Deletion of BDNF in Pax2 Lineage-Derived Interneuron Precursors in the Hindbrain Hampers the Proportion of Excitation/Inhibition, Learning, and Behavior

© 2021 Eckert, Marchetta, Manthey, Walter, Jovanovic, Savitska, Singer, Jacob, Rüttiger, Schimmang, Milenkovic, Pilz and Knipper.Numerous studies indicate that deficits in the proper integration or migration of specific GABAergic precursor cells from the subpallium to the cortex can lead to severe cognitive dysfunctions and neurodevelopmental pathogenesis linked to intellectual disabilities. A different set of GABAergic precursors cells that express Pax2 migrate to hindbrain regions, targeting, for example auditory or somatosensory brainstem regions. We demonstrate that the absence of BDNF in Pax2-lineage descendants of BdnfPax2KOs causes severe cognitive disabilities. In BdnfPax2KOs, a normal number of parvalbumin-positive interneurons (PV-INs) was found in the auditory cortex (AC) and hippocampal regions, which went hand in hand with reduced PV-labeling in neuropil domains and elevated activity-regulated cytoskeleton-associated protein (Arc/Arg3.1; here: Arc) levels in pyramidal neurons in these same regions. This immaturity in the inhibitory/excitatory balance of the AC and hippocampus was accompanied by elevated LTP, reduced (sound-induced) LTP/LTD adjustment, impaired learning, elevated anxiety, and deficits in social behavior, overall representing an autistic-like phenotype. Reduced tonic inhibitory strength and elevated spontaneous firing rates in dorsal cochlear nucleus (DCN) brainstem neurons in otherwise nearly normal hearing BdnfPax2KOs suggests that diminished fine-grained auditory-specific brainstem activity has hampered activity-driven integration of inhibitory networks of the AC in functional (hippocampal) circuits. This leads to an inability to scale hippocampal post-synapses during LTP/LTD plasticity. BDNF in Pax2-lineage descendants in lower brain regions should thus be considered as a novel candidate for contributing to the development of brain disorders, including autism.We acknowledge grants from the Deutsche Forschungsgemeins-chaft FOR 2060 project RU 713/3-2 (WS and LR), GRK 2381 (PM), SPP 1608 RU 316/12-1 (PE and LR), MI 954/3-1 (IM and SJ), KN 316/12-1 (MM and MK), BFU2016-76580-P (TS), and NIH NIMH 1R01MH106623 (MJ)

Anti-CD3 antibody treatment reduces scar formation in a rat model of myocardial infarction

Introduction: Antibody treatment with anti-thymocyte globulin (ATG) has been shown to be cardioprotective. We aimed to evaluate which single anti-T-cell epitope antibody alters chemokine expression at a level similar to ATG and identified CD3, which is a T-cell co-receptor mediating T-cell activation. Based on these results, the effects of anti-CD3 antibody treatment on angiogenesis and cardioprotection were tested in vitro and in vivo. Methods: Concentrations of IL-8 and MCP-1 in supernatants of human peripheral blood mononuclear cell (PBMC) cultures following distinct antibody treatments were evaluated by Enzyme-linked Immunosorbent Assay (ELISA). In vivo, anti-CD3 antibodies or vehicle were injected intravenously in rats subjected to acute myocardial infarction (AMI). Chemotaxis and angiogenesis were evaluated using tube and migration assays. Intracellular pathways were assessed using Western blot. Extracellular vesicles (EVs) were quantitatively evaluated using fluorescence-activated cell scanning, exoELISA, and nanoparticle tracking analysis. Also, microRNA profiles were determined by next-generation sequencing. Results: Only PBMC stimulation with anti-CD3 antibody led to IL-8 and MCP-1 changes in secretion, similar to ATG. In a rat model of AMI, systemic treatment with an anti-CD3 antibody markedly reduced infarct scar size (27.8% (Inter-quartile range; IQR 16.2–34.9) vs. 12.6% (IQR 8.3–27.2); p < 0.01). The secretomes of anti-CD3 treated PBMC neither induced cardioprotective pathways in cardiomyocytes nor pro-angiogenic mechanisms in human umbilical vein endothelial cell (HUVECs) in vitro. While EVs quantities remained unchanged, PBMC incubation with an anti-CD3 antibody led to alterations in EVs miRNA expression. Conclusion: Treatment with an anti-CD3 antibody led to decreased scar size in a rat model of AMI. Whereas cardioprotective and pro-angiogenetic pathways were unaltered by anti-CD3 treatment, qualitative changes in the EVs miRNA expression could be observed, which might be causal for the observed cardioprotective phenotype. We provide evidence that EVs are a potential cardioprotective treatment target. Our findings will also provide the basis for a more detailed analysis of putatively relevant miRNA candidates

Colon Capsule Endoscopy compared to Conventional Colonoscopy under routine screening conditions

Colonoscopy (CSPY) for colorectal cancer screening has several limitations. Colon Capsule Endoscopy (PillCam Colon, CCE) was compared to CSPY under routine screening conditions

Abstracts from the 8th International Conference on cGMP Generators, Effectors and Therapeutic Implications

This work was supported by a restricted research grant of Bayer AG

Role of peripheral BDNF for auditory perceptional learning?

Trabajo presentado en el 42nd Annual MidWinter Meeting of the Association of Otorhinolaryngology, celebrado en Baltimore (Estados Unidos) del 9 al 13 de febrero de 2019.[Background]: While novel studies indicate that perceptional learning is not linked with permanent changes in cortical circuitry but rather with changes that are gated in a task- or context-dependent fashion, the molecular substrate of perceptional learning is still elusive. It is currently speculated that perhaps changes in synaptic weights restricted to a limited set of task-specific synapses play a crucial role (Irvine DRF Hearing Res. 2018, Zhang Y-X et al. Amitay S 2016, Plos One). BDNF is gradually upregulated in the cochlea and ascending auditory pathway onwards from prior hearing onset (postnatal day P4) (Singer et al., Knipper, Neuropharmacol 2014). Previously, we showed that peripheral BDNF in the cochlea or lower brainstem regions, but not in the central higher cortical brain regions is fundamental for improved and optimized auditory fidelity with hearing onset [Zuccotti A et al. Knipper, 2012, J Neuroscience, Chumak T et al., 2016, Mol Neurobiol]. This improved auditory fidelity included greater sensitivity of auditory fibers, lower hearing thresholds, and enlarged dynamic range and inhibitory strength in the inferior colliculus related to lowering of spontaneous firing rate. We here asked to what extend these BDNF driven changes in auditory fidelity may influence memory-related shaping of auditory skills and auditory perceptional learning.[Methods]: Using conditional BDNF Pax2 KO mice, lacking BDNF in the cochlea, DCN and IC, we compared auditory fine structure analysis, auditory steady state response (ASSR), LTP and LTP-dependent task performance in BDNF WT and mutant mice, and investigated changes in markers for excitatory and inhibitory neuronal activity using high-resolution confocal microscopy and quantitative westernblot approaches.[Results]: Fundamental differences were found between BDNF Pax2 WT and KO mice at the molecular, functional, and behavioral level. The findings are discussed in the context of a role of BDNF for auditory perceptional learning in lower auditory brainstem regions.This work was supported by the Deutsche Forschungsgemeinschaft DFG-Kni-316-10-1, FOR 2060 project RU 713/3-2, SPP 1608 RU 316/12-1; KN 316/12-1; the Brain & Behavior Research Foundation NARSAD Young Investigator Grant 20748, BFU2013-40944; DFG KFO134