title: Microglial regulation of cholinergic differentiation in the basal forebrain.
abstract: Because inflammation during pregnancy can lead to neurodevelopmental anomalies, we investigated the role of inflamed microglia on cholinergic precursors in the rat embryonic basal forebrain (BF) cultured on embryonic day 15. Conditioned medium (CM) taken from microglia stimulated variously (microglial CM; MCM) increased activity of choline acetyltransferase (ChAT), the enzyme responsible for acetylcholine biosynthesis and a phenotypic hallmark of the cholinergic neuron. There was a concomitant decline in glutamic acid decarboxylase expression. Of stimulators tested, only β-amyloid failed to produce effective MCM. Infection with a Lac-Z-containing retrovirus revealed that MCM promoted cholinergic differentiation from undifferentiated precursors in the population. Several candidates were tested for their ability to mimic MCM. Mature nerve growth factor (NGF) did not mimic MCM, but acted synergistically with it to promote enormous increases in ChAT activity. However, a microglial cell line produced high-molecular weight forms of NGF (pro-NGF) that were lethal to mature cholinergic neurons. Although bone morphogenetic proteins (BMP) 2, 4, and 9 increased ChAT activity dose-dependently, noggin did not inhibit the effects of the MCM, suggesting that BMPs were not the only active factor(s) in the MCM. Embryonic microglia isolated following maternal inflammation produced a variety of immune system cytokines and chemokines. One of these, interleukin-6 (IL-6), was tested for its ability to promote cholinergic differentiation. Although IL-6 alone did not mimic the action of MCM, neutralization of it inhibited MCM effectiveness. Thus, following maternal inflammation, a complex microglial-derived cocktail of factors can promote excess cholinergic differentiation in the embryonic BF.
authors: Federated Department of Biological Sciences, New Jersey Institute of Technology, Newark, New Jersey, USA. jonakait@andromeda.rutgers.edu
authors: G Miller
authors: GM
authors: Jonakait
authors: Lorelei
authors: L
authors: Pratt
authors: Giselles
authors: G
authors: Acevedo
authors: Li
authors: L
authors: Ni
mesh_terms: D000818:Animals; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002795:Choline O-Acetyltransferase / Q000378:metabolism*; D059329:Cholinergic Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D017628:Microglia / Q000187:drug effects / Q000502:physiology*; D020932:Nerve Growth Factor / Q000494:pharmacology; D016548:Prosencephalon / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D051381:Rats
chemical_list: D015850:Interleukin-6; D007371:Interferon-gamma; D020932:Nerve Growth Factor; D002795:Choline O-Acetyltransferase