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DR Copenhagen, RC Renteria, K-I Takaha, D Krizaj; Glutamate:glutamine Cycling Supports Synaptic Transmission In The Retina . Invest. Ophthalmol. Vis. Sci. 2002;43(13):1945.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: To test the glutamate:glutamine recycling hypothesis. According to the hypothesis, the cycling of glutamine plays a pivotal role in maintaining cytosolic glutamate in presynaptic terminals of glutamatergic neurons. Synaptically released glutamate is thought to be taken up by glial cells, converted to glutamine, transported back to the extracellular spaces where it is taken up by presynaptic neurons and subsequently deamidated to form glutamate. In retina, glial Müller cells express the plasma membrane glutamate transporters and glutamine synthetase necessary to support the glutamate:glutamine cycle. However, the existence of the transporter presumed to efflux glutamine from Müller cells has not been shown. Methods: We studied the functional role of glutamine transport in single Müller cells dissociated from the tiger salamander retina, in the isolated retina and in the retinal eyecup preparations. Immunocythochemistry, pH imaging, ERG and multielectrode arrays were used. Results: We find that salamander Müller cells are labeled with antibodies against SN1, a glutamine/proton transporter. Intracellular pH measurement in dissociated Müller cells show a pH-dependence and substrate specificity very similar to SN1. The existence of a glutamine transport mechanism on Müller cells makes it much more plausible that glutamate:glutamine cycling is important in retinal function. To test the role of the cycle in synaptic function, we examined the effect of MSO, a glutamine synthetase inhibitor, on transmission of light-evoked signals in the intact retina. MSO caused a large reduction in the magnitude and frequency of light-evoked ganglion cell spikes recorded with a multielectrode array. As predicted by Barnett et al (Glia 30:64, 2000), exposure to MSO also resulted in a reduction in the amplitude of the b-wave, suggesting that glutamate:glutamine cycling is important to sustain synaptic transmission at the photoreceptor synapse. These negative effects of MSO on the ERG b-wave and ganglion cell spiking were significantly blocked by co-incubating the retinas with 10 mM glutamine, strongly suggesting that the decrease in light-evoked responses was due to glutamine depletion. Conclusion: Our data suggest that glutamate:glutamine cycling is crucial for maintaining normal synaptic transmission in the retina. We propose that glutamate is taken up by the Müller glia, converted into glutamine, transported out by SN1, and converted back to glutamate in the presynaptic terminals of photoreceptors and bipolar cells, replenishing the presynaptic glutamate pools.
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