br Perspectives br Contributors BP study concept design

Perspectives
Contributors BP: study concept & design, literature review, data analysis & synthesis & presentation, primary draft of the manuscript; JDR: data analysis, Fig. 1 illustration, manuscript review & revision; ZP: study concept & design, manuscript review & edit; MI: manuscript review & edit; EB: manuscript review, R-SM: study concept, manuscript review & supervision.
Conflict of interests
Introduction Glycine is an important amino Afatinib dimaleate in the central nervous system. Besides its metabolic role, glycine serves as a neurotransmitter at many inhibitory synapses in the spinal cord and brainstem [1], [2] and also constitutes a co-agonist of glutamatergic neurotransmission at NMDA subtype of glutamate receptors [3]. In the brain, glycine is derived predominantly by de novo synthesis, via the pathway leading from glucose through serine to glycine [4]. Interestingly, the content of glycine differs very much among areas in the brain. For example, Shank et al. have reported that, in the rat brain, the content of glycine is 0.63 µmol/g in the telencephalon, while that in the spinal cord grey matter is 5.53 µmol/g [4], indicating that glycine content is about 9 times higher in the spinal cord grey matter than in the telencephalon. Similar tendency in glycine content is also reported in other studies [5], [6]. Interestingly, this kind of caudal (spinal cord) to rostral (telencephalon) gradient is never seen in any other neurotrasmitters. For example, the content of glutamate is 11.24 µmol/g in the telencephalon, while that in the spinal cord grey matter is 6.36 µmol/g [4], indicating that glutamate content is nearly half in the spinal cord grey matter compared to that in the telencephalon. In addition, the content of GABA is 1.98 µmol/g in the telencephalon, while that in the spinal cord grey matter is 1.40 µmol/g [4], indicating that there is no difference in GABA content between both regions. Taken together, this very sharp caudal-rostral gradient is very specific to only glycine. However, the cause of this phenomenon remains unknown.
Hypothesis Glycine acts as an inhibitory neurotransmitter at many synapses in the brain stem and spinal cord [1], [2]. For example, glycinergic neurons, which use glycine as a neurotransmitter and contain synaptic vesicles with high amounts of glycine, are mainly observed in brain stem and spinal cord [7]. In addition, Sato et al. have reported that glycine receptors (GlyRs) are mainly expressed in the brainstem and spinal cord [8]. Taken together, glycinergic neurons, receptors are concentrated in the brain stem and spinal cord. Interestingly, the affinity of glycine to the glycine receptor is reported to be about 10 µM [9]. Due to this relatively low affinity, glycine concentrations in the synaptic cleft might be kept high, in addition, glycinergic neurons contain high amount of glycine, leading to the high content of glycine in the brain stem and spinal cord. In contrast, in the upper brain, there are little glycinergic neurons which need higher concentrations of glycine to work [8]. This might be the first reason why glycine contents are low. In addition, glycine has been considered to be a co-agonist of glutamatergic neurotransmission at NMDA subtype of glutamate receptors (NMDARs) [3]. In binding experiments using rodent cerebral cortex, the dissociation constant at the glycine site of NMDARs are 126 nM for glycine [10]. It means that the affinity of glycine to NMDARs is almost 80 times higher than that to GlyRs. I speculate that not to make the glycine binding site of NNDARs saturated, i.e. to keep this site functional, glycine concentrations in the forebrain must be kept lowered. This may be the second reason why glycine contents in the upper brain are low. Here, the hypothesis is as follows (Fig. 1);
Evaluation of the hypothesis
Consequences of the hypothesis and discussion
Grant sponsor The Ministry of Education, Science and Culture of Japan; Shintenkai.