Elevated expression of endogenous glial cell line‐derived neurotrophic factor impairs spatial memory performance and raises inhibitory tone in the hippocampus. (23rd February 2021)

• Record Type: Journal Article
• Authors: Marshall, Pepin; Garton, Daniel R.; Taira, Tomi; Võikar, Vootele; Vilenius, Carolina; Kulesskaya, Natalia; Rivera, Claudio; Andressoo, Jaan‐Olle
• Is Part Of: European journal of neuroscience. Volume 53:Number 8(2021)
• Page Start: 2469
• Page End: 2482
• Publication Date: 2021-02-23
• Subjects: epilepsy -- GABA -- mouse models -- pentylenetetrazole; Nervous system -- Periodicals; 612.8
• DOI: 10.1111/ejn.15126
• Languages: English
• ISSNs: 0953-816X

Abstract

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. Gdnf wt/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. Abstract : Replacement of the Gdnf 3'UTR with a recombinant version less responsive to microRNA binding results in a ~ two‐fold increase in GDNF expression in heterozygous mice limited to natively GDNF‐expressing cells. These GDNF hypermorph mice display impaired memory performance, an increase in parvalbumin interneurons in dorsal hippocampus and cerebral cortex, enhanced GABAergic tone in vitro, and increased seizure threshold in vivo. Our study deepens knowledge on GDNF in vivo function and compliments previous research on parvalbumin‐positive interneurons and GDNF signalling.