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Influence of astrocytic glutamine transporter SN1 deficiency on electrophysiological correlates of glutamatergic transmission

Popek M, Bobula B, Sowa J, Hess G, Albrecht J, Zielinska M
J Neurochem. 2017; 142(suppl 1):125. doi:10.1111/jnc.14093
The N-system glutamine transporter SN1 preferentially transfers glutamine out of astrocytes (Chaudhry et al., Cell 1999), and its depletion causes accumulation of ammonia-derived glutamine in astrocytes in vitro (Zielinska et al., 2015). Since glutamine delivery to neurons is a prerequisite of active glutamatergic transmission (Billups et al., 2013), we hypothesized that SN1 deficiency will impair its electrophysiological manifestations. We used C57Bl6 mice in which knockdown SN1 protein in prefrontal cortex was induced by vivo-morpholino (VM) technique. In all groups SN1 protein expression analysis, HNMR measurements and electrophysiological studies of the pertinent brain regions were conducted. In the prefrontal cortex of mice with local knockdown we observed decreased expression of SN1 protein level by ~55%. HNMR analysis of a pertinent brain region revealed ~12% decrease in glutamate level (a sum of glutamine plus glutamate was decreased by ~15%) and a lack of changes in total glutamine level. KO-SN1 mice showed reduced amplitudes of field potentials evoked in layer V horizontal connections (Vmax was reduced by ~50%) while amplitudes of responses evoked in vertical layer V–layer II/III connections were unchanged. The resting membrane potential of KO-SN1 pyramidal neurons from layer II/III was less negative than control neurons (unchanged in layer V). A tendency toward increase in the mean frequency of sEPSCs in pyramidal neurons originating from the layer II/III of KO-SN1 animals was observed, opposite to the changes in layer V. The causes of insensitivity of cerebral cortical layers other than layer V to SN1 knockout remains to be elucidated. This result supports the hypothesis that SN1 transporter deficiency reduces the neurotransmitter glutamate content and glutamatergic tone in a defined layer of the cerebral cortex, and implicates glutamine retention in astrocytes as a most likely causative factor.
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