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The Journal of Neuroscience, August 16, 2006, 26(33):8537-8548; doi:10.1523/JNEUROSCI.0329-06.2006

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Development/Plasticity/Repair
Dynamic Regulation of Synaptic GABA Release by the Glutamate-Glutamine Cycle in Hippocampal Area CA1

Shu-Ling Liang,¹ Gregory C. Carlson,¹ and Douglas A. Coulter^1,2

¹Division of Neurology and the Pediatric Regional Epilepsy Program, Children’s Hospital of Philadelphia, and ²Departments of Pediatrics, Neurology, and Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Correspondence should be addressed to Dr. Douglas A. Coulter, Children’s Hospital of Philadelphia, Abramson Research Center, Room 409D, 3516 Civic Center Boulevard, Philadelphia, PA 19104-4318. Email: coulterd{at}email.chop.edu

Vesicular GABA and intraterminal glutamate concentrations are in equilibrium, suggesting inhibitory efficacy may depend on glutamate availability. Two main intraterminal glutamate sources are uptake by neuronal glutamate transporters and glutamine synthesized through the astrocytic glutamate-glutamine cycle. We examined the involvement of the glutamate-glutamine cycle in modulating GABAergic synaptic efficacy. In the absence of neuronal activity, disruption of the glutamate-glutamine cycle by blockade of neuronal glutamine transport with -(methylamino) isobutyric acid (MeAIB; 5 mM) or inhibition of glutamine synthesis in astrocytes with methionine sulfoximine (MSO; 1.5 mM) had no effect on miniature IPSCs recorded in hippocampal area CA1 pyramidal neurons. However, after a period of moderate synaptic activity, application of MeAIB, MSO, or dihydrokainate (250 µM; an astrocytic glutamate transporter inhibitor) significantly reduced evoked IPSC (eIPSC) amplitudes. The MSO effect could be reversed by exogenous application of glutamine (5 mM), whereas glutamine could not rescue the eIPSC decreases induced by the neuronal glutamine transporter inhibitor MeAIB. The activity-dependent reduction in eIPSCs by glutamate-glutamine cycle blockers was accompanied by an enhanced blocking effect of the low-affinity GABA_A receptor antagonist, TPMPA [1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid], consistent with diminished GABA release. We further corroborated this hypothesis by examining MeAIB effects on minimal stimulation-evoked quantal IPSCs (meIPSCs). We found that, in MeAIB-containing medium, moderate stimulation induced depression in potency of meIPSCs but no change in release probability, consistent with reduced vesicular GABA content. We conclude that the glutamate-glutamine cycle is a major contributor to synaptic GABA release under physiological conditions, which dynamically regulates inhibitory synaptic strength.

Key words: GABAergic modulation; hippocampus; neurotransmitter; interneuron; astrocyte; astroglia; glutamate transporters; synaptic transmission; GABA; glutamine; patch clamp; unitary

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Received Jan. 24, 2006; revised July 14, 2006; accepted July 15, 2006.

Correspondence should be addressed to Dr. Douglas A. Coulter, Children’s Hospital of Philadelphia, Abramson Research Center, Room 409D, 3516 Civic Center Boulevard, Philadelphia, PA 19104-4318. Email: coulterd{at}email.chop.edu

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