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The Journal of Neuroscience, April 26, 2006, 26(17):4660-4671; doi:10.1523/JNEUROSCI.4241-05.2006

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Cellular/Molecular
Mice Lacking Brain/Kidney Phosphate-Activated Glutaminase Have Impaired Glutamatergic Synaptic Transmission, Altered Breathing, Disorganized Goal-Directed Behavior and Die Shortly after Birth

Justine Masson,^1,8 Michèle Darmon,¹ Agnès Conjard,² Nao Chuhma,^6,8 Nicole Ropert,³ Muriel Thoby-Brisson,⁴ Arthur S. Foutz,⁴ Sandrine Parrot,⁵ Gretchen M. Miller,^9,10 Renée Jorisch,^9,10 Jonathan Polan,^6,11 Michel Hamon,¹ René Hen,^7,8 and Stephen Rayport^6,8,9

¹Unité Mixte de Recherche U677, NeuroPsychoPharmacologie, Faculté de Médecine Pitié-Salpêtrière, 75634 Paris Cedex 13, France, ²Institut National de la Santé et de la Recherche Médicale U499, Physiopathologie Métabolique et Rénale, 69372 Lyon Cedex 08, France, ³Institut National de la Santé et de la Recherche Médicale U603, Centre National de la Recherche Scientifique Formation de Recherche en évolution 2500, Neurophysiologie Nouvelles Microscopies, 75270 Paris Cedex 06, France, ⁴Centre National de la Recherche Scientifique Unité Propre de Recherche 2216, Neurobiologie Génétique et Intégrative, 91198 Gif sur Yvette, France, ⁵Biochimie Fonctionnelle et Neuropharmacologie, Plate-forme de Physiologie, Université Claude Bernard, 69372 Lyon Cedex 08, France, ⁶Department of Psychiatry, ⁷Department of Pharmacology, and ⁸Center for Neurobiology and Behavior, Columbia University, New York, New York 10032, and ⁹Departments of Neuroscience, ¹⁰Analytical Psychopharmacology, and ¹¹Developmental Psychobiology, New York State Psychiatric Institute, New York, New York 10032

Correspondence should be addressed to either of the following: Dr. Justine Masson, Unité Mixte de Recherche U677 Institut National de la Santé et de la Recherche Médicale/Université Pierre et Marie Curie, Faculté de Médecine Pitié-Salpêtrière, 91 Bd de l'Hôpital, 75634 Paris Cedex 13, France, Email: jumasson{at}ext.jussieu.fr; or Dr. Stephen Rayport, Psychiatry/Neuroscience, Columbia University, 1051 Riverside Drive, NYSPI Unit 62, New York, NY 10032, sgr1{at}columbia.edu

Neurotransmitter glutamate has been thought to derive mainly from glutamine via the action of glutaminase type 1 (GLS1). To address the importance of this pathway in glutamatergic transmission, we knocked out GLS1 in mice. The insertion of a STOP cassette by homologous recombination produced a null allele that blocked transcription, encoded no immunoreactive protein, and abolished GLS1 enzymatic activity. Null mutants were slightly smaller, were deficient in goal-directed behavior, hypoventilated, and died in the first postnatal day. No gross or microscopic defects were detected in peripheral organs or in the CNS. In cultured neurons from the null mutants, miniature EPSC amplitude and duration were normal; however, the amplitude of evoked EPSCs decayed more rapidly with sustained 10 Hz stimulation, consistent with an observed reduction in depolarization-evoked glutamate release. Because of this activity-dependent impairment in glutamatergic transmission, we surmised that respiratory networks, which require temporal summation of synaptic input, would be particularly affected. We found that the amplitude of inspirations was decreased in vivo, chemosensitivity to CO₂ was severely altered, and the frequency of pacemaker activity recorded in the respiratory generator in the pre-Bötzinger complex, a glutamatergic brainstem network that can be isolated in vitro, was increased. Our results show that although alternate pathways to GLS1 glutamate synthesis support baseline glutamatergic transmission, the GLS1 pathway is essential for maintaining the function of active synapses, and thus the mutation is associated with impaired respiratory function, abnormal goal-directed behavior, and neonatal demise.

Key words: respiration; neonatal behavior; glutamate release; lethal phenotype; phosphate-activated glutaminase; GLS1; knock-out mice; glutamatergic neurons; synaptic transmission

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Received Oct. 5, 2005; revised March 22, 2006; accepted March 22, 2006.

Correspondence should be addressed to either of the following: Dr. Justine Masson, Unité Mixte de Recherche U677 Institut National de la Santé et de la Recherche Médicale/Université Pierre et Marie Curie, Faculté de Médecine Pitié-Salpêtrière, 91 Bd de l'Hôpital, 75634 Paris Cedex 13, France, Email: jumasson{at}ext.jussieu.fr; or Dr. Stephen Rayport, Psychiatry/Neuroscience, Columbia University, 1051 Riverside Drive, NYSPI Unit 62, New York, NY 10032, sgr1{at}columbia.edu

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