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Gm527 deficiency in dentate gyrus improves memory through upregulating dopamine D1 receptor pathway

Jie Jia1, Hualing Peng1, Rui Tian1

  • 1Department of Physiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

CNS Neuroscience & Therapeutics
|May 30, 2023
PubMed
Abstract

Insights

Knocking out Gm527 in dopamine D1 receptor (D1R) neurons enhances memory and neurogenesis, improving cognitive symptoms in a mouse model of schizophrenia by boosting D1R function.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Dopamine D1 receptor (D1R) hypofunction is linked to schizophrenia's negative and cognitive deficits.
  • Gm527, a homolog of the schizophrenia-related gene C14orf28, is a predicted D1R-interacting protein.
  • The precise role of Gm527 in D1R function and its implication in schizophrenia remain unclear.

Purpose of the Study:

  • To investigate the role of Gm527 in modulating D1R function.
  • To explore the impact of Gm527-D1R interaction on schizophrenia-related phenotypes.
  • To elucidate the molecular mechanisms underlying Gm527's influence on D1R signaling.

Main Methods:

  • Generation of Gm527-floxed mice crossed with D1-Cre mice to create D1:Gm527-/- mice for targeted Gm527 knockout in D1R-positive neurons.
  • Behavioral tests to assess schizophrenia-related phenotypes, including memory and neurogenesis.
  • Molecular and cellular techniques such as immunofluorescence, in situ hybridization, electrophysiology, qPCR, and Western blotting to investigate mechanisms.

Main Results:

  • D1:Gm527-/- mice exhibited enhanced working memory, long-term memory, and adult neurogenesis in the dentate gyrus (DG).
  • Increased long-term potentiation (LTP) was observed in the DG of D1:Gm527-/- mice.
  • Gm527 knockout led to increased D1R expression on the plasma membrane, activating cAMP signaling and NMDA receptor pathways.

Conclusions:

  • Targeted knockout of Gm527 in the dentate gyrus (DG) results in D1R hyperfunction.
  • This D1R hyperfunction ameliorates cognitive symptoms relevant to schizophrenia.
  • Gm527 plays a critical role in regulating D1R activity and has therapeutic potential for schizophrenia.
Keywords:
D1 receptorGm527NMDAadult neurogenesislong-term memoryworking memory

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