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

Abstract

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 M; 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.

Astroglial Glutamate–Glutamine Shuttle Is Involved in Central Sensitization of Nociceptive Neurons in Rat Medullary Dorsal Horn

“…MSO has been widely used as a GS inhibitor in astroglia in studies of hyperammonemia, memory consolidation, and seizures, and its effects can be counteracted by glutamine application (Bacci et al, 2002;Suarez et al, 2002;Gibbs and Hertz, 2005;Tanigami et al, 2005;Liang et al, 2006). One recent study has used MSO to examine the effect of inflammatory stimuli on activation of GS in astroglia and found that GS activation is related to glutamatergic receptor activation (Muscoli et al, 2005).…”

“…This shuttle includes the uptake of excessive extrasynaptic glutamate and the production [via glutamine synthetase (GS)] and release from astroglia of glutamine, which is then taken up by neuronal elements to replenish the supply of glutamate (Zwingmann and Leibfritz, 2003;Hertz, 2004;Hertz and Zielke, 2004;Fonseca et al, 2005). A potent inhibitor of GS in astroglia is methionine sulfoximine (MSO), and its effects can be counteracted by glutamine application (Bacci et al, 2002;Blin et al, 2002;Suarez et al, 2002;Shin et al, 2003;Gibbs and Hertz, 2005;Tanigami et al, 2005;Liang et al, 2006). However, only one study has used MSO to investigate the involvement of astroglial GS in the effects of noxious stimuli on glutamatergic receptor-related events in astroglia (Muscoli et al, 2005), and no studies have tested its effects on central sensitization in functionally identified nociceptive neurons.…”

Intrahippocampal glutamine administration inhibits mTORC1 signaling and impairs long-term memory

“…In addition to influencing mTORC1 activity, glutamine is a precursor used in the synthesis of the neurotransmitters glutamate, aspartate, and GABA (Wang et al 2007;Albrecht et al 2010). It has been previously shown that glutamine can play an important role in regulating synaptic signaling, having impacts on both excitatory (Albrecht et al 2010;Uwechue et al 2012;Tani et al 2014) and inhibitory (Liang et al 2006;Wang et al 2007) synaptic signaling through its effects on glutamate and GABA synthesis and release. As shown in Figure 1, we did not observe any significant change in the overall hippocampal levels of glutamate or aspartate 30 min post-glutamine infusion, although changes in the synaptic levels of these neurotransmitters could not be excluded.…”

Expression of glutamine transporter isoforms in cerebral cortex of rats with chronic hepatic encephalopathy

“…Concerning the GABAergic synapses, the majority of this neurotransmitter is recycled in neurons, but part of the released GABA is taken up by surrounding astrocytes and therefore lost from the transmitter pool (Schousboe et al, 2013) . The latter event is compensated by glutamine acting to replenish the neurotransmitter pool of GABA (Liang et al, 2006;Patel et al, 2001;Schousboe, 2003).…”