Tonic Inhibitory control of dentate gyrus granule cells by α5-containing GABAA receptors reduces memory interference

Elif Engin, Ewa D. Zarnowska, Dietmar Benke, Evgeny Tsvetkov, Maksim Sigal, Ruth Keist, Vadim Y. Bolshakov, Robert A. Pearce, Uwe Rudolph

Research output: Contribution to journalArticlepeer-review

Abstract

Interference between similar or overlapping memories formed at different times poses an important challenge on the hippocampal declarative memory system. Difficulties in managing interference are at the core of disabling cognitive deficits in neuropsychiatric disorders. Computational models have suggested that, in the normal brain, the sparse activation of the dentate gyrus granule cells maintained by tonic inhibitory control enables pattern separation, an orthogonalization process that allows distinct representations of memories despite interference. To test this mechanistic hypothesis, we generated mice with significantly reduced expression of the α5-containing GABAA (α5-GABAARs) receptors selectively in the granule cells of the dentate gyrus (α5DGKO mice). α5DGKO mice had reduced tonic inhibition of the granule cells without any change in fast phasic inhibition and showed increased activation in the dentate gyrus when presented with novel stimuli. α5DGKO mice showed impairments in cognitive tasks characterized by high interference, without any deficiencies in low-interference tasks, suggesting specific impairment of pattern separation. Reduction of fast phasic inhibition in the dentate gyrus through granule cell-selective knock-out of α2-GABAARs or the knock-out of the α5-GABAARs in the downstream CA3 area did not detract from pattern separation abilities, which confirms the anatomical and molecular specificity of the findings. In addition to lending empirical support to computational hypotheses, our findings have implications for the treatment of interference-related cognitive symptoms in neuropsychiatric disorders, particularly considering the availability of pharmacological agents selectively targeting α5-GABAARs.

Original languageEnglish (US)
Pages (from-to)13698-13712
Number of pages15
JournalJournal of Neuroscience
Volume35
Issue number40
DOIs
StatePublished - Oct 7 2015
Externally publishedYes

Keywords

  • Alpha5 subunit
  • Dentate gyrus
  • GABA receptors
  • Interference
  • Pattern separation
  • Reversal learning

ASJC Scopus subject areas

  • General Neuroscience

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