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J Neurophysiol (February 1, 2003). 10.1152/jn.00680.2002
Submitted on Submitted 15 August 2002; accepted in final form 15 October 2002
Neuroscience Discovery, Eli Lilly and Co., Lilly Corporate Center, Indianapolis, Indiana 46220
Chen, Long,
Mark Muhlhauser, and
Charles R. Yang.
Glycine Tranporter-1 Blockade Potentiates NMDA-Mediated Responses
in Rat Prefrontal Cortical Neurons In Vitro and In Vivo. J. Neurophysiol. 89: 691-703, 2003. The
N-methyl-D-aspartate (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
glycine-B (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 prefrontal cortex (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 µM), potentiated synaptically evoked NMDA excitatory postsynaptic currents (EPSCs) in
vitro. Furthermore, in urethan-anesthetized rats, microiontophoretic NMDA pulses excite single PFC neurons. When these responses were blocked by approximately 50% to approximately 90% on 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 iv) 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
iv) or NFPS (1-2 mg/kg iv) 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. Hence, 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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