Glial activation and increased blood brain barrier permeability in the medial preoptic area of male mice lacking neural androgen receptor

Abstract

We have previously shown that testosterone depletion in adult male mice induced neural androgen receptor (Ar) down-regulation and led to neuroinflammation and increased blood brain barrier (BBB) permeability in the medial preoptic area. In the present study, we investigated the effects of neural Ar deletion on glial function and BBB integrity in male mice. For this purpose, we used control and mutant littermates obtained from a mouse line deleted for the Ar in neural progenitors by Cre-loxP technology. Neural Ar deletion induced glial activation evidenced by increased immunoreactivity against markers of astrocytes (glial fibrillary acidic protein -GFAP- and N-myc downstream-regulated gene 2) and microglia (ionized calcium binding adaptor molecule 1). Fluoro-Jade® C fluorescent labeling was increased and inflammatory molecules such as inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX2) were detected in the vicinity of capillaries in the male medial preoptic area of neural Ar knockout mice. Analysis of BBB integrity showed enhanced permeability for Evans Blue tracer and endogenous immunoglobulins in mutant animals compared to their control littermates. In addition, modifications in the ultrastructural organization of capillary endothelial tight junctions were observed by electron tomography. These effects were specific to neural Ar deletion since no changes were observed for GFAP-immunoreactivity, BBB permeability or Fluoro-Jade® C labeling in male mice expressing the wild type Ar allele and carrying the Cre transgene.

Altogether, these data indicate the key role of the neural AR in testosterone-induced regulation of astrocyte, microglial and BBB functions in the medial preoptic area of male mice.