title: Synaptic underpinnings of altered hippocampal function in glutaminase-deficient mice during maturation.
abstract: 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.
authors.affiliation: Department of Psychiatry, Columbia University, New York, NY 10032, USA.
authors.forename: Inna
authors.initials: I
authors.lastname: Gaisler-Salomon
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Wang
authors.forename: Nao
authors.initials: N
authors.lastname: Chuhma
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.forename: Yaela N
authors.initials: YN
authors.lastname: Golumbic
authors.forename: Andra
authors.initials: A
authors.lastname: Mihali
authors.forename: Ottavio
authors.initials: O
authors.lastname: Arancio
authors.forename: Etienne
authors.initials: E
authors.lastname: Sibille
authors.forename: Stephen
authors.initials: S
authors.lastname: Rayport
mesh_terms: D000367:Age Factors; D000818:Animals; D003213:Conditioning, Psychological / Q000502:physiology; D005239:Fear / Q000502:physiology; D005260:Female; D015870:Gene Expression; D018698:Glutamic Acid / Q000378:metabolism; D005972:Glutaminase / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism* / Q000503:physiopathology; D007266:Inhibition, Psychological; D017774:Long-Term Potentiation / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018091:Receptors, AMPA / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012559:Schizophrenia / Q000201:enzymology; D013569:Synapses / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology
chemical_list: D018698:Glutamic Acid; D005972:Glutaminase; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C409466:NR1 NMDA receptor; C574238:GLS1 protein, mouse