Glycinergic Transmission: Physiological, Developmental and Pathological Implications

The last few years have seen remarkable developments in our understanding of the physiology, pharmacology and genetics of inhibitory glycinergic synapses. In part, this has been due to the development of new resources such as specific antisera recognizing glycine receptor (GlyR) and transporter (GlyT) subtypes, but also the characterization of new mouse, zebrafish and bovine genetic models of glycinergic dysfunction. What is also evident is the high quality and impact of the research conducted in this field. This is reflected in the reviews and research articles in this Special Issue entitled " Glycinergic transmission: physiological, developmental and pathological implications ". The study of inhibitory synaptic transmission has a long and illustrious history, as documented by Callister and Graham (2010). Key in vivo experiments on spinal glycinergic synapses conducted in the 1950s and 1960s helped to define key concepts in chemical neu-rotransmission and the distinct pharmacological and electrophysi-ological properties of what we now know to be inhibitory GlyRs containing the α1 and β subunits. This major adult GlyR isoform predominates in the spinal cord and brainstem (Baer et al., 2009) and has a major role the control of spinal motor reflex circuits. Defects in the corresponding genes, GLRA1 and GLRB, result in an inherited motor disorder in humans known as hyperekplexia, characterized by neonatal hypertonia and an exaggerated startle reflex. Modern genetics techniques (Davies et al., 2010) have revealed that hyperekplexia is best thought of as a synaptopathy, since mutations in SLC6A5 – encoding the presynaptic glycine transporter GlyT2 – can also cause startle disease. Other GlyR subtypes, such as those containing the α2, α3 and α4 subunits, may play more diverse biological roles in retinal circuitry (Wässle et al., 2009) and central inflammatory pain sensitization (Harvey et al., 2009). GlyR α2 and α3 subunit transcripts are also unusual in that they undergo both alternative splicing and cytidine to uracil RNA editing (C to U), resulting in a proline to leucine substitution (P185L in α3, P192L in α2) that confers high agonist sensitivity and phar-macology to " edited " GlyRs (Legendre et al., 2009). GlyR transcript editing may promote the generation of sustained chloride con-ductances associated with tonic inhibition and is modulated by brain lesions, suggesting a possible involvement with pathogenic processes. These " orphan " GlyR subtypes may also have key roles in peripheral tissues, since GlyRs have been located on sperm and neutrophils. However, in renal, liver and endothelial …