Dopamine-dependent QR2 pathway activation in ca1 interneurons enhances novel memory formation

Nathaniel L. Gould, Vijendra Sharma, Mohammad Hleihil, Sailendrakumar Kolatt Chandran, Orit David, Efrat Edry, Kobi Rosenblum

Research output: Contribution to journalArticlepeer-review


The formation of memory for a novel experience is a critical cognitive capacity. The ability to form novel memories is sensitive to age-related pathologies and disease, to which prolonged metabolic stress is a major contributing factor. Presently, we describe a dopamine-dependent redox modulation pathway within the hippocampus of male mice that promotes memory consolidation. Namely, following novel information acquisition, quinone reductase 2 (QR2) is suppressed by miRNA-182 (miR-182) in the CA1 region of the hippocampus via dopamine D1 receptor (D1R) activation, a process largely facilitated by locus coeruleus activity. This pathway activation reduces ROS generated by QR2 enzymatic activity, a process that alters the intrinsic properties of CA1 interneurons 3 h following learning, in a form of oxidative eustress. Interestingly, novel experience decreases QR2 expression predominately in inhibitory interneurons. Additionally, we find that in aged animals this newly described QR2 pathway is chronically under activated, resulting in miR-182 underexpression and QR2 overexpression. This leads to accumulative oxidative stress, which can be seen in CA1 via increased levels of oxidized, inactivated potassium channel Kv2.1, which undergoes disulfide bridge oligomerization. This newly described interneuron-specific molecular pathway lies alongside the known mRNA translation-dependent processes necessary for long-term memory formation, entrained by dopamine in CA1. It is a process crucial for the distinguishing features of novel memory, and points to a promising new target for memory enhancement in aging and age-dependent diseases.

Original languageEnglish
Pages (from-to)8698-8714
Number of pages17
JournalJournal of Neuroscience
Issue number45
StatePublished - 4 Nov 2020

Bibliographical note

Funding Information:
This work was supported by the Legacy Heritage Biomedical Science Partnership Program of the Israel Science Foundation Grant 604/15 to K.R. N.L.G. is a recipient of the University of Haifa President Fellowship for Excellent PhD students. We thank laboratory members of the K.R. laboratory and specifically Dr. Shunit Gal-Ben-Ari and Gila Scherer for valued input during the writing of the present work; Dr. Shahaf Edut for assistance with DAT Cre mice; Dr. Barak Carni and Dr. Corina Dolinger for veterinary supervision of the animal facilities; Prof. Eran Hornstein for guidance with the miR experiments; and Fadi Sheban for assistance in carrying out experiments and calibrating protocols. The authors declare no competing financial interests. Correspondence should be addressed to Kobi Rosenblum at Copyright © 2020 the authors

Publisher Copyright:
© 2020 the authors


  • Dopamine
  • Hippocampus
  • Memory consolidation
  • Novelty
  • Protein synthesis
  • ROS
  • MicroRNAs/biosynthesis
  • Oxidative Stress
  • Interneurons/physiology
  • Male
  • Recognition, Psychology
  • CA1 Region, Hippocampal/growth & development
  • Signal Transduction/physiology
  • Aging/physiology
  • Memory/physiology
  • Reactive Oxygen Species/metabolism
  • Memory, Long-Term
  • Memory Consolidation/physiology
  • Mice, Inbred C57BL
  • Dopamine Antagonists/pharmacology
  • Dopamine/physiology
  • Shab Potassium Channels/metabolism
  • Fear/psychology
  • Animals
  • Mice
  • Quinone Reductases/physiology

ASJC Scopus subject areas

  • Neuroscience (all)


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