LEVELS OF TRKA AND BDNF MESSENGER-RNA, BUT NOT NGF MESSENGER-RNA, FLUCTUATE ACROSS THE ESTROUS-CYCLE AND INCREASE IN RESPONSE TO ACUTE HORMONE REPLACEMENT
Rb. Gibbs, LEVELS OF TRKA AND BDNF MESSENGER-RNA, BUT NOT NGF MESSENGER-RNA, FLUCTUATE ACROSS THE ESTROUS-CYCLE AND INCREASE IN RESPONSE TO ACUTE HORMONE REPLACEMENT, Brain research, 787(2), 1998, pp. 259-268
Recent studies suggest that hormone replacement therapy can help to re
duce the risk and severity of Alzheimer's-related dementia in postmeno
pausal women. We have hypothesized that these effects are due, in part
, to the ability for estrogen and progesterone to enhance hippocampal
function, as well as the functional status of cholinergic projections
to the hippocampus and cortex, by influencing the expression of specif
ic neurotrophins and neurotrophin receptors. In the present study, qua
ntitative in situ hybridization techniques were used to determine whet
her the levels of trkA mRNA in the basal forebrain, and nerve growth f
actor (NGF) mRNA and brain-derived neurotrophic factor (BDNF) mRNA in
the hippocampus, are significantly affected by physiological changes i
n circulating gonadal steroids. Gonadally intact animals were sacrific
ed at different stages of the estrous cycle and ovariectomized animals
were sacrificed at different times following the administration of ei
ther estrogen or estrogen plus progesterone. In gonadally intact anima
ls, significant fluctuations in the levels of trkA mRNA in the medial
septum (MS), and BDNF mRNA in regions CA1 and CA3/4 of the hippocampus
, were detected across the estrous cycle. In animals that received hor
mone replacement, a significant increase (30.4%) in trkA mRNA was dete
cted in the MS of animals sacrificed 24 h following estrogen administr
ation. Levels of trkA mRNA in the MS declined to control levels over t
he next 48 h; however, a single injection of progesterone administered
48 h after estradiol appeared to prevent any further decline in trkA
mRNA over the next 24 h. In addition, significant increases in BDNF mR
NA were detected in the dentate granule cell layer (73.4%), region CA1
(28.1%), and region CA3/4 (76.9%) of animals sacrificed 53 h after re
ceiving estrogen and 5 h after receiving progesterone. No significant
changes in trkA mRNA were detected in the nucleus basalis magnocellula
ris, and no significant changes in NGF mRNA were detected in the hippo
campus. These data demonstrate that levels of trkA mRNA in the MS, and
BDNF mRNA in the hippocampus, are affected by physiological changes i
n the levels of circulating gonadal steroids and are elevated in respo
nse to acute hormone replacement. The relevance of these effects to th
e ability for estrogen replacement to enhance cholinergic activity and
hippocampal function, and thereby reduce the risk and severity of Alz
heimer's-related dementia in postmenopausal women, is discussed. (C) 1
998 Elsevier Science B.V.