Absence of colony stimulation factor-1 receptor results in loss of microglia, disrupted brain development and olfactory deficits.

The brain contains numerous mononuclear phagocytes called microglia. These cells express the transmembrane tyrosine kinase receptor for the macrophage growth factor colony stimulating factor-1 (CSF-1R). Using a CSF-1R-GFP reporter mouse strain combined with lineage defining antibody staining we show in the postnatal mouse brain that CSF-1R is expressed only in microglia and not neurons, astrocytes or glial cells. To study CSF-1R function we used mice homozygous for a null mutation in the Csflr gene. In these mice microglia are >99% depleted at embryonic day 16 and day 1 post-partum brain. At three weeks of age this microglial depletion continues in most regions of the brain although some contain clusters of rounded microglia. Despite the loss of microglia, embryonic brain development appears normal but during the post-natal period the brain architecture becomes perturbed with enlarged ventricles and regionally compressed parenchyma, phenotypes most prominent in the olfactory bulb and cortex. In the cortex there is increased neuronal density, elevated numbers of astrocytes but reduced numbers of oligodendrocytes. Csf1r nulls rarely survive to adulthood and therefore to study the role of CSF-1R in olfaction we used the viable null mutants in the Csf1 (Csf1(op)) gene that encodes one of the two known CSF-1R ligands. Food-finding experiments indicate that olfactory capacity is significantly impaired in the absence of CSF-1. CSF-1R is therefore required for the development of microglia, for a fully functional olfactory system and the maintenance of normal brain structure.

Biphasic stimulant and sedative effects of ethanol: are children of alcoholics really different?

Children of alcoholics (COAs) have an increased risk of developing alcoholism themselves. The mechanisms responsible are not yet known. One compelling theory postulates that COAs may have an increased sensitivity to the stimulant effects of alcohol during the ascending limb of the blood alcohol curve combined with a decreased sensitivity to the putatively undesirable sedative effects of the drug during the descending limb, providing a particularly strong motivation to drink. Consistent with this theory, we hypothesized that compared to children of nonalcoholics (CONAs), COAs would display higher levels of ascending limb stimulation and lower levels of descending limb sedation. In the present study, 100 college students, who were either COAs (n=18) or CONAs (n=82), completed the Biphasic Alcohol Effects Scale (a self-report measure of stimulation and sedation): (1) before consuming 0.85n ml/kg ethanol; (2) during the ascending limb of their BAC, and; (3) during the descending limb of their BAC. Although findings indicated that COAs and CONAs had comparable levels of sedation at each time point, a significant GroupxTime interaction (P<.02) indicated that COAs had greater increases in stimulation from baseline than CONAs, providing partial support for our hypothesis. Interestingly, simple effects analyses revealed that COAs had lower baseline levels of stimulation but almost identical levels of ascending and descending limb stimulation as CONAs, suggesting that increased sensitivity to alcohol among COAs may be the result of baseline understimulation. Overall, findings suggest that theorized differences between COAs and CONAs may be due in part to broader trait differences or other nonpharmacological factors.

A peptide DNA surrogate accelerates autoimmune manifestations and nephritis in lupus-prone mice.

Lupus-associated anti-DNA Abs display features of Ag selection, yet the triggering Ag in the disease is unknown. We previously demonstrated that the peptide DWEYSVWLSN is bound by a pathogenic anti-DNA Ab, and that immunization of nonautoimmune mice with this peptide induces autoantibodies and renal Ig deposition. To elucidate differences in the induced B cell responses in mice genetically predisposed to autoimmunity, young (NZB x NZW)F(1) mice were immunized with this peptide DNA mimetope. DWEYSVWLSN-immunized mice had significantly increased IgG anti-dsDNA, anti-laminin, and anti-cardiolipin Ab titers compared with controls. In addition, glomerular histopathology in the form of endocapillary disease and crescent formation was markedly more severe in DWEYSVWLSN-immunized mice. Analysis of mAbs from DWEYSVWLSN-immunized mice revealed that anti-peptide Abs were often cross-reactive with DNA. Genetic elements used in the Ab response in immunized mice were homologous to those used in the spontaneous anti-DNA response in (NZB x NZW)F(1) mice, as well as in other, experimentally induced anti-DNA Abs. Our results indicate that peptide immunization can induce a molecular genetic response common to a variety of stimuli that break tolerance to mammalian dsDNA. Based on the similarity between spontaneously arising anti-DNA Abs and several types of induced anti-DNA Abs, we suggest that there may be more than a single Ag that can trigger systemic lupus erythematosus.