D-serine as a gliotransmitter and its roles in brain development and disease

Abstract

The development of new techniques to study glial cells has revealed that they are active participants in the development of functional neuronal circuits. Calcium imaging studies demonstrate that glial cells actively sense and respond to neuronal activity. Glial cells can produce and release neurotransmitter-like molecules, referred to as gliotransmitters, that can in turn influence the activity of neurons and other glia. One putative gliotransmitter, D-serine is believed to be an endogenous co-agonist for synaptic N-methyl-D-aspartate receptors (NMDARs), modulating synaptic transmission and plasticity mediated by this receptor. The observation that D-serine levels in the mammalian brain increase during early development, suggests a possible role for this gliotransmitter in normal brain development and circuit refinement. In this review we will examine the data that D-serine and its associated enzyme serine racemase are developmentally regulated. We will consider the evidence that D-serine is actively released by glial cells and examine the studies that have implicated D-serine as a critical player involved in regulating NMDAR-mediated synaptic transmission and neuronal migration during development. Furthermore, we will consider how dysregulation of D-serine may play an important role in the etiology of neurological and psychiatric diseases.

Cell-type specific mechanisms of D-serine uptake and release in the brain

“…In addition to glutamate, NMDAR activation, i.e., channel opening, requires the binding of a coagonist, initially thought to be glycine (Johnson and Ascher, 1987; Kleckner and Dingledine, 1988; Figure 1 ). However, many studies during the last 15 years have shown that D -serine, an unusual amino acid synthesized in the brain by serine racemase (SR; Campanini et al, 2013) and degraded by the peroxysomal flavoprotein D -amino acid oxidase (DAAO; Sacchi et al, 2012), is the main coagonist of synaptic NMDARs in various brain areas (Martineau et al, 2006; Wolosker, 2011; Billard, 2012; Van Horn et al, 2013). Accordingly, D -serine is a physiological modulator of many NMDAR-dependent functions, including brain development (Kim et al, 2005), synaptic transmission and long-term synaptic plasticity ( Figure 1 ; Mothet et al, 2000; Yang et al, 2003; Papouin et al, 2012; Li et al, 2013; Rosenberg et al, 2013), as well as learning, memory, and social interactions (Labrie et al, 2008; DeVito et al, 2011).…”

S-Trityl-(R)-Cysteine, a Multipurpose Chiral Selector for Ligand-Exchange Liquid Chromatography Applications

“…A CLEC method enabling the separation of serine enantiomers can be of practical relevance in the case of analysis of brain samples or cerebrospinal fluids. Indeed, it is widely known that the (S)-serine is involved in several pathophysiological central nervous system (CNS) states (Van Horn et al, 2013;Xia and Xiong, 2013).…”

Interactions of HIV and Drugs of Abuse

“…However, in these studies, the transmitter substance(s) released during gliotransmission are uncertain. Gliotransmission can involve the vesicular release of excitatory transmitters, including glutamate, serine, and adenosine triphosphate (ATP) (Pascual et al, 2005; D’Ascenzo et al, 2007; Parpura & Zorec, 2010; Santello, Cali, & Bezzi, 2012; Martineau, 2013; Van Horn, Sild, & Ruthazer, 2013). Of these, glutamate appears to contribute to drug-seeking behavior and other aspects of cocaine addiction (Beardsley & Hauser, 2014)…”