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1 Neuroscience Discovery, Eli Lilly & Co., Indianapololis, IN, USA
* To whom correspondence should be addressed. E-mail: cyang{at}lilly.com.
The NMDA receptor (NMDA-R) has pivotal roles in neural development, learning, memory and synaptic plasticity. Functional impairment of NMDA-R has been implicated in schizophrenia. NMDA-R activation requires glycine to act on the GlyB site of the NMDA-R as an obligatory co-agonist with glutamate. Extracellular glycine near NMDA-R is regulated effectively by a glial glycine transporter (GLYT1). Using whole-cell voltage-clamp recordings in PFC slices, we have shown that exogenous GlyB site agonists glycine and D-serine, or a specific GlyT1 inhibitor N[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl]sarcosine (NFPS) in the presence of exogenous glycine (10 uM) potentiated synaptically evoked NMDA EPSCs in vitro. Furthermore, in urethane-anesthetized rats, microiontophoretic NMDA pulses excite single PFC neurons. When these responses were blocked by ~50 to ~90 % upon continuous iontophoretic application of the GlyB site antagonist (+)HA-966, intravenous NFPS (5 mg/kg), or a GlyB site agonist D-serine (50 mg/kg, i.v.) reversed this (+)HA-966 block. NFPS may elevate endogenous glycine levels sufficiently to displace (+)HA-966 from the GlyB sites of the NMDA-R, thus enabling reactivation of the NMDA-Rs by iontophoretic NMDA applications. D-serine (50-100 mg/kg, i.v.) or NFPS (1-2 mg/kg, i.v.) alone also augmented NMDA-evoked excitatory responses. These data suggest that direct GlyB site stimulation by D-serine, or blockade of GLYT1 to elevate endogenous glycine to act on unsaturated GlyB sites on NMDA-Rs, potentiated NMDA-R mediated firing responses in rat PFC. Blockade of GlyT1 to elevate glycine near the NMDA-R may activate hypofunctional NMDA-R, which has been implicated to play a critical role in the pathophysiology of schizophrenia.
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