Recombinant human erythropoietin (EPO) improves cognitive performance in
neuropsychiatric diseases ranging from schizophrenia and multiple sclerosis to
major depression and bipolar disease. This consistent EPO effect on cognition is
independent of its role in hematopoiesis. The cellular mechanisms of action in
brain, however, have remained unclear. Here we studied healthy young mice and
observed that 3-week EPO administration was associated with an increased number
of pyramidal neurons and oligodendrocytes in the hippocampus of ~20%.
Under constant cognitive challenge, neuron numbers remained elevated until >6
months of age. Surprisingly, this increase occurred in absence of altered cell
proliferation or apoptosis. After feeding a 15N-leucine diet, we used
nanoscopic secondary ion mass spectrometry, and found that in EPO-treated mice,
an equivalent number of neurons was defined by elevated 15N-leucine
incorporation. In EPO-treated NG2-Cre-ERT2 mice, we confirmed enhanced
differentiation of preexisting oligodendrocyte precursors in the absence of
elevated DNA synthesis. A corresponding analysis of the neuronal lineage awaits
the identification of suitable neuronal markers. In cultured neurospheres, EPO
reduced Sox9 and stimulated miR124, associated with advanced neuronal
differentiation. We are discussing a resulting working model in which EPO drives
the differentiation of non-dividing precursors in both (NG2+)
oligodendroglial and neuronal lineages. As endogenous EPO expression is induced
by brain injury, such a mechanism of adult neurogenesis may be relevant for
central nervous system regeneration.
Background: Ceramide synthase 1 catalyzes the synthesis of C18 ceramide and is mainly expressed in neurons of the brain. Results: Ablation of ceramide synthase 1 decreases ganglioside levels and expression of oligodendrocytic myelin-associated glycoprotein in motor-impaired mice. Conclusion: CerS1-derived C18 gangliosides are essential for cerebellar development and neurodevelopmentally regulated behavior in mice. Significance: Neuronal gangliosides regulate expression of myelin-associated glycoprotein in oligodendrocytes.
Autoantibodies of the IgG class against N-methyl-D-aspartate-receptor subunit-NR1 (NMDAR1-AB) were considered pathognomonic for anti-NMDAR encephalitis. This view has been challenged by the age-dependent seroprevalence (up to >20%) of functional NMDAR1-AB of all immunoglobulin classes found in >5000 individuals, healthy or affected by different diseases. These findings question a merely encephalitogenic role of NMDAR1-AB. Here, we show that NMDAR1-AB belong to the normal autoimmune repertoire of dogs, cats, rats, mice, baboons, and rhesus macaques, and are functional in the NMDAR1 internalization assay based on human IPSC-derived cortical neurons. The age dependence of seroprevalence is lost in nonhuman primates in captivity and in human migrants, raising the intriguing possibility that chronic life stress may be related to NMDAR1-AB formation, predominantly of the IgA class. Active immunization of ApoE −/− and ApoE +/+ mice against four peptides of the extracellular NMDAR1 domain or ovalbumin (control) leads to high circulating levels of specific AB. After 4 weeks, the endogenously formed NMDAR1-AB (IgG) induce psychosis-like symptoms upon MK-801 challenge in ApoE −/− mice, characterized by an open blood-brain barrier, but not in their ApoE +/+ littermates, which are indistinguishable from ovalbumin controls. Importantly, NMDAR1-AB do not induce any sign of inflammation in the brain. Immunohistochemical staining for microglial activation markers and T lymphocytes in the hippocampus yields comparable results in ApoE −/− and ApoE +/+ mice, irrespective of immunization against NMDAR1 or ovalbumin. These data suggest that NMDAR1-AB of the IgG class shape behavioral phenotypes upon access to the brain but do not cause brain inflammation on their own.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.