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

J. Masson
Journal of Neuroscience. 2006-04-26; 26(17): 4660-4671
DOI: 10.1523/jneurosci.4241-05.2006

Lire sur PubMed

1. J Neurosci. 2006 Apr 26;26(17):4660-71.

Mice lacking brain/kidney phosphate-activated glutaminase have impaired
glutamatergic synaptic transmission, altered breathing, disorganized
goal-directed behavior and die shortly after birth.

Masson J(1), Darmon M, Conjard A, Chuhma N, Ropert N, Thoby-Brisson M, Foutz AS,
Parrot S, Miller GM, Jorisch R, Polan J, Hamon M, Hen R, Rayport S.

Author information:
(1)Unité Mixte de Recherche U677, NeuroPsychoPharmacologie, Faculté de Médecine
Pitié-Salpêtrière, 75634 Paris Cedex 13, France.

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

DOI: 10.1523/JNEUROSCI.4241-05.2006
PMCID: PMC2745954
PMID: 16641247 [Indexed for MEDLINE]

Auteurs Bordeaux Neurocampus