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Glutaminase activity in GLS1 Het mouse brain compared to putative pharmacological inhibition by ebselen using ex vivo MRS.

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.

SUBMITTER: Kosten L

PROVIDER: S-EPMC6941670 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Glutaminase activity in GLS1 Het mouse brain compared to putative pharmacological inhibition by ebselen using ex vivo MRS.

Kosten Lauren L Chowdhury Golam M I GMI Mingote Susana S Staelens Steven S Rothman Douglas L DL Behar Kevin L KL Rayport Stephen S

Neurochemistry international 20190719

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 i ...[more]

PMID: 31326460

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Dataset Information

Glutaminase activity in GLS1 Het mouse brain compared to putative pharmacological inhibition by ebselen using ex vivo MRS.

Publications

Glutaminase activity in GLS1 Het mouse brain compared to putative pharmacological inhibition by ebselen using ex vivo MRS.

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