Crucial role of fabp3 in αsyn-induced reduction of septal gabaergic neurons and cognitive decline in mice

Kazuya Matsuo, Yasushi Yabuki, Ronald Melki, Luc Bousset, Yuji Owada, Koji Fukunaga

Research output: Contribution to journalArticlepeer-review

Abstract

In synucleinopathies, while motor symptoms are thought to be attributed to the accumulation of misfolded α-synuclein (αSyn) in nigral dopaminergic neurons, it remains to be elucidated how cognitive decline arises. Here, we investigated the effects of distinct αSyn strains on cognition and the related neuropathology in the medial septum/diagonal band (MS/DB), a key region for cognitive processing. Bilateral injection of αSyn fibrils into the dorsal striatum potently impaired cognition in mice. The cognitive decline was accompanied by accumulation of phosphorylated αSyn at Ser129 and reduction of gamma-aminobutyric acid (GABA)-ergic but not cholinergic neurons in the MS/DB. Since we have demonstrated that fatty acid-binding protein 3 (FABP3) is critical for αSyn neurotoxicity in nigral dopaminergic neurons, we investigated whether FABP3 also participates in αSyn pathology in the MS/DB and cognitive decline. FABP3 was highly expressed in GABAergic but rarely in cholinergic neurons in the MS/DB. Notably, Fabp3 deletion antagonized the accumulation of phosphorylated αSyn, decrease in GABAergic neurons, and cognitive impairment caused by αSyn fibrils. Overall, the present study indicates that FABP3 mediates αSyn neurotoxicity in septal GABAergic neurons and the resultant cognitive impairment, and that FABP3 in this subpopulation could be a therapeutic target for dementia in synucleinopathies.

Original languageEnglish
Article number400
Pages (from-to)1-18
Number of pages18
JournalInternational journal of molecular sciences
Volume22
Issue number1
DOIs
Publication statusPublished - 2021 Jan 1

Keywords

  • Cognition
  • Fatty acid-binding protein
  • Gamma-aminobutyric acid
  • Medial septum
  • α-synuclein

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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