Abstract:
:Glutaminase mediates the recycling of neurotransmitter glutamate, supporting most excitatory neurotransmission in the mammalian central nervous system. A constitutive heterozygous reduction in GLS1 engenders in mice a model of schizophrenia resilience and associated increases in Gln, reductions in Glu and activity-dependent attenuation of excitatory synaptic transmission. Hippocampal brain slices from GLS1 heterozygous mice metabolize less Gln to Glu. Whether glutaminase activity is diminished in the intact brain in GLS1 heterozygous mice has not been assessed, nor the regional impact. Moreover, it is not known whether pharmacological inhibition would mimic the genetic reduction. We addressed this using magnetic resonance spectroscopy to assess amino acid content and 13C-acetate loading to assess glutaminase activity, in multiple brain regions. Glutaminase activity was reduced significantly in the hippocampus of GLS1 heterozygous mice, while acute treatment with the putative glutaminase inhibitor ebselen did not impact glutaminase activity, but did significantly increase GABA. This approach identifies a molecular imaging strategy for testing target engagement by comparing genetic and pharmacological inhibition, across brain regions.
journal_name
Neurochem Intjournal_title
Neurochemistry internationalauthors
Kosten L,Chowdhury GMI,Mingote S,Staelens S,Rothman DL,Behar KL,Rayport Sdoi
10.1016/j.neuint.2019.104508subject
Has Abstractpub_date
2019-10-01 00:00:00pages
104508eissn
0197-0186issn
1872-9754pii
S0197-0186(19)30263-3journal_volume
129pub_type
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journal_title:Neurochemistry international
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