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Over the last century, it has been considered that amino acids in mammalian tissues and body fluids occur solely in the L-configuration whether free or as components of peptides and proteins. However, the recent discovery that high levels of D-serine and D-aspartate are present in Mammals overturns this long-cherished theory. In this review, we focus on recent findings regarding the physiological relevance of D-serine, a new neurotransmitter formed in glial cells, that serves as the endogenous ligand for the accessory strychnine-insensitive glycine site of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors. This unusual molecule not only questions our basic ideas about how nerve cells converse but also offers a novel way to treat some brain disorders as both over-stimulation and down regulation of NMDA receptors has been implicated in a large number of acute and chronic degenerative conditions.

N-methyl-D-aspartate receptors (NMDARs) populate GABAergic interneurons, where they play a critical role in shaping circuit motifs and memory. However, we are largely ignoring whether and how NMDARs at GABAergic interneurons are gated by signals released in their surrounding microenvironment. Here we explore the dynamics of the co-agonist site occupancy by D-serine and glycine at glutamatergic synapses onto parvalbumin positive GABAergic interneurons in the adolescent prefrontal cortex, an area central to complex cognitive operation. We discovered that D-serine but not glycine is required for maintaining the activity of NMDAR at the GABAergic interneurons and that the identity of the co-agonist is not determined by the synaptic regime. Our study extends the physiological implications of D-serine in brain physiopathology by uncovering its control of inhibitory synaptic networks through NMDARs.

NMDA receptors (NMDARs) populate the complex between inner hair cell (IHC) and spiral ganglion neurons (SGNs) in the developing and mature cochlea. However, in the mature cochlea, activation of NMDARs is thought to mainly occur under pathological conditions such as excitotoxicity. Ototoxic drugs such as aspirin enable cochlear arachidonic-acid-sensitive NMDAR responses, and induced chronic tinnitus was blocked by local application of NMDAR antagonists into the cochlear fluids. We largely ignore if other modulators are also engaged. In the brain, D-serine is the primary physiological co-agonist of synaptic NMDARs. Whether D-serine plays a role in the cochlea had remained unexplored. We now reveal the presence of D-serine and its metabolic enzymes prior to, and at hearing onset, in the sensory and non-neuronal cells of the cochlea of several vertebrate species. In vivo intracochlear perfusion of D-serine in guinea pigs reduces sound-evoked activity of auditory nerve fibers without affecting the receptor potentials, suggesting that D-serine acts specifically on the postsynaptic auditory neurons without altering the functional state of IHC or of the stria vascularis. Indeed, we demonstrate in vitro that agonist-induced activation of NMDARs produces robust calcium responses in rat SGN somata only in the presence of D-serine, but not of glycine. Surprisingly, genetic deletion in mice of serine racemase (SR), the enzyme that catalyzes D-serine, does not affect hearing function, but offers protection against noise-induced permanent hearing loss as measured 3 months after exposure. However, the mechanisms of activation of NMDA receptors in newborn rats may be different from those in adult guinea pigs. Taken together, these results demonstrate for the first time that the neuro-messenger D-serine has a pivotal role in the cochlea by promoting the activation of silent cochlear NMDAR in pathological situations. Thus, D-serine and its signaling pathway may represent a new druggable target for treating sensorineural hearing disorders (i.e., hearing loss, tinnitus).

Free d- aspartate and d- serine occur at substantial levels in the mammalian brain. d- Serine is a physiological endogenous co-agonist for synaptic N-Methyl d -Aspartate (NMDA) receptors (NMDARs), and is involved in the pathophysiology of schizophrenia. Much less is known about the biological meaning of d- aspartate. d- Aspartate is present at high levels in the embryo brain and strongly decreases at post-natal phases. Temporal reduction of d- aspartate levels depends on the post-natal onset of d- aspartate oxidase (DDO), an enzyme able to selectively catabolize this d- amino acid. Pharmacological evidence indicates that d- aspartate binds to and activates NMDARs. Characterization of genetic and pharmacological mouse models with abnormally higher levels of d- aspartate has evidenced that increased d- aspartate enhances hippocampal NMDAR-dependent synaptic plasticity, dendritic morphology and spatial memory. In line with the hypothesis of a hypofunction of NMDARs in the pathogenesis of schizophrenia, it has been shown that increased d- aspartate levels also improve brain connectivity, produce corticostriatal adaptations resembling those observed after chronic haloperidol treatment, and protects against prepulse inhibition deficits and abnormal circuits activation induced by psychotomimetic drugs. In healthy humans, genetic variation predicting reduced expression of DDO in post-mortem prefrontal cortex is associated with greater prefrontal gray matter and activity during working memory. On the other side, evaluation of d- aspartate content in post-mortem patients with schizophrenia has shown a significant reduction of this d- amino acid in the prefrontal cortex and striatum. Generation of mouse models with reduced embryonic levels of d- aspartate may disclose unprecedented role for d- aspartate in developmental brain processes associated with vulnerability to psychotic-like symptoms.

Perampanel is an aryl substituted 2-pyridone AMPA receptor antagonist that was recently approved as a treatment for epilepsy. The drug potently inhibits AMPA receptor responses but the mode of block has not been characterized. Here the action of perampanel on AMPA receptors was investigated by whole-cell voltage-clamp recording in cultured rat hippocampal neurons. Perampanel caused a slow (t,1 s at 3 mM), concentration-dependent inhibition of AMPA receptor currents evoked by AMPA and kainate. The rates of block and unblock of AMPA receptor currents were 1.5610 5 M 21 s 21 and 0.58 s 21 , respectively. Perampanel did not affect NMDA receptor currents. The extent of block of non-desensitizing kainate-evoked currents (IC50 ,0 .56mM) was similar at all kainate concentrations (3–100 mM), demonstrating a noncompetitive blocking action. Parampanel did not alter the trajectory of AMPA evoked currents indicating that it does not influence AMPA receptor desensitization. Perampanel is a selective negative allosteric AMPA receptor antagonist of high-affinity and slow blocking kinetics.

The enteric nervous system (ENS) is a complex network of diverse molecularly defined classes of neurons embedded in the gastrointestinal wall and responsible for controlling the major functions of the gut. As in the central nervous system, the vast array of ENS neurons is interconnected by chemical synapses. Despite several studies reporting the expression of ionotropic glutamate receptors in the ENS, their roles in the gut remain elusive. Here, by using an array of immunohistochemistry, molecular profiling and functional assays, we uncover a new role for d-serine (d-Ser) and non-conventional GluN1-GluN3 N-methyl d-aspartate receptors (NMDARs) in regulating ENS functions. We demonstrate that d-Ser is produced by serine racemase (SR) expressed in enteric neurons. By using both in situ patch clamp recording and calcium imaging, we show that d-Ser alone acts as an excitatory neurotransmitter in the ENS independently of the conventional GluN1-GluN2 NMDARs. Instead, d-Ser directly gates the non-conventional GluN1-GluN3 NMDARs in enteric neurons from both mouse and guinea-pig. Pharmacological inhibition or potentiation of GluN1-GluN3 NMDARs had opposite effects on mouse colonic motor activities, while genetically driven loss of SR impairs gut transit and fluid content of pellet output. Our results demonstrate the existence of native GluN1-GluN3 NMDARs in enteric neurons and open new perspectives on the exploration of excitatory d-Ser receptors in gut function and diseases., Competing Interests: Conflicts of interest The authors disclose no conflicts.