Publications by authors named "Hannelore Ehrenreich"

166 Publications

Inducing sterile pyramidal neuronal death in mice to model distinct aspects of gray matter encephalitis.

Acta Neuropathol Commun 2021 07 2;9(1):121. Epub 2021 Jul 2.

Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Hermann-Rein-Str.3, 37075, Göttingen, Germany.

Up to one person in a population of 10,000 is diagnosed once in lifetime with an encephalitis, in 50-70% of unknown origin. Recognized causes amount to 20-50% viral infections. Approximately one third of affected subjects develops moderate and severe subsequent damage. Several neurotropic viruses can directly infect pyramidal neurons and induce neuronal death in cortex and hippocampus. The resulting encephalitic syndromes are frequently associated with cognitive deterioration and dementia, but involve numerous parallel and downstream cellular and molecular events that make the interpretation of direct consequences of sudden pyramidal neuronal loss difficult. This, however, would be pivotal for understanding how neuroinflammatory processes initiate the development of neurodegeneration, and thus for targeted prophylactic and therapeutic interventions. Here we utilized adult male NexCreERT2xRosa26-eGFP-DTA (= 'DTA') mice for the induction of a sterile encephalitis by diphtheria toxin-mediated ablation of cortical and hippocampal pyramidal neurons which also recruits immune cells into gray matter. We report multifaceted aftereffects of this defined process, including the expected pathology of classical hippocampal behaviors, evaluated in Morris water maze, but also of (pre)frontal circuit function, assessed by prepulse inhibition. Importantly, we modelled in encephalitis mice novel translationally relevant sequelae, namely altered social interaction/cognition, accompanied by compromised thermoreaction to social stimuli as convenient readout of parallel autonomic nervous system (dys)function. High resolution magnetic resonance imaging disclosed distinct abnormalities in brain dimensions, including cortical and hippocampal layering, as well as of cerebral blood flow and volume. Fluorescent tracer injection, immunohistochemistry and brain flow cytometry revealed persistent blood-brain-barrier perturbance and chronic brain inflammation. Surprisingly, blood flow cytometry showed no abnormalities in circulating major immune cell subsets and plasma high-mobility group box 1 (HMGB1) as proinflammatory marker remained unchanged. The present experimental work, analyzing multidimensional outcomes of direct pyramidal neuronal loss, will open new avenues for urgently needed encephalitis research.
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http://dx.doi.org/10.1186/s40478-021-01214-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253243PMC
July 2021

Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders.

Biol Psychiatry 2021 Mar 23. Epub 2021 Mar 23.

Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, Illinois; Department of Psychiatry and Behavioral Sciences, North Shore University Health System, Evanston, Illinois.

Background: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk.

Methods: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH.

Results: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10; rs73033497, p = 8.8 × 10; rs7914279, p = 6.4 × 10), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05).

Conclusions: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.
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http://dx.doi.org/10.1016/j.biopsych.2021.02.972DOI Listing
March 2021

Autoantibodies against the NMDAR subunit NR1 are associated with neuropsychiatric outcome after ischemic stroke.

Brain Behav Immun 2021 Aug 16;96:73-79. Epub 2021 May 16.

Department of Neurology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. Electronic address:

Background And Purpose: Preexisting autoantibodies against N-methyl-D-aspartate-receptor subunit NR1 (NMDAR1-AB) in acute ischemic stroke patients with previously intact blood-brain-barrier were associated with smaller evolution of lesion size. Effects of chronic exposure to NMDAR1-AB long after stroke, however, have remained unclear. We investigated in a prospective follow-up study whether long-term neuropsychiatric outcome after stroke differs depending on NMDAR1-AB status.

Methods: Blood samples for NMDAR1-AB analysis were collected within 24 h after ischemic stroke from n = 114 patients. Outcome was assessed 1-3 years later using NIHSS, modified Rankin-scale, Barthel-Index, RBANS (Repeatable Battery for the Assessment of Neuropsychological Status) subcategories (immediate/delayed memory, attention, visuoconstruction), anamnesis evaluating neuropsychiatric symptoms (e.g. hallucinations, psychomotor slowing, reduced alertness, depressiveness, fatigue) and questionnaires (Beck's Depression Inventory-BDI, Fatigue Impact Scale-FIS). Scores were generated to cover RBANS plus neuropsychiatric symptoms (Score A; n = 96) or only neuropsychiatric symptoms (Score B; n = 114, including patients unable to conduct RBANS). Depression/fatigue were measured in patients, capable to perform questionnaires (n = 86).

Results: NMDAR1-AB (IgM, IgA, IgG) were detected in n = 27 patients (23.7%). NMDAR1-AB seropositive patients showed inferior results in Score A (p = 0.006), Score B (p = 0.004), BDI (p = 0.013) and FIS (p = 0.018), compared to seronegative patients. Multiple regression analysis including covariates age, NIHSS at day 7 post-stroke, and days from stroke to follow-up, showed NMDAR1-AB seropositivity associated with worse outcome in Scores A (b: 1.517, 95%CI: 0.505-2.529, p = 0.004) and B (b: 0.803, 95%CI: 0.233-1.373; p = 0.006). Also FIS was unfavorably associated with NMDAR1-AB seropositivity (binary logistic regression: OR: 3.904, 95%CI: 1.200-12.695; p = 0.024).

Conclusions: Even though the numbers of included patients are low, our data apparently indicate that NMDAR1-AB seropositivity at the time point of acute ischemic stroke is associated with neuropsychiatric symptoms including cognitive dysfunction and fatigue years after stroke. Preclinical proof of a causal relation provided, targeted immunosuppression may be a future prophylactic option to be clinically evaluated.
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http://dx.doi.org/10.1016/j.bbi.2021.05.011DOI Listing
August 2021

Effect of Early Recombinant Human Erythropoietin on Neurodevelopmental Outcomes at Age 5 Years.

JAMA 2021 04;325(14):1470-1471

Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

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http://dx.doi.org/10.1001/jama.2021.0833DOI Listing
April 2021

Preadult polytoxicomania-strong environmental underpinnings and first genetic hints.

Mol Psychiatry 2021 Apr 7. Epub 2021 Apr 7.

Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.

Considering the immense societal and personal costs and suffering associated with multiple drug use or "polytoxicomania", better understanding of environmental and genetic causes is crucial. While previous studies focused on single risk factors and selected drugs, effects of early-accumulated environmental risks on polytoxicomania were never addressed. Similarly, evidence of genetic susceptibility to particular drugs is abundant, while genetic predisposition to polytoxicomania is unexplored. We exploited the GRAS data collection, comprising information on N~2000 deep-phenotyped schizophrenia patients, to investigate effects of early-life environmental risk accumulation on polytoxicomania and additionally provide first genetic insight. Preadult accumulation of environmental risks (physical or sexual abuse, urbanicity, migration, cannabis, alcohol) was strongly associated with lifetime polytoxicomania (p  = 1.5 × 10; OR = 31.4), preadult polytoxicomania with OR = 226.6 (p = 1.0 × 10) and adult polytoxicomania with OR = 17.5 (p = 3.4 × 10). Parallel accessibility of genetic data from GRAS patients and N~2100 controls for genome-wide association (GWAS) and phenotype-based genetic association studies (PGAS) permitted the creation of a novel multiple GWAS-PGAS approach. This approach yielded 41 intuitively interesting SNPs, potentially conferring liability to preadult polytoxicomania, which await replication upon availability of suitable deep-phenotyped cohorts anywhere world-wide. Concisely, juvenile environmental risk accumulation, including cannabis and alcohol as starter/gateway drugs, strongly predicts polytoxicomania during adolescence and adulthood. This pivotal message should launch more effective sociopolitical measures to prevent this deleterious psychiatric condition.
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http://dx.doi.org/10.1038/s41380-021-01069-2DOI Listing
April 2021

CaMKIIα Expressing Neurons to Report Activity-Related Endogenous Hypoxia upon Motor-Cognitive Challenge.

Int J Mol Sci 2021 Mar 20;22(6). Epub 2021 Mar 20.

Clinical Neuroscience, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany.

We previously introduced the brain erythropoietin (EPO) circle as a model to explain the adaptive 'brain hardware upgrade' and enhanced performance. In this fundamental circle, brain cells, challenged by motor-cognitive tasks, experience functional hypoxia, triggering the expression of EPO among other genes. We attested hypoxic cells by a transgenic reporter approach under the ubiquitous CAG promoter, with Hif-1α oxygen-dependent degradation-domain (ODD) fused to CreERT2-recombinase. To specifically focus on the functional hypoxia of excitatory pyramidal neurons, here, we generated CaMKIIα-CreERT2-ODD::R26R-tdTomato mice. Behavioral challenges, light-sheet microscopy, immunohistochemistry, single-cell mRNA-seq, and neuronal cultures under normoxia or hypoxia served to portray these mice. Upon complex running wheel performance as the motor-cognitive task, a distinct increase in functional hypoxic neurons was assessed immunohistochemically and confirmed three-dimensionally. In contrast, fear conditioning as hippocampal stimulus was likely too short-lived to provoke neuronal hypoxia. Transcriptome data of hippocampus under normoxia versus inspiratory hypoxia revealed increases in CA1 CaMKIIα-neurons with an immature signature, characterized by the expression of α, , and , and consistent with accelerated differentiation. The hypoxia reporter response was reproduced in vitro upon neuronal maturation. To conclude, task-associated activity triggers neuronal functional hypoxia as a local and brain-wide reaction mediating adaptive neuroplasticity. Hypoxia-induced genes such as EPO drive neuronal differentiation, brain maturation, and improved performance.
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http://dx.doi.org/10.3390/ijms22063164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003772PMC
March 2021

Hippocampal neurons respond to brain activity with functional hypoxia.

Mol Psychiatry 2021 Feb 9. Epub 2021 Feb 9.

Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.

Physical activity and cognitive challenge are established non-invasive methods to induce comprehensive brain activation and thereby improve global brain function including mood and emotional well-being in healthy subjects and in patients. However, the mechanisms underlying this experimental and clinical observation and broadly exploited therapeutic tool are still widely obscure. Here we show in the behaving brain that physiological (endogenous) hypoxia is likely a respective lead mechanism, regulating hippocampal plasticity via adaptive gene expression. A refined transgenic approach in mice, utilizing the oxygen-dependent degradation (ODD) domain of HIF-1α fused to CreERT2 recombinase, allows us to demonstrate hypoxic cells in the performing brain under normoxia and motor-cognitive challenge, and spatially map them by light-sheet microscopy, all in comparison to inspiratory hypoxia as strong positive control. We report that a complex motor-cognitive challenge causes hypoxia across essentially all brain areas, with hypoxic neurons particularly abundant in the hippocampus. These data suggest an intriguing model of neuroplasticity, in which a specific task-associated neuronal activity triggers mild hypoxia as a local neuron-specific as well as a brain-wide response, comprising indirectly activated neurons and non-neuronal cells.
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http://dx.doi.org/10.1038/s41380-020-00988-wDOI Listing
February 2021

Spontaneous serum autoantibody fluctuations: To be or not to be.

Mol Psychiatry 2020 Sep 23. Epub 2020 Sep 23.

Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.

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http://dx.doi.org/10.1038/s41380-020-00883-4DOI Listing
September 2020

Erythropoietin as candidate for supportive treatment of severe COVID-19.

Mol Med 2020 06 16;26(1):58. Epub 2020 Jun 16.

Psychiatric Centre Copenhagen, University Hospital, Rigshospitalet, Copenhagen, Denmark.

In light of the present therapeutic situation in COVID-19, any measure to improve course and outcome of seriously affected individuals is of utmost importance. We recap here evidence that supports the use of human recombinant erythropoietin (EPO) for ameliorating course and outcome of seriously ill COVID-19 patients. This brief expert review grounds on available subject-relevant literature searched until May 14, 2020, including Medline, Google Scholar, and preprint servers. We delineate in brief sections, each introduced by a summary of respective COVID-19 references, how EPO may target a number of the gravest sequelae of these patients. EPO is expected to: (1) improve respiration at several levels including lung, brainstem, spinal cord and respiratory muscles; (2) counteract overshooting inflammation caused by cytokine storm/ inflammasome; (3) act neuroprotective and neuroregenerative in brain and peripheral nervous system. Based on this accumulating experimental and clinical evidence, we finally provide the research design for a double-blind placebo-controlled randomized clinical trial including severely affected patients, which is planned to start shortly.
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http://dx.doi.org/10.1186/s10020-020-00186-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297268PMC
June 2020

Accumulated environmental risk in young refugees - A prospective evaluation.

EClinicalMedicine 2020 May 11;22:100345. Epub 2020 May 11.

Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.

Background: Recently, we reported a strong, disease-independent relationship between accumulated preadult environmental risks and violent aggression later in life. Risk factors were interchangeable, and migration was among the explored risks. Alarmed by these data, we assessed collected risk load in young 'healthy' refugees as a specific subgroup of current migration streams and evaluated first signals of behavioral abnormalities.

Methods: In 9 German refugee centers,  = 133 young refugees, not previously in contact with the health system, were recruited, many of them unaccompanied minors. Risk factors experienced apart from migration/refuge were carefully assessed: Traumatic experiences before/during/after flight (including war, genocide, human trafficking, torture, murder, slavery, terrorist attacks), urbanicity, physical and sexual abuse, problematic alcohol and cannabis use (lifetime). Evaluation comprised physical exam and psychopathology screening.

Findings: Refugees arrived in Germany via Eastern Mediterranean/Balkan route (34.6%), from Africa via Central Mediterranean route (39.1%), by plane (17.3%) or other routes, such as Western Mediterranean or Atlantic (9.0%). Flight reasons were war/expulsion (25.6%), persecution/threats to life (51.9%), economical/others (22.5%). On top of migration/refuge, 42.8% of subjects had ≥3 risk factors; only 4.5% of refugees had no additional risks. Global level of functioning and severity of psychopathology were strongly associated with number of accumulated risks (Jonckheere-Terpstra trend-test:  = 7.61 × 10 and  = 3.62 × 10, respectively).

Interpretation: Young refugees, arriving in hosting countries with alarming 'risk burden', should be considered as highly vulnerable towards development of global functional deficits, behavioral abnormalities, and neuropsychiatric disorders. Rapid proactive integration or sustainable support of those who will return to rebuild their countries are mandatory.

Funding: The Max Planck Society supported this work.
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http://dx.doi.org/10.1016/j.eclinm.2020.100345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264975PMC
May 2020

Erythropoietin in Preterm Infants.

N Engl J Med 2020 05;382(19):1862

Copenhagen University Hospital, Copenhagen, Denmark.

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http://dx.doi.org/10.1056/NEJMc2002493DOI Listing
May 2020

Functional hypoxia drives neuroplasticity and neurogenesis via brain erythropoietin.

Nat Commun 2020 03 9;11(1):1313. Epub 2020 Mar 9.

Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.

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. Single-cell 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.
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http://dx.doi.org/10.1038/s41467-020-15041-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062779PMC
March 2020

Vascular response to social cognitive performance measured by infrared thermography: A translational study from mouse to man.

FASEB Bioadv 2020 Jan 23;2(1):18-32. Epub 2019 Dec 23.

Clinical Neuroscience Max Planck Institute of Experimental Medicine Göttingen Germany.

To assess complex social recognition in mice, we previously developed the paradigm. Unexpectedly, 4 weeks after performing in the mice displayed robust social avoidance during Y-maze sociability testing. This unique "sociophobia" acquisition could be documented in independent cohorts. We therefore employed infrared thermography as a non-invasive method of stress-monitoring during testing (presentation of five other mice) versus empty box. A higher (body/tail temperature) in the correlated negatively with social recognition memory and, after 4 weeks, with social preference in the Y-maze. Assuming that social stimuli might be associated with characteristic thermo-responses, we exposed healthy men (N = 103) with a comparably high intelligence level to a standardized test session including two cognitive tests with or without social component (face versus pattern recognition). In some analogy to the (within-subject measure) used in mice, the (ratio nose/malar cheek temperature) was introduced to determine the autonomic facial response/flushing during social recognition testing. Whereas cognitive performance and salivary cortisol were comparable across human subjects and tests, the was associated with a characteristic profile. Infrared thermography may have potential for discriminating disturbed social behaviors.
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http://dx.doi.org/10.1096/fba.2019-00085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996302PMC
January 2020

Multiple inducers and novel roles of autoantibodies against the obligatory NMDAR subunit NR1: a translational study from chronic life stress to brain injury.

Mol Psychiatry 2020 Feb 24. Epub 2020 Feb 24.

Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.

Circulating autoantibodies (AB) of different immunoglobulin classes (IgM, IgA, and IgG), directed against the obligatory N-methyl-D-aspartate-receptor subunit NR1 (NMDAR1-AB), belong to the mammalian autoimmune repertoire, and appear with age-dependently high seroprevalence across health and disease. Upon access to the brain, they can exert NMDAR-antagonistic/ketamine-like actions. Still unanswered key questions, addressed here, are conditions of NMDAR1-AB formation/boosting, intraindividual persistence/course in serum over time, and (patho)physiological significance of NMDAR1-AB in modulating neuropsychiatric phenotypes. We demonstrate in a translational fashion from mouse to human that (1) serum NMDAR1-AB fluctuate upon long-term observation, independent of blood-brain barrier (BBB) perturbation; (2) a standardized small brain lesion in juvenile mice leads to increased NMDAR1-AB seroprevalence (IgM + IgG), together with enhanced Ig-class diversity; (3) CTLA4 (immune-checkpoint) genotypes, previously found associated with autoimmune disease, predispose to serum NMDAR1-AB in humans; (4) finally, pursuing our prior findings of an early increase in NMDAR1-AB seroprevalence in human migrants, which implicated chronic life stress as inducer, we independently replicate these results with prospectively recruited refugee minors. Most importantly, we here provide the first experimental evidence in mice of chronic life stress promoting serum NMDAR1-AB (IgA). Strikingly, stress-induced depressive-like behavior in mice and depression/anxiety in humans are reduced in NMDAR1-AB carriers with compromised BBB where NMDAR1-AB can readily reach the brain. To conclude, NMDAR1-AB may have a role as endogenous NMDAR antagonists, formed or boosted under various circumstances, ranging from genetic predisposition to, e.g., tumors, infection, brain injury, and stress, altogether increasing over lifetime, and exerting a spectrum of possible effects, also including beneficial functions.
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http://dx.doi.org/10.1038/s41380-020-0672-1DOI Listing
February 2020

Genetically induced brain inflammation by deletion transiently benefits from microglia depletion.

FASEB J 2019 07 15;33(7):8634-8647. Epub 2019 May 15.

Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.

Reduced expression of 2'-3'-cyclic nucleotide 3'-phosphodiesterase () in humans and mice causes white matter inflammation and catatonic signs. These consequences are experimentally alleviated by microglia ablation colony-stimulating factor 1 receptor (CSF1R) inhibition using PLX5622. Here we address for the first time preclinical topics crucial for translation, most importantly ) the comparison of 2 long-term PLX5622 applications (prevention and treatment) 1 treatment alone, ) the correlation of catatonic signs and executive dysfunction, ) the phenotype of leftover microglia evading depletion, and ) the role of intercellular interactions for efficient CSF1R inhibition. Based on our mouse model and time-lapse imaging, we report the unexpected discovery that microglia surviving under PLX5622 display a highly inflammatory phenotype including aggressive premortal phagocytosis of oligodendrocyte precursor cells. Interestingly, ablating microglia requires mixed glial cultures, whereas cultured pure microglia withstand PLX5622 application. Importantly, 2 extended rounds of CSF1R inhibition are not superior to 1 treatment regarding any readout investigated (magnetic resonance imaging and magnetic resonance spectroscopy, behavior, immunohistochemistry). Catatonia-related executive dysfunction and brain atrophy of mice fail to improve under PLX5622. To conclude, even though microglia depletion is temporarily beneficial and worth pursuing, complementary treatment strategies are needed for full and lasting recovery.-Fernandez Garcia-Agudo, L., Janova, H., Sendler, L. E., Arinrad, S., Steixner, A. A., Hassouna, I., Balmuth, E., Ronnenberg, A., Schopf, N., van der Flier, F. J., Begemann, M., Martens, H., Weber, M. S., Boretius, S., Nave, K.-A., Ehrenreich, H. Genetically induced brain inflammation by deletion transiently benefits from microglia depletion.
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http://dx.doi.org/10.1096/fj.201900337RDOI Listing
July 2019

Time to revisit oligodendrocytes in multiple sclerosis.

Nat Med 2019 03;25(3):364-366

Max Planck Institute of Experimental Medicine, Göttingen, Germany.

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http://dx.doi.org/10.1038/s41591-019-0388-4DOI Listing
March 2019

IgSF9b regulates anxiety behaviors through effects on centromedial amygdala inhibitory synapses.

Nat Commun 2018 12 20;9(1):5400. Epub 2018 Dec 20.

Department of Molecular Neurobiology, Max Planck Institute of Experimental Medicine, 37075, Göttingen, Germany.

Abnormalities in synaptic inhibition play a critical role in psychiatric disorders, and accordingly, it is essential to understand the molecular mechanisms linking components of the inhibitory postsynapse to psychiatrically relevant neural circuits and behaviors. Here we study the role of IgSF9b, an adhesion protein that has been associated with affective disorders, in the amygdala anxiety circuitry. We show that deletion of IgSF9b normalizes anxiety-related behaviors and neural processing in mice lacking the synapse organizer Neuroligin-2 (Nlgn2), which was proposed to complex with IgSF9b. This normalization occurs through differential effects of Nlgn2 and IgSF9b at inhibitory synapses in the basal and centromedial amygdala (CeM), respectively. Moreover, deletion of IgSF9b in the CeM of adult Nlgn2 knockout mice has a prominent anxiolytic effect. Our data place IgSF9b as a key regulator of inhibition in the amygdala and indicate that IgSF9b-expressing synapses in the CeM may represent a target for anxiolytic therapies.
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http://dx.doi.org/10.1038/s41467-018-07762-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6302093PMC
December 2018

Effects of recombinant human erythropoietin on cognition and neural activity in remitted patients with mood disorders and first-degree relatives of patients with psychiatric disorders: a study protocol for a randomized controlled trial.

Trials 2018 Nov 6;19(1):611. Epub 2018 Nov 6.

Neurocognition and Emotion in Affective Disorder (NEAD) Group, Copenhagen Affective Disorder Research Centre (CADIC), Psychiatric Centre Copenhagen, Copenhagen University Hospital, Blegdamsvej 9, DK-2100, Copenhagen, Denmark.

Background: Bipolar disorder (BD) and unipolar disorder (UD) are associated with cognitive deficits and abnormal neural activity in a "cognitive control network." There is an increased prevalence of cognitive dysfunction in psychiatric patients' first-degree relatives, which constitutes a risk factor for psychiatric illness onset. However, there is no treatment with enduring pro-cognitive efficacy. We found preliminary evidence for beneficial effects of eight weekly doses of recombinant human erythropoietin (EPO) on cognition in BD in a recent randomized controlled trial (RCT). The present RCT consists of two sub-studies that extend our previous work by investigating important novel aspects: (1) the effects of 12 weekly doses of EPO on cognition in first-degree relatives of patients with BD, UD, or schizophrenia; and (2) the effects of extending the treatment schedule from 8 to 12 weeks in remitted patients with BD or UD; and (3) assessment of early treatment-associated neural activity changes that may predict cognitive improvement.

Methods: The trial comprises two parallel sub-studies with randomized, controlled, double-blinded, parallel group designs. First-degree relatives (sub-study 1; n = 52) and partially or fully remitted patients with BD or UD (sub-study 2; n = 52) with objectively verified cognitive dysfunction are randomized to receive weekly high-dose EPO (40,000 IU/mL) or placebo (saline) infusions for 12 weeks. Assessments of cognition and mood are conducted at baseline, after two weeks of treatment, after treatment completion, and at six-month follow-up. Functional magnetic resonance imaging (fMRI) is conducted at baseline and after two weeks of treatment. Psychosocial function is assessed at baseline, after treatment completion and six-month follow-up. The primary outcome is change in a cognitive composite score of attention, verbal memory, and executive functions. Statistical power of ≥ 80% is reached to detect a clinically relevant between-group difference by including 52 first-degree relatives and 52 patients with BD or UD, respectively. Behavioral data are analyzed with an intention-to-treat approach using mixed models. fMRI data are analyzed with the FMRIB Software Library.

Discussion: If this trial reveals pro-cognitive effects of EPO, this may influence future treatment of mood disorders and/or preventive strategies in at-risk populations. The fMRI analyses may unravel key neurobiological targets for pro-cognitive treatment.

Trial Registration: ClinicalTrials.gov , NCT03315897. Registered on 20 October 2017.
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http://dx.doi.org/10.1186/s13063-018-2995-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6220567PMC
November 2018

Excitation-inhibition dysbalance as predictor of autistic phenotypes.

J Psychiatr Res 2018 09 2;104:96-99. Epub 2018 Jun 2.

Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany. Electronic address:

Autistic traits are normally distributed across health and disease, with autism spectrum disorders (ASD) at the extreme end. As we learned from mutations of synaptic or synapse regulating genes, leading to monogenetic forms of autism, the heterogeneous etiologies of ASD converge at the synapse. They result in a mild synaptic dysfunction as the final common pathway, also addressed as synaptopathy. Based on genetic rodent models and EEG/MEG findings in autists, a neuronal excitation-inhibition dysbalance is considered autism-pathognomonic. We hypothesized that this objectively measurable consequence is not restricted to the diagnosis of ASD but transcends disease borders and is of quantitative rather than qualitative nature. For proof-of-principle, we conducted a transcranial magnetic stimulation (TMS) study, monitoring corticospinal excitability and intracortical inhibition of the motor cortex. Employing the GRAS data collection of N > 1200 deep-phenotyped schizophrenic subjects, we had the chance to select for this study N = 20 perfectly matched men. They differed highly significantly by autistic trait severity, as assessed using PANSS autism severity score (PAUSS), capturing the continuum of autistic behaviors. Applying TMS to these men, we provide first intriguing hints of a positive correlation of autistic phenotype severity with functional cortical correlates, mainly alterations in GABAergic system and ion channels. This 'dose-response relationship' between severity of autistic traits and excitation-inhibition ratio in non-ASD subjects underlines the biological basis of this continuous trait. Based on these data, TMS may evolve as new add-on biomarker of autistic traits across disease groups. Finally, common treatment strategies targeting the excitation-inhibition dysbalance in humans may develop. To ultimately achieve this goal, however, replication studies with larger numbers of individuals would be desirable.
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http://dx.doi.org/10.1016/j.jpsychires.2018.06.004DOI Listing
September 2018

Convergence of placenta biology and genetic risk for schizophrenia.

Nat Med 2018 06 28;24(6):792-801. Epub 2018 May 28.

Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.

Defining the environmental context in which genes enhance disease susceptibility can provide insight into the pathogenesis of complex disorders. We report that the intra-uterine environment modulates the association of schizophrenia with genomic risk (in this study, genome-wide association study-derived polygenic risk scores (PRSs)). In independent samples from the United States, Italy, and Germany, the liability of schizophrenia explained by PRS is more than five times greater in the presence of early-life complications (ELCs) compared with their absence. Patients with ELC histories have significantly higher PRS than patients without ELC histories, which is confirmed in additional samples from Germany and Japan. The gene set composed of schizophrenia loci that interact with ELCs is highly expressed in placenta, is differentially expressed in placentae from complicated in comparison with normal pregnancies, and is differentially upregulated in placentae from male compared with female offspring. Pathway analyses reveal that genes driving the PRS-ELC interaction are involved in cellular stress response; genes that do not drive such interaction implicate orthogonal biological processes (for example, synaptic function). We conclude that a subset of the most significant genetic variants associated with schizophrenia converge on a developmental trajectory sensitive to events that affect the placental response to stress, which may offer insights into sex biases and primary prevention.
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http://dx.doi.org/10.1038/s41591-018-0021-yDOI Listing
June 2018

Violent aggression predicted by multiple pre-adult environmental hits.

Mol Psychiatry 2019 10 24;24(10):1549-1564. Epub 2018 May 24.

Department of Psychiatry & Psychotherapy, University of Göttingen, Göttingen, Germany.

Early exposure to negative environmental impact shapes individual behavior and potentially contributes to any mental disease. We reported previously that accumulated environmental risk markedly decreases age at schizophrenia onset. Follow-up of matched extreme group individuals (≤1 vs. ≥3 risks) unexpectedly revealed that high-risk subjects had >5 times greater probability of forensic hospitalization. In line with longstanding sociological theories, we hypothesized that risk accumulation before adulthood induces violent aggression and criminal conduct, independent of mental illness. We determined in 6 independent cohorts (4 schizophrenia and 2 general population samples) pre-adult risk exposure, comprising urbanicity, migration, physical and sexual abuse as primary, and cannabis or alcohol as secondary hits. All single hits by themselves were marginally associated with higher violent aggression. Most strikingly, however, their accumulation strongly predicted violent aggression (odds ratio 10.5). An epigenome-wide association scan to detect differential methylation of blood-derived DNA of selected extreme group individuals yielded overall negative results. Conversely, determination in peripheral blood mononuclear cells of histone-deacetylase1 mRNA as 'umbrella mediator' of epigenetic processes revealed an increase in the high-risk group, suggesting lasting epigenetic alterations. Together, we provide sound evidence of a disease-independent unfortunate relationship between well-defined pre-adult environmental hits and violent aggression, calling for more efficient prevention.
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http://dx.doi.org/10.1038/s41380-018-0043-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756097PMC
October 2019

Cognitive, emotional and social phenotyping of mice in an observer-independent setting.

Neurobiol Learn Mem 2018 04 21;150:136-150. Epub 2018 Feb 21.

Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany; DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany. Electronic address:

Based on the intellicage paradigm, we have developed a novel cognitive, emotional and social phenotyping battery that permits comprehensive standardized behavioral characterization of mice in an experimenter-independent social setting. Evaluation of this battery in a large number of male and female C57BL/6 wildtype mice, tested in >20 independent cohorts, revealed high reproducibility of the behavioral readouts and may serve as future reference tool. We noticed robust sex-specific differences in general activity, cognitive and emotional behavior, but not regarding preference for social pheromones. Specifically, female mice revealed higher activity, decreased sucrose preference, impaired reversal and place-time-reward learning. Furthermore, female mice reacted more sensitively than males to reward-withdrawal showing a negative emotional contrast/Crespi-effect. In a series of validation experiments, we tested mice with different pathologies, including neuroligin-3 deficient mice (male Nlgn3 and female Nlgn3) for autistic behavior, oligodendrocyte-specific erythropoietin receptor knockout (oEpoR) mice for cognitive impairment, as well as mouse models of renal failure (unilateral ureteral obstruction and 5/6 nephrectomy) and of type 2 diabetes (ApoE) - for delineating potentially confounding effects of motivational factors (thirst, glucose-craving) on learning and memory assessments. As prominent features, we saw in Nlgn3 mutants reduced preference for social pheromones, whereas oEpoR mice showed learning deficits in place or reversal learning tasks. Renal failure led to increased water intake, and diabetic metabolism to enhanced glucose preference, limiting interpretation of hereon based learning and memory performance in these mice. The phenotyping battery presented here may be well-suited as high-throughput multifaceted diagnostic instrument for translational neuropsychiatry and behavioral genetics.
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http://dx.doi.org/10.1016/j.nlm.2018.02.023DOI Listing
April 2018

Autoantibodies against N-methyl-d-aspartate receptor 1 in health and disease.

Curr Opin Neurol 2018 06;31(3):306-312

Clinical Neuroscience, Max Planck Institute of Experimental Medicine.

Purpose Of Review: Humoral autoimmunity has gained highest interest in neurology and psychiatry. Despite numerous recent articles on this hot topic, however, the biological significance of natural autoantibodies (AB) and the normal autoimmune repertoire of mammals remained quite obscure. AB may contribute to disorder-relevant phenotypes and are even believed to induce diseases themselves, but the circumstances under which AB become pathogenic are not fully understood. This review will focus on the highly frequent AB against the N-methyl-d-aspartate receptor 1 (NMDAR1-AB) as an illustrating example and provide a critical overview of current work (please note that the new nomenclature, GluN1, is disregarded here for consistency with the AB literature). In particular, it will demonstrate how little is known at this point and how many conclusions are drawn based on small numbers of individuals, fragmentary experimental approaches or missing controls.

Recent Findings: NMDAR1-AB were investigated by clinicians world-wide with numerous small studies and case reports appearing yearly. Many publications were on 'anti-NMDAR encephalitis' cases or tried to separate those from other NMDAR1-AB associated conditions. Original exclusivity claims (e.g. electroencephalogram, EEG or functional magnetic resonance imaging, fMRI findings) turned out not to be exclusive for 'anti-NMDAR encephalitis'. Systematic analyses of representative NMDAR1-AB positive sera of all immunoglobulin (Ig) classes showed comparable distribution of different epitopes, often polyspecific/polyclonal, across health and disease. Sophisticated imaging tools provided findings on synapse trafficking changes induced by NMDAR1-AB from psychotic subjects but still lack epitope data to support any claimed disorder link. Persistently high titers of NMDAR1-AB (IgG) in immunized mice with open blood-brain barrier (BBB)-induced psychosis-like symptoms but failed to induce inflammation in the brain. Knowledge on peripheral NMDAR, for example in the immune system, and on potential inducers of NMDAR1-AB is only slowly increasing.

Summary: The present knowledge on the (patho) physiological role of NMDAR1-AB is very limited and still characterized by adamant rumors. Much more experimental work and more solid and informative clinical reports, including large numbers of subjects and adequate control groups, follow-up investigations and interdisciplinary approaches will be necessary to obtain a better understanding of the significance of humoral autoimmunity in general (in focus here: NMDAR1-AB) and its disease-relevance in particular.
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http://dx.doi.org/10.1097/WCO.0000000000000546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5959203PMC
June 2018

Uncoupling the widespread occurrence of anti-NMDAR1 autoantibodies from neuropsychiatric disease in a novel autoimmune model.

Mol Psychiatry 2019 10 9;24(10):1489-1501. Epub 2018 Feb 9.

Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.

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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http://dx.doi.org/10.1038/s41380-017-0011-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756099PMC
October 2019

A bloody brake on myelin repair.

Nature 2018 01;553(7686):31-32

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http://dx.doi.org/10.1038/d41586-017-08232-2DOI Listing
January 2018

A bloody brake on myelin repair.

Nature 2018 Jan;553(7686):31-32

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http://dx.doi.org/10.1038/d41586-017-08232-2DOI Listing
January 2018

Pursuing functional connectivity in NMDAR1 autoantibody carriers.

Lancet Psychiatry 2018 01;5(1):21-22

Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Hermann-Rein-Strasse 3, 37075 Goettingen, Germany. Electronic address:

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http://dx.doi.org/10.1016/S2215-0366(17)30465-0DOI Listing
January 2018

Microglia ablation alleviates myelin-associated catatonic signs in mice.

J Clin Invest 2018 02 18;128(2):734-745. Epub 2017 Dec 18.

DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany.

The underlying cellular mechanisms of catatonia, an executive "psychomotor" syndrome that is observed across neuropsychiatric diseases, have remained obscure. In humans and mice, reduced expression of the structural myelin protein CNP is associated with catatonic signs in an age-dependent manner, pointing to the involvement of myelin-producing oligodendrocytes. Here, we showed that the underlying cause of catatonic signs is the low-grade inflammation of white matter tracts, which marks a final common pathway in Cnp-deficient and other mutant mice with minor myelin abnormalities. The inhibitor of CSF1 receptor kinase signaling PLX5622 depleted microglia and alleviated the catatonic symptoms of Cnp mutants. Thus, microglia and low-grade inflammation of myelinated tracts emerged as the trigger of a previously unexplained mental condition. We observed a very high (25%) prevalence of individuals with catatonic signs in a deeply phenotyped schizophrenia sample (n = 1095). Additionally, we found the loss-of-function allele of a myelin-specific gene (CNP rs2070106-AA) associated with catatonia in 2 independent schizophrenia cohorts and also associated with white matter hyperintensities in a general population sample. Since the catatonic syndrome is likely a surrogate marker for other executive function defects, we suggest that microglia-directed therapies may be considered in psychiatric disorders associated with myelin abnormalities.
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http://dx.doi.org/10.1172/JCI97032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5785265PMC
February 2018

Impact of SSRI Therapy on Risk of Conversion From Mild Cognitive Impairment to Alzheimer's Dementia in Individuals With Previous Depression.

Am J Psychiatry 2018 03 28;175(3):232-241. Epub 2017 Nov 28.

From the Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany; the Department of Psychiatry and Psychotherapy and the Department of Neurodegenerative Diseases and Geriatric Psychiatry, University of Bonn, Bonn, Germany; the German Center for Neurodegenerative Diseases, Bonn; and the Max Planck Institute of Experimental Medicine, Göttingen.

Objective: Depression is associated with an increased risk of Alzheimer's disease. Research has shown that the selective serotonin reuptake inhibitor (SSRI) citalopram decreases amyloid-β generation and plaque load. The authors evaluated the impact of SSRI treatment on CSF biomarkers and progression from mild cognitive impairment (MCI) to Alzheimer's dementia.

Method: Data sets from 755 currently nondepressed participants from the longitudinal Alzheimer's Disease Neuroimaging Initiative were evaluated by Kaplan-Meier analysis and analyses of variance and covariance with ApoE4 status and age as covariates.

Results: In MCI patients with a history of depression, long-term SSRI treatment (>4 years) was significantly associated with a delayed progression to Alzheimer's dementia by approximately 3 years, compared with short-term SSRI treatment, treatment with other antidepressants, or no treatment and compared with MCI patients without a history of depression. No differences in CSF biomarker levels were observed between treatment groups.

Conclusions: Long-term SSRI treatment may delay progression from MCI to Alzheimer's dementia.
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http://dx.doi.org/10.1176/appi.ajp.2017.17040404DOI Listing
March 2018

„Hirn-Doping“: Erythropoietin zur Verbesserung kognitiver Leistung bei Mensch und Maus.

Drug Res (Stuttg) 2017 Nov 25;67(S 01):S14-S15. Epub 2017 Oct 25.

Klinische Neurowissenschaften, Max-Planck-Institut für Experimentelle Medizin, und DFG Forschungszentrum CNMPB, Göttingen.

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http://dx.doi.org/10.1055/s-0043-116529DOI Listing
November 2017
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