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Elevated expression of endogenous glial cell line-derived neurotrophic factor impairs spatial memory performance and raises inhibitory tone in the hippocampus.

Authors
  • Marshall, Pepin1
  • Garton, Daniel R2
  • Taira, Tomi1, 3
  • Võikar, Vootele1
  • Vilenius, Carolina1
  • Kulesskaya, Natalia1
  • Rivera, Claudio1, 4
  • Andressoo, Jaan-Olle2, 5
  • 1 HiLIFE Neuroscience Centre, University of Helsinki, Helsinki, Finland. , (Finland)
  • 2 Department of Pharmacology, Faculty of Medicine & Helsinki Institute of Life Science (HiLIFE) Helsinki, University of Helsinki, Helsinki, Finland. , (Finland)
  • 3 Veterinary Biosciences, University of Helsinki, Helsinki, Finland. , (Finland)
  • 4 Institut de Neurobiologie de la Méditerranée, INMED UMR901, Marseille, France. , (France)
  • 5 Karolinska Institute, Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society (NVS), Stockholm, Sweden. , (Sweden)
Type
Published Article
Journal
European Journal of Neuroscience
Publisher
Wiley (Blackwell Publishing)
Publication Date
Apr 01, 2021
Volume
53
Issue
8
Pages
2469–2482
Identifiers
DOI: 10.1111/ejn.15126
PMID: 33481269
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Parvalbumin-positive interneurons (PV+) are a key component of inhibitory networks in the brain and are known to modulate memory and learning by shaping network activity. The mechanisms of PV+ neuron generation and maintenance are not fully understood, yet current evidence suggests that signalling via the glial cell line-derived neurotrophic factor (GDNF) receptor GFRα1 positively modulates the migration and differentiation of PV+ interneurons in the cortex. Whether GDNF also regulates PV+ cells in the hippocampus is currently unknown. In this study, we utilized a Gdnf "hypermorph" mouse model where GDNF is overexpressed from the native gene locus, providing greatly increased spatial and temporal specificity of protein expression over established models of ectopic expression. Gdnfwt/hyper mice demonstrated impairments in long-term memory performance in the Morris water maze test and an increase in inhibitory tone in the hippocampus measured electrophysiologically in acute brain slice preparations. Increased PV+ cell number was confirmed immunohistochemically in the hippocampus and in discrete cortical areas and an increase in epileptic seizure threshold was observed in vivo. The data consolidate prior evidence for the actions of GDNF as a regulator of PV+ cell development in the cortex and demonstrate functional effects upon network excitability via modulation of functional GABAergic signalling and under epileptic challenge. © 2021 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

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