Estradiol Modulation of Neurotrophin Receptor Expression in Female Mouse Basal Forebrain Cholinergic Neurons In Vivo

The neuroprotective effect of estradiol (E2) on basal forebrain cholinergic neurons (BFCNs) has been suggested to occur as a result of E2 modulation of the neurotrophin system on these neurons. The present study provides a comprehensive examination of the relationship between E2 and neurotrophin signaling on BFCNs by investigating the effect of E2 deficiency on the expression levels of neurotrophin receptors (NRs), TrkA, TrkB, and p75 on BFCNs. The number of TrkA receptor expressing choline acetyltransferase-positive neurons was significantly reduced in the medial septum (MS) in the absence of E2. A significant reduction in TrkB-expressing choline acetyltransferase-positive cells was also observed in ovariectomized mice in the MS and nucleus basalis magnocellularis (NBM). p75 receptor expression was reduced in the NBM and striatum but not in the MS. We also showed that estrogen receptor (ER)-alpha was expressed by a small percentage of TrkA- and TrkB-positive neurons in the MS (12%) and NBM (19%) and by a high percentage of TrkB-positive neurons in the striatum (69%). Similarly, ER-alpha was expressed at low levels by p75 neurons in the MS (6%) and NBM (9%) but was not expressed on striatal neurons. Finally, ER-alpha knockout using neuron-specific estrogen receptor-alpha knockout transgenic mice abolished all E2-mediated changes in the NR expression on BFCNs. These results indicate that E2 differentially regulates NR expression on BFCNs, with effects depending on the NR type and neuroanatomical location, and also provide some evidence that alterations in the NR expression are, at least in part, mediated via ER alpha.