How Glutamate and GABA «Became» Neurotransmitters: Personal Account of a 65 Years' Voyage

With 65 years in neuroscience research, I have witnessed the discovery of all of the neurotransmitters, after acetylcholine. My own contribution has been mainly on glutamate and GABA. Localisation of neurotransmitters is my specialty. The present account focuses on what I consider the highlights and the aspects where I have participated, with some anecdotes for flavour. We showed for the first time that GABA in the brain is synthesised selectively in inhibitory neurons (1969 -) and that glutamate uptake labels selectively putative glutamatergic nerve endings (1976 -). Then I made antibodies to amino acids (1982 -) and showed that glutamate and GABA are localised in the glutamatergic and GABAergic nerve endings, respectively, and concentrated in their synaptic vesicles (1983 Nature -). We demonstrated microscopically the metabolic compartmentation of glutamate during release from nerve terminals and recycling through astrocytes (1984 -). We also showed that glycine is the transmitter of the inhibitory neuron of a spinal motor pattern generator (1986 Nature -). I contributed to the molecular identification of the first glutamate transporter (1992 Nature -), and to delineating its localisation and function. Similarly, to the vesicular transporters (1998 -), VGAT and VGLUT1-VGLUT2-VGLUT3, and to the discovery of the new family of glutamine transporters, now known as SLC38 (1999 Cell -). The discovery (by others) of the richness of receptor proteins mediating transmitter action settled the question of whether glutamate and GABA were actually neurotransmitters. Presently, their elaborate roles in physiology and the implications for precision medicine are explored.