Decreased interactions in protein kinase A-glucocorticoid receptor signaling in the hippocampus after selective removal of the basal forebrain cholinergic input.
Removal of the cholinergic innervation to the hippocampus via selective immunolesions of septohippocampal cholinergic neurons induces dysfunction of the hypothalamic-pituitary-adrenocortical (HPA) axis and decreases glucocorticoid receptor (GR) mRNA. This study examined whether removal of the cholinergic innervation decreased GR protein levels and induced changes in the interaction between GR and the cytoplasmic catalytic subunit of protein kinase A (PKAc) in the hippocampus. In lesioned animals, GR protein levels were markedly decreased in the nucleus, but not in the cytosol of hippocampal neurons, whereas mineralocorticoid receptor (MR) levels remained unchanged in both the nucleus and cytosol. PKAc levels did not differ between lesioned and control groups, but PKAc activity was reduced in lesion tissue compared with the controls. The interaction between GR and PKAc was also decreased in the hippocampus without cholinergic input. These results indicate that degeneration of septohippocampal cholinergic neurons leads to reduced PKAc activity in the hippocampus which, in turn, alters GR signaling. The altered GR signaling induced by the degeneration of basal forebrain cholinergic neurons may contribute to dysfunction of the HPA axis in aged animals and patients with Alzheimer's disease (AD) and lead to neuropsychiatric symptoms that occur throughout the course of AD.
Blanchette Rockefeller Neurosciences Institute at West Virginia University, Morgantown, West Virginia, USA.
Chol Seung
CS
Lim
Youn Jung
YJ
Kim
Yoo Kyeong
YK
Hwang
Christina
C
Bañuelos
Jennifer L
JL
Bizon
Jung-Soo
JS
Han
D000818:Animals; D059329:Cholinergic Neurons / Q000378:metabolism*; D003345:Corticosterone / Q000097:blood; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism*; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism; D008297:Male; D009434:Neural Pathways / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000378:metabolism; D016548:Prosencephalon / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D017868:Cyclic AMP-Dependent Protein Kinases; D003345:Corticosterone