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The Na+/H+ exchanger Nhe1 modulates network excitability via GABA release

: Bocker, Hartmut T.; Heinrich, Theresa; Liebmann, Lutz; Hennings, J. Christopher; Seemann, Eric; Gerth, Melanie; Jakovcevski, Igor; Preobraschenski, Julia; Kessels, Michael M.; Westermann, Martin; Isbrandt, Dirk; Jahn, Reinhard; Qualmann, Britta; Hübner, Christian A.


Cerebral cortex 29 (2019), No.10, pp.4263-4276
ISSN: 1047-3211
Journal Article
Fraunhofer IZI ()
Ataxie; Epilepsie; ion homeostasis; Lichtenstein-Knorr syndrome; synaptic pH regulation

Brain functions are extremely sensitive to pH changes because of the pH-dependence of proteins involved in neuronal excitability and synaptic transmission. Here, we show that the Na+/H+ exchanger Nhe1, which uses the Na+ gradient to extrude H+, is expressed at both inhibitory and excitatory presynapses. We disrupted Nhe1 specifically in mice either in Emx1-positive glutamatergic neurons or in parvalbumin-positive cells, mainly GABAergic interneurons. While Nhe1 disruption in excitatory neurons had no effect on overall network excitability, mice with disruption of Nhe1 in parvalbumin-positive neurons displayed epileptic activity. From our electrophysiological analyses in the CA1 of the hippocampus, we conclude that the disruption in parvalbumin-positive neurons impairs the release of GABA-loaded vesicles, but increases the size of GABA quanta. The latter is most likely an indirect pH-dependent effect, as Nhe1 was not expressed in purified synaptic vesicles itself. Conclusively, our data provide first evidence that Nhe1 affects network excitability via modulation of inhibitory interneurons.