Glycine and glycine receptor signaling in hippocampal neurons: diversity, function and regulation.
Glycine is a primary inhibitory neurotransmitter in the spinal cord and brainstem. It acts at glycine receptor (GlyR)-chloride channels, as well as a co-agonist of NMDA receptors (NMDARs). In the hippocampus, the study of GlyRs has largely been under-appreciated due to the apparent absence of glycinergic synaptic transmission. Emerging evidence has shown the presence of extrasynaptic GlyRs in the hippocampus, which exert a tonic inhibitory role, and can be highly regulated under many pathophysiological conditions. On the other hand, besides d-serine, glycine has also been shown to modulate NMDAR function in the hippocampus. The simultaneous activation of excitatory NMDARs and inhibitory GlyRs may provide a homeostatic regulation of hippocampal network function. Furthermore, glycine can regulate hippocampal neuronal activity through GlyR-mediated cross-inhibition of GABAergic inhibition, or through the glycine binding site-dependent internalization of NMDARs. Therefore, hippocampal glycine and its receptors may operate in concert to finely regulate hippocampus-dependent high brain function such as learning and memory. Finally, dysfunction of hippocampal glycine signaling is associated with neuropsychiatric disorders. We speculate that further studies of hippocampal glycine-mediated regulation may help develop novel glycine-based approaches for therapeutic developments.
Xu
Tian-Le
TL
Institute of Neuroscience and State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China. tlxu@ion.ac.cn
Gong
Neng
N
D000818:Animals; D005998:Glycine / Q000378:metabolism* / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology* / Q000187:drug effects; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D017393:RNA Editing / Q000235:genetics; D018009:Receptors, Glycine / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D018009:Receptors, Glycine; D005998:Glycine