Suggestion of creatine as a new neurotransmitter by approaches ranging from chemical analysis and biochemistry to electrophysiology

• Published in: eLife 2023-12, Vol.12
• Main Authors: Bian, Xiling, Zhu, Jiemin, Jia, Xiaobo, Liang, Wenjun, Yu, Sihan, Li, Zhiqiang, Zhang, Wenxia, Rao, Yi
• Format: Article
• Language: English
• Subjects: Acetylcholine; Amino acids; Analytical chemistry; Animals; biochemical purification; Biochemistry; Brain; Brain slice preparation; Calcium; Central Nervous System; Creatine; Creatine - genetics; Electrophysiology; GABA; Glutamate; Glycine amidinotransferase; Humans; Intellectual disabilities; Intellectual Disability - genetics; Male; Mice; Mutation; Nervous system; Neurons; Neuroscience; neurotransmission; Neurotransmitter Agents; Neurotransmitters; Physiological aspects; Pyramidal cells; Scientific equipment and supplies industry; synaptic transmission; Synaptic vesicles; Synaptosomes; Textbooks; γ-Aminobutyric acid
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.89317

The discovery of a new neurotransmitter, especially one in the central nervous system, is both important and difficult. We have been searching for new neurotransmitters for 12 y. We detected creatine (Cr) in synaptic vesicles (SVs) at a level lower than glutamate and gamma-aminobutyric acid but higher than acetylcholine and 5-hydroxytryptamine. SV Cr was reduced in mice lacking either arginine:glycine amidinotransferase (a Cr synthetase) or SLC6A8, a Cr transporter with mutations among the most common causes of intellectual disability in men. Calcium-dependent release of Cr was detected after stimulation in brain slices. Cr release was reduced in and mutants. Cr inhibited neocortical pyramidal neurons. SLC6A8 was necessary for Cr uptake into synaptosomes. Cr was found by us to be taken up into SVs in an ATP-dependent manner. Our biochemical, chemical, genetic, and electrophysiological results are consistent with the possibility of Cr as a neurotransmitter, though not yet reaching the level of proof for the now classic transmitters. Our novel approach to discover neurotransmitters is to begin with analysis of contents in SVs before defining their function and physiology.