Investigating the Interactive Effects of Sex Steroid Hormones and Brain-Derived Neurotrophic Factor during Adolescence on Hippocampal NMDA Receptor Expression.

Cushla R Mccarthny,Yeewen Candace Wu,Rachel A Hill,Xin Du

doi:10.1155/2018/7231915

Abstract

Sex steroid hormones have neuroprotective properties which may be mediated by brain-derived neurotrophic factor (BDNF). This study sought to determine the interactive effects of preadolescent hormone manipulation and BDNF heterozygosity (+/−) on hippocampal NMDA-R expression. Wild-type and BDNF+/− mice were gonadectomised, and females received either 17β-estradiol or progesterone treatment, while males received either testosterone or dihydrotestosterone (DHT) treatment. Dorsal (DHP) and ventral hippocampus (VHP) were dissected, and protein expression of GluN1, GluN2A, GluN2B, and PSD-95 was assessed by Western blot analysis. Significant genotype × OVX interactions were found for GluN1 and GluN2 expression within the DHP of female mice, suggesting modulation of select NMDA-R levels by female sex hormones is mediated by BDNF. Furthermore, within the DHP BDNF+/− mice show a hypersensitive response to hormone treatment on GluN2 expression which may result from upstream alterations in TrkB phosphorylation. In contrast to the DHP, the VHP showed no effects of hormone manipulation but significant effects of genotype on NMDA-R expression. Castration had no effect on NMDA-R expression; however, androgen treatment had selective effects on GluN2B. These data show case distinct, interactive roles for sex steroid hormones and BDNF in the regulation of NMDA-R expression that are dependent on dorsal versus ventral hippocampal region.

Highlights

Sex steroid hormones have been widely investigated in the brain and are known to exert a range of neuroprotective effects including antiapoptotic and antioxidant properties in addition to the enhancement of neurogenesis and synaptic plasticity [1, 2]
We report striking region-specific effects of sex steroid hormones and brain-derived neurotrophic factor (BDNF) genotype on hippocampal NMDA-R
Sex steroid hormone manipulation significantly altered GluN1, GluN2A, and GluN2B expression only in the DHP, with no effects of OVX or treatment found within the ventral hippocampus (VHP)

Summary

Introduction

Sex steroid hormones have been widely investigated in the brain and are known to exert a range of neuroprotective effects including antiapoptotic and antioxidant properties in addition to the enhancement of neurogenesis and synaptic plasticity [1, 2]. The predominant female sex steroid hormone, 17β-estradiol, is renowned for its neuroprotective properties, which it exerts via activation of its high-affinity receptor ERs α and β and the recently characterised G-protein-coupled receptor (GPER1). Estradiol’s effect at the synapse may not be exclusively mediated via ER-dependent signalling; alternatively, estradiol may operate in a more indirect fashion, by activating growth factors such as BDNF [3]. BDNF plays an integral role in the growth and survival of new synapses in addition to the strengthening of existing connections [4]. The Val66Met polymorphism, which leads to a functional reduction in activity-dependent release of BDNF, has been linked to psychiatric illnesses such as major depression and schizophrenia [5]

Objectives

Results

Conclusion