Loss of cholinergic phenotype in septohippocampal projection neurons: relation to brain versus peripheral IL-2...

In the peripheral immune system, IL-2 is essential for immune homeostasis, normal T regulatory cell function, and self-tolerance. IL-2 knockout (IL-2KO) mice develop spontaneous autoimmunity characterized by increased T cell trafficking to multiple organs. The IL-2 gene is also expressed in the brain, and in vitro studies have shown that IL-2 is a potent modulator of acetylcholine release from septohippocampal neurons and exerts trophic effects on septal neurons in culture. We previously described the apparent loss of cholinergic cell bodies in the medial septum of IL-2KO mice. Here we investigated if loss of brain-derived IL-2, or autoimmunity stemming from loss of peripheral IL-2, is responsible for the alteration in choline acetyltransferase (ChAT) expression in the medial septum of IL-2KO mice. To accomplish this objective, we compared ChAT-positive neurons between wild-type (WT) mice, IL-2KO mice, and congenic mice with a double gene deletion for the IL-2 gene and the recombinase activating gene-2 (RAG-2) which are referred to as IL-2KO/RAG-2KO mice (congenic mice which lack mature T and B cells as well as peripheral and brain-derived IL-2). We found that the loss of ChAT staining did not coincide with an overall loss of cells in the medial septum, suggesting that loss of brain IL-2 results in a change in cholinergic phenotype unrelated to cell death. No differences were noted in the endogenous expression of cytokines and chemokines tested in the medial septum. Evaluation of BDNF and NGF levels between WT and IL-2KO mice in medial septal homogenates revealed that IL-2KO mice have markedly higher levels of NGF in the medial septum compared to WT mice. Our findings suggest that brain-derived IL-2 plays an essential role in the maintainance of septohippocampal projection neurons in vivo.