Erythropoietin (EPO), named after its role in hematopoiesis, is also expressed in mammalian brain. In clinical settings, recombinant EPO treatment has revealed a remarkable improvement of cognition, but underlying mechanisms have remained obscure. Here, we show with a novel line of reporter mice that cognitive challenge induces local/endogenous hypoxia in hippocampal pyramidal neurons, hence enhancing expression of EPO and EPO receptor (EPOR). High-dose EPO administration, amplifying auto/paracrine EPO/EPOR signaling, prompts the emergence of new CA1 neurons and enhanced dendritic spine densities. Singlecell sequencing reveals rapid increase in newly differentiating neurons. Importantly, improved performance on complex running wheels after EPO is imitated by exposure to mild exogenous/inspiratory hypoxia. All these effects depend on neuronal expression of the Epor gene. This suggests a model of neuroplasticity in form of a fundamental regulatory circle, in which neuronal networks-challenged by cognitive tasks-drift into transient hypoxia, thereby triggering neuronal EPO/EPOR expression. 1 1234567890():,;E rythropoietin (EPO) is a hypoxia-inducible growth factor in mammalian kidney, named after its role in hematopoiesis 1,2 . Unexpectedly, both EPO and its receptor (EPOR) were later detected in the brain, where they are upregulated by injury conditions. High-dose recombinant human (rh) EPO, a drug in clinical use for anemic patients, exerts neuroprotective and neuroregenerative effects that are independent of the hematocrit, which is mechanistically unexplained 3-8 . Moreover, rhEPO improves cognitive function and reduces gray matter loss in a range of neuropsychiatric conditions 9-13 . Even in healthy mice, rhEPO treatment improves cognition, which is associated with enhanced hippocampal long-term potentiation [14][15][16] . Surprisingly, rhEPO increases the number of mature hippocampal pyramidal neurons without underlying effect on cell proliferation or cell death 17 . This effect is mediated in neurons mainly by JAK-STAT, PI3K/AKT/PKB, Ras-MEK, and ERK1/2, as well as NF-κB; pathways widely comparable to the hematopoietic system [18][19][20] . This raises the question whether the expression of EPO and its receptor serves a physiological function in the nervous system, and what could be the triggering factors of EPO expression under physiological conditions. ResultsGeneration of pyramidal neurons in adult mice and amplification by rhEPO. First, we developed a method to directly label and quantify newly generated neurons in the hippocampal cornu ammonis (CA) field of adult mice. This was possible by permanently labeling all mature pyramidal neurons present at P27 using a tamoxifen-inducible reporter gene in NexCreERT2::R26R-tdT mice (Fig. 1a, b) 21 . Thus, all neurons differentiating and maturing after termination of the tamoxifen-induced Cre recombination lack tdTomato, but can be positively identified by Ctip2, a specific marker of pyramidal neurons, thereby revealing adult 'neurogenesis' independent of DNA synt...

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.

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Two of the most common neurodegenerative disorders – Alzheimer’s and Parkinson’s diseases – are characterized by synaptic dysfunction and degeneration that culminate in neuronal loss due to abnormal protein accumulation. The intracellular aggregation of hyper-phosphorylated tau and the extracellular aggregation of amyloid beta plaques form the basis of Alzheimer’s disease pathology. The major hallmark of Parkinson’s disease is the loss of dopaminergic neurons in the substantia nigra pars compacta, following the formation of Lewy bodies, which consists primarily of alpha-synuclein aggregates. However, the discrete mechanisms that contribute to neurodegeneration in these disorders are still poorly understood. Both neuronal loss and impaired adult neurogenesis have been reported in animal models of these disorders. Yet these findings remain subject to frequent debate due to a lack of conclusive evidence in post mortem brain tissue from human patients. While some publications provide significant findings related to axonal regeneration in Alzheimer’s and Parkinson’s diseases, they also highlight the limitations and obstacles to the development of neuroregenerative therapies. In this review, we summarize in vitro and in vivo findings related to neurogenesis, neuroregeneration and neurodegeneration in the context of Alzheimer’s and Parkinson’s diseases.

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