Synaptic underpinnings of altered hippocampal function in glutaminase-deficient mice during maturation

Inna Gaisler-Salomon, Yvonne Wang, Nao Chuhma, Hong Zhang, Yaela N. Golumbic, Andra Mihali, Ottavio Arancio, Etienne Sibille, Stephen Rayport

Research output: Contribution to journalArticlepeer-review


Glutaminase-deficient mice (GLS1 hets), with reduced glutamate recycling, have a focal reduction in hippocampal activity, mainly in CA1, and manifest behavioral and neurochemical phenotypes suggestive of schizophrenia resilience. To address the basis for the hippocampal hypoactivity, we examined synaptic plastic mechanisms and glutamate receptor expression. Although baseline synaptic strength was unaffected in Schaffer collateral inputs to CA1, we found that long-term potentiation was attenuated. In wild-type (WT) mice, GLS1 gene expression was highest in the hippocampus and cortex, where it was reduced by about 50% in GLS1 hets. In other brain regions with lower WT GLS1 gene expression, there were no genotypic reductions. In adult GLS1 hets, NMDA receptor NR1 subunit gene expression was reduced, but not AMPA receptor GluR1 subunit gene expression. In contrast, juvenile GLS1 hets showed no reductions in NR1 gene expression. In concert with this, adult GLS1 hets showed a deficit in hippocampal-dependent contextual fear conditioning, whereas juvenile GLS1 hets did not. These alterations in glutamatergic synaptic function may partly explain the hippocampal hypoactivity seen in the GLS1 hets. The maturity-onset reduction in NR1 gene expression and in contextual learning supports the premise that glutaminase inhibition in adulthood should prove therapeutic in schizophrenia.

Original languageEnglish
Pages (from-to)1027-1039
Number of pages13
Issue number5
StatePublished - May 2012


  • GLS1
  • Glutamate
  • Hippocampus
  • NR1
  • Schizophrenia

ASJC Scopus subject areas

  • Cognitive Neuroscience


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