Browsing by Subject "Hippocampus"

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    Der Beitrag von Neurofascin zur Entstehung und Lokalisation von Gephyrinclustern während der inhibitorischen Synaptogenese im ZNS
    (2008) Burkarth, Nadine; Volkmer, Hansjürgen
    Membrane-bound cell adhesion molecules (CAMs) were discovered to be key players in initiating excitatory synapse formation in the CNS. However, so far little is known about the role of CAMs in inhibitory synapse development. In particular, a functional link between CAMs and the clustering of postsynaptic scaffold component gephyrin, which is a critical determinant of y-aminobutyric acid A (GABAA) clustering, still needs to be elaborated. Neurofascin belongs to the L1-subgroup of the immunoglobuline like CAMs (IgCAMs). In vivo Neurofascin has been shown to direct the formation and localization of GABAergic Input on cerebellar Purkinje neurons. Thus it serves as a candidate molecule recruiting gephyrin to inhibitory postsynaptic sites. At early stages of inhibitory synaptogenesis, formation of gephyrin clusters and their translocation to the axon hillock correlated with a somatic expression of neurofascin in rat hippocampal neurons. Furthermore, a neurofascin splice variant lacking the extracellular fifth fibronectine-III like domain (NF-5te FN-III) was predominantely expressed at early stages of synapse formation. In contrast expression of NF+5te FN-III harbouring the fifth fibronectine-III like domain was prominent only in adult brain. Transfection of expression vectors for different splice variants and deletion mutants of neurofascin revealed that the embryonic neurofascin isoform NF-5te FN-III is required for the formation of gephyrin clusters. This process is presumably dependent on extracellular interactions with molecules on pre- and postsynaptic terminals, respectively. However, possible interaction partners for neurofascin are unknown. Point mutations in the cytoplasmatic domain of neurofascin inhibited the formation of gephyrin clusters suggesting intracellular signal transduction pathways triggered by neurofascin. Furthermore, expression of neurofascin is necessary for the translocation of gephyrin clusters to the axon hillock of hippocampal neurons as shown by shRNA-mediated knockdown. In addition, overexpression of an embryonic neurofascin isoform was sufficient for functional rescue after knockdown of endogenous neurofascin. Expression of NF-5te FN-III resulted in the accumulation of exogenous GFP-Gephyrin at the axon initial segment AIS suggesting a functional link between neurofascin and gephyrin. However, colocalization studies in HEK293 and PC12E2 cells, respectively, did not provide an indication of direct neurofascin gephyrin interactions leading to the observed effects.
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    Cognitive alterations in old mice are associated with intestinal barrier dysfunction and induced toll-like receptor 2 and 4 signaling in different brain regions
    (2023) Brandt, Annette; Kromm, Franziska; Hernández-Arriaga, Angélica; Martínez Sánchez, Inés; Bozkir, Haktan Övül; Staltner, Raphaela; Baumann, Anja; Camarinha-Silva, Amélia; Heijtz, Rochellys Diaz; Bergheim, Ina
    Emerging evidence implicate the ‘microbiota–gut–brain axis’ in cognitive aging and neuroinflammation; however, underlying mechanisms still remain to be elucidated. Here, we assessed if potential alterations in intestinal barrier function and microbiota composition as well as levels of two key pattern-recognition receptors namely Toll-like receptor (TLR) 2 and TLR4, in blood and different brain regions, and depending signaling cascades are paralleling aging associated alterations of cognition in healthy aging mice. Cognitive function was assessed in the Y-maze and intestinal and brain tissue and blood were collected in young (4 months old) and old (24 months old) male C57BL/6 mice to determine intestinal microbiota composition by Illumina amplicon sequencing, the concentration of TLR2 and TLR4 ligands in plasma and brain tissue as well as to determine markers of intestinal barrier function, senescence and TLR2 and TLR4 signaling. Cognitive function was significantly impaired in old mice. Also, in old mice, intestinal microbiota composition was significantly altered, while the relative abundance of Gram-negative or Gram-positive bacteria in the small and large intestines at different ages was not altered. Moreover, intestinal barrier function was impaired in small intestine of old mice, and the levels of TLR2 and TLR4 ligands were also significantly higher in both portal and peripheral blood. Furthermore, levels of TLR2 and TLR4 ligands, and downstream markers of TLR signaling were higher in the hippocampal and prefrontal cortex of old mice compared to young animals. Taken together, our results suggest that even in ‘healthy’ aging, cognitive function is impaired in mice going along with an increased intestinal translocation of TLR ligands and alterations of TLR signaling in several brain regions.