Increased interactions between PKA and NF-κB signaling in the hippocampus following loss of cholinergic input

Neuropsychiatric disorders such as depression are frequently associated with Alzheimer's disease (AD) and the degeneration of cholinergic basal forebrain neurons and reductions in acetylcholine that occur in AD have been identified as potential mediators of these secondary neuropsychiatric symptomologies. Indeed, removal of 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 expression (GR). A subsequent study showed that loss of cholinergic input decreases the activity of the catalytic subunit of protein kinase A (PKAc) and lessens the interaction of protein kinase A (PKA) with GR. Because cross-coupling between nuclear factor-κB (NF-κB) p65 and GR depends on PKA signaling, the present study was conducted to evaluate the status of NF-κB as well as interactions of PKA with NF-κB in the hippocampus following cholinergic denervation. Expression of cytosolic NF-κB p65 was diminished and IκB was degraded in the hippocampus of cholinergic immunolesioned rats compared to the controls. Immunolesions also increased NF-κB p65 Ser276 phosphorylation, as well as interactions between PKAc and NF-κB p65. These results indicate that loss of cholinergic input to the hippocampus results in decreased PKA activity and increased NF-κB activity. Such altered signaling may contribute to psychiatric symptoms, including depression, in patients with AD.