Abstract
Endogenous D-serine is a putative dominant co-agonist for the N-methyl-D-aspartate glutamate receptor (NMDAR) in the mammalian forebrain. Although the NMDAR regulates the higher order brain functions by interacting with various neurotransmitter systems, the possible interactions between D-serine and an extra-glutamatergic system largely remain elusive. For the first time, we show in the rat and mouse using an in vivo microdialysis technique that the extracellular D-serine concentrations are under tonic increasing control by a major inhibitory transmitter, GABA, via the GABAA (GABAAR) in the medial prefrontal cortex (mPFC). Thus, an intra-mPFC infusion of a selective GABAAR antagonist, bicuculline (BIC), caused a concentration-dependent and reversible decrease in the extracellular levels of D-serine in the rat mPFC without affecting those of another intrinsic NMDAR coagonist, glycine and an NMDAR agonist, L-glutamate. The decreasing effects of BIC were eliminated by co-infusion of a selective GABAA agonist, muscimol (MUS) and were mimicked by a GABAA antagonist, gabazine (GBZ). In contrast, selective blockade of the GABAB or homomeric ρGABAA (formerly GABAC) receptor by saclofen or (1,2,5,6-tetrahydropyridin-4-yl)-methylphosphinic acid (TPMPA), respectively, failed to downregulate the prefrontal extracellular D-serine levels. Moreover, the local BIC application attenuated the ability of NMDA given to the mPFC to increase the cortical extracellular concentrations of taurine, indicating the hypofunction of the NMDAR. Finally, in the mouse mPFC, the reduction of the extracellular D-serine levels by a local injection of BIC into the prefrontal portion was replicated, and was precluded by inhibition of the neuronal or glial activity by co-local injection with tetrodotoxin (TTX) or fluorocitrate (Fluo), respectively. These findings suggest that the GABAAR-mediated regulation of the D-serine signaling may exert fine-tuning of the NMDAR function and require both neuronal and glial activities in the mammalian mPFC.
Highlights
A body of evidence has been accumulated indicating that D-serine in mammalian brains is an intrinsic coagonist for the N-methyl-D-aspartate type glutamate receptor (NMDAR) that plays a pivotal role in the expression and control of higher order brain functions
In terms of the significance of the GABA system and its balance with the excitatory glutamate system in the brain (Nestler et al, 2009), to explore the possible GABAergic control and its molecular basis, we investigated in the rat and mouse the influence of pharmacological manipulation of the various GABA receptor (GABAR) subtypes on the extracellular D-serine levels by using their respective selective antagonists and agonists in the medial prefrontal cortex
The reductions in the contents of the extracellular D-serine and L-glutamine were significantly inhibited by the local infusion of a selective GABAA receptor (GABAAR) agonist, MUS (Enna and McCarson, 2013), which alone slightly increased the D-serine (Figures 1A,B) and L-glutamine (Figures 1E,F) concentrations
Summary
A body of evidence has been accumulated indicating that D-serine in mammalian brains is an intrinsic coagonist for the N-methyl-D-aspartate type glutamate receptor (NMDAR) that plays a pivotal role in the expression and control of higher order brain functions (for a review see Nishikawa, 2011). In terms of the significance of the GABA system and its balance with the excitatory glutamate system in the brain (Nestler et al, 2009), to explore the possible GABAergic control and its molecular basis, we investigated in the rat and mouse the influence of pharmacological manipulation of the various GABA receptor (GABAR) subtypes on the extracellular D-serine levels by using their respective selective antagonists and agonists in the medial prefrontal cortex (mPFC). The mPFC was chosen according to the accumulating data that this region is one of the brain areas with the highest tissue and extracellular concentration of D-serine and enriched by glutamate and GABA synapses (Nestler et al, 2009; Nishikawa, 2011)
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