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

Rachel Anne Hill; Adrienne Mary Grech; Michael J Notaras; Mauricio Sepulveda; Maarten van den Buuse

doi:10.1016/j.ynstr.2020.100253

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

Neurobiol Stress. 2020 Sep 28:13:100253. doi: 10.1016/j.ynstr.2020.100253. eCollection 2020 Nov.

Authors

Rachel Anne Hill^{1

2}, Adrienne Mary Grech^{1

2}, Michael J Notaras^{2

3}, Mauricio Sepulveda^{2

4}, Maarten van den Buuse^{4

5

6}

Affiliations

¹ Department of Psychiatry, School of Clinical Sciences, Monash University, Monash Medical Centre, Clayton, VIC, Australia.
² The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.
³ Weill Cornell Medical College of Cornell University, Centre for Neurogenetics, Brain & Mind Research Institute, New York City, New York, USA.
⁴ School of Psychology and Public Health, La Trobe University, Melbourne, VIC, Australia.
⁵ Department of Pharmacology, University of Melbourne, VIC, Australia.
⁶ The College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, QLD, Australia.

Abstract

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 BDNF^Val66Met 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.

Keywords: Brain-derived neurotrophic factor; Hippocampus; Interneurons; Somatostatin; Stress.