply of neurons with the necessary high-energy compounds for energy metabolism activation 61 as well as excretion of the products of ATP reactions, thereby enabling the neuroreparative function of NAAG. Increased relative cerebral blood flow (rCBF) in the left insula and left dorsal anterior cingulate cortex, as assessed with arterial spin labelling (ASL), has been revealed in adolescents with sport-related concussion at approximately 2 and 6 weeks post injury.…”

The Bimodal Nature of Neurovascular Coupling: Slow Tonic and Rapid Phasic Responses are Separately Controlled by Specific Astrocyte Metabotropic and Ionotropic Glutamate Receptors

“…Neurons produce approximately 1 molecule of NAAG for every 400 molecules of glucose (Glc) oxidized [17]. Based on the specific characteristics of the slow tonic trigger [3] and listed in Table 1, it was recently proposed that NAAG was the astrocyte-targeted neurotransmitter for regulation of tonic control of CBF [18]. NAAG fits the description closely in that it is directly tied to the rate of Glc oxidation rather than to synaptic events, and can be liberated to ECF via a non-synaptic mechanism, perhaps associated with the neuron membrane ATP-binding cassette subfamily C, member 5 (ABCC5) NAAG efflux transporter [19].…”