Brain-Derived Neurotrophic Factor Val66Met polymorphism interacts with adolescent stress to alter hippocampal interneuron density and dendritic morphology in mice

Neurobiology of Stress

Michael J. Notaras¹  Maarten van den Buuse²  Adrienne Mary Grech²  Mauricio Sepulveda³  Rachel Anne Hill³ 

[1] Corresponding author. Department of Psychiatry, School of Clinical Sciences at Monash Health, Monash University Level 3, Monash Medical Centre 27Wright St Clayton VIC 3168 Australia, .;The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia;Department of Psychiatry, School of Clinical Sciences, Monash University, Monash Medical Centre, Clayton, VIC, Australia;

关键词: Brain-derived neurotrophic factor;    Interneurons;    Stress;    Hippocampus;    Somatostatin;   

DOI  :  

来源: DOAJ

【 摘 要 】

Brain-derived neurotrophic factor (BDNF) plays essential roles in GABAergic interneuron development. The common BDNF val66met polymorphism, leads to decreased activity-dependent release of BDNF. The current study used a humanized mouse model of the BDNF val66met polymorphism to determine how reduced activity-dependent release of BDNF, both on its own, and in combination with chronic adolescent stress hormone, impact hippocampal GABAergic interneuron cell density and dendrite morphology.Male and female Val/Val and Met/Met mice were exposed to corticosterone (CORT) or placebo in their drinking water from weeks 6–8, before brains were perfuse-fixed at 15 weeks. Cell density and dendrite morphology of immunofluorescent labelled inhibitory interneurons; somatostatin, parvalbumin and calretinin in the CA1, and 3 and dentate gyrus (DG) across the dorsal (DHP) and ventral hippocampus (VHP) were assessed by confocal z-stack imaging, and IMARIS dendritic mapping software.Mice with the Met/Met genotype showed significantly lower somatostatin cell density compared to Val/Val controls in the DHP, and altered somatostatin interneuron dendrite morphology including branch depth, and spine density. Parvalbumin-positive interneurons were unchanged between genotype groups, however BDNF val66met genotype influenced the dendritic volume, branch level and spine density of parvalbumin interneurons differentially across hippocampal subregions. Contrary to this, no such effects were observed for calretinin-positive interneurons. Adolescent exposure to CORT treatment also significantly altered somatostatin and parvalbumin dendrite branch level and the combined effect of Met/Met genotype and CORT treatment significantly reduced somatostatin and parvalbumin dendrite spine density.In sum, the BDNFVal66Met polymorphism significantly alters somatostatin and parvalbumin-positive interneuron cell development and dendrite morphology. Additionally, we also report a compounding effect of the Met/Met genotype and chronic adolescent CORT treatment on dendrite spine density, indicating that adolescence is a sensitive period of risk for Val66Met polymorphism carriers.

【 授权许可】

Unknown