Proton MR spectroscopy-detectable major neurotransmitters of the brain: biology and possible clinical applications

Abstract

Neurotransmitters are chemical substances that, by definition, allow communication between neurons and permit most neuronal-glial interactions in the CNS. Approximately 80% of all neurons use glutamate, and almost all interneurons use GABA. A third neurotransmitter, NAAG, modulates glutamatergic neurotransmission. Concentration changes in these molecules due to defective synthetic machinery, receptor expression, or errors in their degradation and metabolism are accepted causes of several neurologic disorders. Knowledge of changes in neurotransmitter concentrations in the brain can add useful information in making a diagnosis, helping to pick the right drug of treatment, and monitoring patient response to drugs in a more objective manner. Recent advances in (1)H-MR spectroscopy hold promise in providing a more reliable in vivo detection of these neurotransmitters. In this article, we summarize the essential biology of 3 major neurotransmitters: glutamate, GABA, and NAAG. Finally we illustrate possible applications of (1)H-MR spectroscopy in neuroscience research.

Fig 1.

Glutamatergic synapse: Glutamate determines neurotransmission by acting on postsynaptic receptors. EAATs, localized on the astrocytic membrane, rapidly terminate glutamatergic activity. EAAT activity is tightly coupled to glucose consumption, causing transient increase in lactate levels. Increased lactate may be an important immediate source of energy to firing neurons. Note the tight neuronal-astrocytic interaction, which is fundamental for the glutamate/glutamine coupling and the compartmentalization of glutamate. Glutamine synthesis in astrocytes is an important mechanism of ammonia detoxification. Note:—Pyr indicates pyruvate; Lac = lactate; GS = glutamine synthetase.

Fig 2.

GABAergic synapse. GABA is synthesized from glutamate by the action of GAD and is stored in vesicles by a vesicular neurotransmitter transporter. Once released in the synapse, GABA acts on its receptors (GABA Rc) and shapes the inhibitory action potential. GABA activity is terminated by its uptake through GABA transporters by surrounding neurons and astrocytes. GABA is metabolized through transamination into succinic semialdehyde catalyzed by GABA-transaminase (GABA shunt). Note:—GABA Rc = GABA receptors.

Fig 3.

NAAG neurotransmission and neuromodulation. NAAG is synthesized in neurons via NAAG synthase. NAAG is co-released with glutamate from actively firing neurons. Intrasynaptic NAAG binds as a weak antagonist on NMDAR and also to mGlu3 receptors inhibiting further release of glutamate (inhibitory feedback loop). NAAG is hydrolyzed to NAA and Glu by GCPII enzyme on astrocytes.