Sex differences in rapid nonclassical action of 17β-oestradiol on intracellular signalling and oestrogen receptor α expression in basal forebrain cholinergic neurones in mouse.

Abstract

Rapid nonclassical effects of 17β-oestradiol (E2 ) on intracellular signalling have been identified in the basal forebrain, although the extent to which these actions may be different in males and females is unknown. Previous work has shown that E2 rapidly phosphorylates cAMP responsive element binding protein (CREB) via ΕRα in female cholinergic neurones. Using this indicator, the present study examined whether nonclassical actions of E2 occur in a sexually dimorphic manner within basal forebrain cholinergic neurones in mice. In addition, we investigated the expression and intracellular distribution of oestrogen receptor (ΕR)α in cholinergic neurones in female and male mice. Animals were gonadectomised and treated 2weeks later with E2 . The number of CREB-expressing cholinergic neurones was not altered in any of the brain regions after E2 treatment in both males and females. However, E2 treatment rapidly (<15minutes) increased (P<0.05) the number of cholinergic neurones expressing phosphorylated CREB (pCREB) in the substantia innominata and medial septum but not in the striatum in female mice. By contrast, E2 did not change pCREB expression in cholinergic neurones in male mice at any time point (15minutes, 1hour, 4hours), irrespective of the neuroanatomical location. We also observed that, in females, more cholinergic neurones expressed nuclear ΕRα in all regions, whereas males showed more cholinergic neurones with cytoplasmic or both nuclear and cytoplasmic expression of ΕRα. Taken together, these results demonstrate a marked sex difference in the E2 -induced nonclassical effect and intracellular distribution of ΕRα in basal forebrain cholinergic neurones in vivo.