br Brief overview of the glutamate

Brief overview of the glutamate system and rationale for targeting the glycine site of NMDARs In the central nervous system (CNS), glutamate is the major excitatory neurotransmitter and works in concert with gamma-aminobutyric Methylpiperidino pyrazole receptor (GABA), the primary inhibitory neurotransmitter. Together, GABA and glutamate facilitate the majority of neuronal communication in the brain (Schoepp, 2001). There are two groups of glutamate receptors: ionotropic and metabotropic (Javitt et al., 2011). NMDARs are glutamate-gated ion tetramers channels and consist of several subunits namely, GluN1, GluN2A–GluN2D, GluN3A, and GluN3B (Traynelis et al., 2010). Each NMDA receptor is formed of two GluN1 subunits together with either two GluN2 subunits or a combination of GluN2 and GluN3 subunits (Ulbrich and Isacoff, 2008). Uniquely, NMDARs are not activated with their principal agonist, glutamate, unless a co-agonist binding site located at the GluN1 subunit is also occupied (McBain et al., 1989; Paoletti and Neyton, 2007; Traynelis et al., 2010). Although this co-agonist site is generally referred to as the ‘glycine site’ as it was initially considered to be bound by glycine (Johnson and Ascher, 1987), it is now known to be activated with either d-serine or glycine (Wolosker et al., 2008). For full activation of NMDAR, agonist binding at two glycine and two glutamate receptors on the tetrameric complex is required (Benveniste and Mayer, 1991; Clements and Westbrook, 1991). Glutamate binds to GluN2 (Furukawa et al., 2005) while Glycine binds to GlueN1 and/or GluN3 (Ulbrich and Isacoff, 2007). As shown in Fig. 1, numerous agents have been identified that target these different subunits of the NMDAR. In 1990, the first preliminary rodent model study suggested that NMDARs might be involved in the pathophysiology of depression (Trullas and Skolnick, 1990). The role of NMDARs in depression was further validated through clinical trials demonstrating the rapid and robust antidepressant effects of the NMDARs antagonist, ketamine (Berman et al., 2000; Parsaik et al., 2015; Zarate et al., 2012). As the evidence for ketamine in mood disorders has grown, the interest in targeting NMDARs in patients with MDD has also evolved (Feyissa et al., 2009; Hasler et al., 2007; Luykx et al., 2012). Other glutaminergic modulators (both agonist and antagonists) have been investigated in pre-clinical and clinical studies regarding their possible antidepressant effects (Henter et al., 2018). Numerous studies have demonstrated that the NMDAR blockade can result in psychotomimetic effects and impaired cognition (Krystal et al., 1994), and their activation may result in improving cognitive function (Danysz and Parsons, 1998). For example, rodent studies proposed that the activation of NMDARs are involved in the acquisition of hippocampal-dependent learning tasks such as trace eyeblink conditioning (Weiss et al., 1999). Also, sub-chronic treatment with phencyclidine (PCP), an NMDAR antagonist, could induce remarkable deficits in the novel object recognition test (an animal model of learning and memory) (Diamond et al., 2005; Horiguchi et al., 2013). Furthermore, NMDARs play an integral role in hippocampal regulation (Burgdorf et al., 2011a; Diamond et al., 2005; Kemp and Manahan-Vaughan, 2007), neuronal communication, and neuroplasticity. These include long-term potentiation (LTP) and long-term depression (LTD) (Rison and Stanton, 1995), forms of activity-dependent synaptic plasticity (Stanton, 1996) believed to be related to learning (Martin et al., 2000; Morris et al., 1986), facilitating the acquisition and consolidation of long-term declarative (semantic) (Manns et al., 2003) as well as episodic memories (Eichenbaum and Fortin, 2005; Viskontas et al., 2000). It has been suggested that the activation of NMDARs leads to production of brain-derived neurotrophic factor (BDNF) through influx of calcium in hippocampal neurons (Maqsood and Stone, 2016). BDNF seems to be involved in synaptic plasticity by meditating activity-induced LTP (Lu et al., 2015; Park and Poo, 2013).