1. Elevated expression of endogenous glial cell line‐derived neurotrophic factor impairs spatial memory performance and raises inhibitory tone in the hippocampus
- Author
-
Pepin Marshall, Tomi Taira, Natalia Kulesskaya, Jaan-Olle Andressoo, Carolina Vilenius, Claudio Rivera, Vootele Voikar, Daniel R Garton, HiLIFE - Neuroscience Center (NC), Helsinki Institute of Life Science (HiLIFE), University of Helsinki-University of Helsinki, University of Helsinki, Department of Veterinary Biosciences [Helsinki], Faculty of Veterinary Medicine [Helsinki], Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université] (INMED - INSERM U1249), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Karolinska Institutet [Stockholm], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Neuroscience Center, Department of Pharmacology, Medicum, Synaptic Plasticity and Neuronal Synchronization, Veterinary Biosciences, Tomi Taira / Principal Investigator, Helsinki Institute of Life Science HiLIFE, Biosciences, Institute of Biotechnology, Helsinki In Vivo Animal Imaging Platform (HAIP), and pellegrino, Christophe
- Subjects
TBSTD ,Gdnf wt/wt ,CA3 ,PT ,PV ,PP ,trunk ,wild running and jumping ,CA1 ,DOPAC ,Mice ,0302 clinical medicine ,tris buffered saline with 0.1% tween and 5% DMSO ,Glial cell line-derived neurotrophic factor ,rearranged during transfection ,PBS ,dopamine transporter ,0303 health sciences ,ANOVA ,sIPSC ,Gdnf wild-type / hypermorphic heterozygote ,GDNF ,Parvalbumins ,cortex ,GFRα1 ,GFRα2 ,cornu ammonis 3 ,millivolt ,dopamine ,standard deviation ,S1B ,glial cell line-derived neurotrophic factor ,WRJ ,retrosplenial cortex ,DAergic ,PTZ ,S1T ,Gdnf wild-type / wild-type ,N-syndecan ,RT ,03 medical and health sciences ,Slice preparation ,picoampere ,primary somatosensory cortex ,bovine serum albumin ,guanosine triphosphate ,PV+ ,mouse models ,[SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,dopaminergic ,SD ,probe trials ,dopamine receptor 1 ,3112 Neurosciences ,reversal training ,EGTA ,barrer ,dimethylsulfoxide ,dopamine receptor 5 ,IT ,nervous system ,epilepsy ,CTX ,Neuroscience ,HEPES ,030217 neurology & neurosurgery ,GTP ,SPSS ,BSA ,DA ,ethylene glycol-bis(β-aminoethyl ether)-N ,Morris water navigation task ,Hippocampus ,DG ,GABA ,Neurotrophic factors ,parvalbumin ,mV ,dentate gyrus ,DMSO ,Spatial Memory ,RSP ,biology ,General Neuroscience ,GABAA ,mIPSC ,SS ,D1 ,SEM ,standard error of the mean ,GDNF family receptor alpha 2 ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,GDNF family receptor alpha 1 ,D5 ,γ-aminobutyric acid ,posteriorparietal cortex ,analysis of variance ,somatosensory cortex ,adenosine triphosphate ,cornu ammonis 1 ,phosphate-buffered saline ,Inhibitory postsynaptic potential ,IBM ,GABA receptor type A ,3N-terminal syndecan 3 ,Interneurons ,spontaneous inhibitory post-synaptic current ,Animals ,water maze ,initial training ,Statistics Package for Social Scientists ,WM ,030304 developmental biology ,pA ,pentylenetetrazole ,parvalbumin-positive ,N′ ,Gdnf wt/hyper ,DAT ,4-dihydroxyphenylacetic acid ,Cortex (botany) ,ATP ,International Business Machines ,minitature inhibitory post-synaptic current ,biology.protein ,4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid ,Ectopic expression ,RET ,N′-tetraacetic acid - 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 GFR alpha 1 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.
- Published
- 2021