Glycine tranporter-1 blockade potentiates NMDA-mediated responses in rat prefrontal cortical neurons in vitro and in vivo.

Content Provider	Semantic Scholar
Author	Chen, Long Muhlhauser, Mark A. Yang, Charles R.
Copyright Year	2003
Abstract	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 microM), 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.
Starting Page	691
Ending Page	703
Page Count	13
File Format	PDF HTM / HTML
Alternate Webpage(s)	http://jn.physiology.org/content/jn/early/2002/10/30/jn.00680.2002.full.pdf
Alternate Webpage(s)	http://jn.physiology.org/content/jn/89/2/691.full.pdf
Alternate Webpage(s)	http://www2.neuroscience.umn.edu/eanwebsite/PDF%20GJClub/J%20Neurophysiol%2089%20691%202003.pdf
Alternate Webpage(s)	http://jn.physiology.org/content/early/2002/10/30/jn.00680.2002.full.pdf
PubMed reference number	12574447v1
Volume Number	89
Issue Number	2
Journal	Journal of neurophysiology
Language	English
Access Restriction	Open
Subject Keyword	Activation action Aspartic Acid CFP gene CFP wt Allele Excitation Excitatory Postsynaptic Currents Glutamic Acid HA-966 In Vitro [Publication Type] L-Serine Dehydratase N-Methylaspartate Neurogenesis Neuroglia Neuronal Plasticity Phase I/II Trial Postsynaptic Current Prefrontal Cortex Protein-Serine-Threonine Kinases SLC6A9 gene Schizophrenia Urethane glycine N-methyltransferase glycine transporter mg/kg serine, D- voltage
Content Type	Text
Resource Type	Article