Aktuelle Publikationen

Andre Dik, Roja Saffari, Mingyue Zhang, Weiqi Zhang (2018) Contradictory effects of erythropoietin on inhibitory synaptic transmission in left and right prelimbic cortex of mice. Neurobiology of Stress  9: 113-123; doi: 10.1016/j.ynstr.2018.08.008.

Abstract:

Erythropoietin (EPO) has been shown to improve cognitive function in mammals as well as in patients of psychiatric diseases by directly acting on the brain. In addition, EPO attenuates the synaptic transmission and enhances short- and long-term synaptic plasticity in hippocampus of mice, although there are still many discrepancies between different studies. It has been suggested that the divergences of different studies take root in different in-vivo application schemata or in long-term trophic effects of EPO. In the current study, we investigated the direct effects of EPO in slices of prelimbic cortex (PrL) by acute ex-vivo application of EPO, so that the erythropoietic or other trophic effects could be entirely excluded. Our results showed that the EPO effects were contradictory between the left and the right PrL. It enhanced the inhibitory transmission in the left and depressed the inhibitory transmission in the right PrL. Strikingly, this lateralized effect of EPO could be consistently found in individual bi-lateral PrL of all tested mice. Thus, our data suggest that EPO differentially modulates the inhibitory synaptic transmission of neuronal networks in the left and the right PrL. We hypothesize that such lateralized effects of EPO contribute to the development of the lateralization of stress reaction in PFC and underlie the altered bilateral GAGAergic synaptic transmission and oscillation patterns under stress that impact the central emotional and cognitive control in physiology as well as in pathophysiology.

Ilona Schneider, Harald Kugel, Ronny Redlich, Dominik Grotegerd, Christian Bürger, Paul-Christian Bürkner, Nils Opel, Katharina Dohm, Dario Zaremba, Susanne Meinert, Nina Schröder, Anna Milena Straßburg, Kathrin Schwarte, Christiane Schettler, Oliver Ambrée, Stephan Rust, Katharina Domschke, Volker Arolt, Walter Heindel, Bernhard T Baune, Weiqi Zhang, Udo Dannlowski, Christa Hohoff (in press) Association of Serotonin Transporter Gene AluJb Methylation with Major Depression, Amygdala Responsiveness, 5-HTTLPR/rs25531 Polymorphism, and Stress. Neuropsychopharmacology doi: 10.1038/npp.2017.273.

Abstract:

DNA methylation profiles of the serotonin transporter gene (SLC6A4) have been shown to alter SLC6A4 expression, drive antidepressant treatment response and modify brain functions. This study investigated whether methylation of an AluJb element in the SLC6A4 promotor was associated with major depressive disorder (MDD), amygdala reactivity to emotional faces, 5-HTTLPR/rs25531 polymorphism, and recent stress. MDD patients (n=122) and healthy controls (HC, n=176) underwent fMRI during an emotional face-matching task. Individual SLC6A4 AluJb methylation profiles were ascertained and associated with MDD, amygdala reactivity, 5-HTTLPR/rs25531, and stress. SLC6A4 AluJb methylation was significantly lower in MDD compared to HC and in stressed compared to less stressed participants. Lower AluJb methylation was particularly found in 5-HTTLPR/rs25531 risk allele carriers under stress and correlated with less depressive episodes. fMRI analysis revealed a significant interaction of AluJb methylation and diagnosis in the amygdala, with MDD patients showing lower AluJb methylation associated with decreased amygdala reactivity. While no joint effect of AluJb methylation and 5-HTTLPR/rs25531 existed, risk allele carriers showed significantly increased bilateral amygdala activation. These findings suggest a role of SLC6A4 AluJb methylation in MDD, amygdala reactivity, and stress reaction, partly interwoven with 5-HTTLPR/rs25531 effects. Patients with low methylation in conjunction with a shorter MDD history and decreased amygdala reactivity might feature a more stress-adaptive epigenetic process, maybe via theoretically possible endogenous antidepressant-like effects. In contrast, patients with higher methylation might possibly suffer from impaired epigenetic adaption to chronic stress. Further, the 5-HTTLPR/rs25531 association with amygdala activation was confirmed in our large sample.

M. Wehr, W. Hinrichs, M. Brzózka, T. Unterbarnscheidt, Al. Herholt, J. Wintgens, S. Papiol, M. Soto-Bernardini, M. Kravchenko, M. Zhang, K-A Nave, S. Wichert, P. Falkai, W. Zhang, M. Schwab & M. Rossner (2017) Spironolactone is an antagonist of NRG1-ERBB4 signaling and schizophrenia-relevant endophenotypes in mice. EMBO Molecular Medicine e201707691; DOI 10.15252/emmm.201707691

Abstract:

Enhanced NRG1‐ERBB4 signaling is a risk pathway in schizophrenia, and corresponding mouse models display several endophenotypes of the disease. Nonetheless, pathway‐directed treatment strategies with clinically applicable compounds have not been identified. Here, we applied a cell‐based assay using the split TEV technology to screen a library of clinically applicable compounds to identify modulators of NRG1‐ERBB4 signaling for repurposing. We recovered spironolactone, known as antagonist of corticosteroids, as an inhibitor of the ERBB4 receptor and tested it in pharmacological and biochemical assays to assess secondary compound actions. Transgenic mice overexpressing Nrg1 type III display cortical Erbb4 hyperphosphorylation, a condition observed in postmortem brains from schizophrenia patients. Spironolactone treatment reverted hyperphosphorylation of activated Erbb4 in these mice. In behavioral tests, spironolactone treatment of Nrg1 type III transgenic mice ameliorated schizophrenia‐relevant behavioral endophenotypes, such as reduced sensorimotor gating, hyperactivity, and impaired working memory. Moreover, spironolactone increases spontaneous inhibitory postsynaptic currents in cortical slices supporting an ERBB4‐mediated mode‐of‐action. Our findings suggest that spironolactone, a clinically safe drug, provides an opportunity for new treatment options for schizophrenia.

Jens Buschert, Marna E. Sakalem, Roja Saffari, Christa Hohoff, Matthias Rothermundt, Volker Arolt, Weiqi Zhang, Oliver Ambrée (2016) Prenatal immune activation in mice blocks the effects of environmental enrichment on exploratory behavior and microglia density. Neuro-psychopharmacology & Biological Psychiatry 67:10–20Abstract: Adverse environmental factors including prenatal maternal infection are capable of inducing long-lasting behavioral and neural alterations which can enhance the risk to develop schizophrenia. It is so far not clear whether supportive postnatal environments are able to modify such prenatally-induced alterations. In rodent models, environmental enrichment influences behavior and cognition, for instance by affecting endocrinologic, immunologic, and neuroplastic parameters. The current study was designed to elucidate the influence of postnatal environmental enrichment on schizophrenia-like behavioral alterations induced by prenatal polyI:C immune stimulation at gestational day 9 in mice. Adult offspring were tested for amphetamine-induced locomotion, social interaction, and problem-solving behavior as well as expression of dopamine D1 and D2 receptors and associated molecules, microglia density and adult neurogenesis. Prenatal polyI:C treatment resulted in increased dopamine sensitivity and dopamine D2 receptor expression in adult offspring which was not reversed by environmental enrichment. Prenatal immune activation prevented the effects of environmental enrichment which increased exploratory behavior and microglia density in NaCl treated mice. Problem-solving behavior as well as the number of immature neurons was affected by neither prenatal immune stimulation nor postnatal environmental enrichment. The behavioral and neural alterations that persist into adulthood could not generally be modified by environmental enrichment. This might be due to early neurodevelopmental disturbances which could not be res- cued or compensated for at a later developmental stage. 
Saffari R, Teng Z, Zhang M, Kravchenko M, Hohoff C, Ambrée O, Zhang W (2016) NPY+-, but not PV+-GABAergic neurons mediated long-range inhibition from infra- to prelimbic cortex. Transl Psychiatry 6:e736.Abstract:Anxiety disorders are thought to reflect deficits in the regulation of fear memories. While the amygdala has long been considered a site of storage of fear memories, newer findings suggest that the prefrontal cortex (PFC) is essential in the regulation of amygdala-dependent memories and fear expression. Here, activation of the prelimbic cortex (PrL) enhances the expression of fear, while an elevated activity in the infralimbic cortex (IL) enhances fear extinction. Despite the presence of these facts, we still know very little about the synaptic interconnectivity within the PFC. The aim of the present study was to investigate the inhibitory circuits between prelimbic and IL using morphological and electrophysiological methods. Our immunohistochemical analysis revealed that the distribution of PV+- and NPY+-GABAergic neurons was strikingly different within the PFC. In addition, we provided the first experimental evidence that the pyramidal neurons in the PrL received a direct inhibitory input mediated by bipolar NPY+-GABAergic projection neurons in the IL. Deletion of the anxiety-related neuroligin 2 gene caused a decrease of this direct synaptic inhibition that originated from the IL. Thus, our data suggested that activation of the IL might not only directly activate the corresponding downstream anxiolytic pathway, but also suppress the PrL-related anxiogenic pathway and thus could differentially bias the regulation of fear expression and extinction.