GLS1 Mutant Mice Display Moderate Alterations of Hippocampal Glutamatergic Neurotransmission Associated with Specific Adaptive Behavioral Changes

Neuroscience. 2019 Jan 1;396:175-186. doi: 10.1016/j.neuroscience.2018.11.022. Epub 2018 Nov 23.

Abstract

Significant alterations in glutamatergic neurotransmission have been reported in major depressive disorder (MDD) that could underlie psychiatric traits. Studies were mainly interested in synaptic dysfunction in the prefrontal cortex, a key structure involved in depressive-like behavior, however hippocampus has been shown to be important in MDD. As cognitive deficits such as hippocampus-memory process were observed in MDD, we investigated in a mild hypoglutamatergic model behaviors related to depression and memory, synaptic transmission parameters and glutamatergic state specifically in the hippocampus. We thus characterized these phenotypes in adult male mice partially depleted in glutaminase type 1 or GLS1 (GLS1 HET), the enzyme responsible for glutamate synthesis in neurons, that we previously characterized as displaying moderate lower levels of glutamate in brain. We showed that GLS1 mutant mice display AMPA-R-mediated response deficits after prolonged repetitive stimulation with electrophysiological recording and inability to sustain glutamate release by microdialysis experiments with no consequences on behavioral spatial learning performances. However, their ability to escape from unpleasant but repeated escapable condition was attenuated whereas they were more immobile in the unescapable situation in the FST during re-test. These results show that GLS1 mutant mice display moderate impairments of hippocampal glutamatergic neurotransmission and moderate changes in adaptive behaviors that have been shown to participate to the development of depressive-like state.

Keywords: GLS1; depression; glutamate; hippocampus; memory; synaptic plasticity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Avoidance Learning / physiology*
  • Corticosterone / blood
  • Electric Stimulation
  • Excitatory Postsynaptic Potentials / physiology
  • Glutamic Acid / metabolism
  • Glutamic Acid / physiology*
  • Glutaminase / genetics
  • Glutaminase / physiology*
  • Hippocampus / physiology*
  • Immobility Response, Tonic / physiology*
  • Long-Term Potentiation / physiology
  • Male
  • Mice
  • Microdialysis
  • Mutation
  • Restraint, Physical / physiology
  • Spatial Learning / physiology*
  • Synaptic Transmission / physiology*

Substances

  • Glutamic Acid
  • GLS1 protein, mouse
  • Glutaminase
  • Corticosterone