Biology subjects

Faissner, A.

Publications and source records attributed to Faissner, A..

4 recordsLinked to original sources

bioRxiv2023

Neural extracellular matrix regulates visual sensory motor integration

Visual processing depends on sensitive and balanced synaptic neurotransmission. Extracellular matrix proteins in the environment of cells are key modulators in synaptogenesis and synaptic plasticity. In the present study, we provide evidence that the combined loss of the four extracellular matrix components brevican, neurocan, tenascin-C and tenascin-R in quadruple knockout mice leads to severe retinal dysfunction and diminished visual motion processing in vivo. Remarkably, impaired visual motion processing was accompanied by a developmental loss of cholinergic direction-selective starburst amacrine cells. Additionally, we noted imbalance of inhibitory and excitatory synaptic signaling in the quadruple knockout retina. Collectively, the study offers novel insights into the functional importance of four key extracellular matrix proteins for retinal function, visual motion processing and synaptic integrity. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=73 SRC="FIGDIR/small/537074v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@eec571org.highwire.dtl.DTLVardef@1e4b282org.highwire.dtl.DTLVardef@18398a7org.highwire.dtl.DTLVardef@9b113b_HPS_FORMAT_FIGEXP M_FIG C_FIG In briefIn their study, Reinhard et al. show that the combined loss of the extracellular matrix components brevican, neurocan, tenascin-C and tenascin-R in quadruple knockout mice leads to retinal dysfunction, diminished visual motion processing, developmental loss of cholinergic direction-selective starburst amacrine cells and imbalance of inhibitory and excitatory synaptic integrity. HighlightsO_LICombined loss of the four extracellular matrix molecules brevican, neurocan, tenascin-C and tenascin-R causes retinal dysfunction C_LIO_LIImpaired visual motion processing in quadruple, tenascin-C and tenascin-R knockout mice C_LIO_LILoss of cholinergic direction-selective starburst amacrine cells in the quadruple knockout retina C_LIO_LIThe matrisome influences inhibitory and excitatory synaptic balance C_LI

neuroscience↗

bioRxiv2022

Brevican, Neurocan, Tenascin-C and Tenascin-R Act as Important Regulators of the Interplay between Perineuronal Nets, Synaptic Integrity, Inhibitory Interneurons and Otx2

Fast-spiking parvalbumin interneurons are critical for the function of mature cortical inhibitory circuits. Most of these neurons are enwrapped by a specialized extracellular matrix structure (ECM) called perineuronal net (PNN), which can regulate their synaptic input. In this study, we investigated the relationship between PNNs, parvalbumin interneurons and synaptic distribution on these cells in the adult primary visual cortex (V1) of quadruple knockout mice deficient for the ECM molecules brevican, neurocan, tenascin-C and tenascin-R. We used super-resolution structured illumination microscopy (SIM) to analyze PNN structure and associated synapses. Additionally, we examined parvalbumin and calretinin interneuron populations. We observed a reduction in the number of PNN-enwrapped cells and a clear disorganization of the PNN structure in the quadruple knockout V1. This was accompanied by an imbalance of inhibitory and excitatory synapses with a reduction of inhibitory and an increase of excitatory synaptic elements along the PNNs. Also, the number of parvalbumin interneurons was reduced in the quadruple knockout, while calretinin interneurons, which do not wear PNNs did not display differences in number. Interestingly, we found the transcription factor Otx2 homeoprotein positive cell population also reduced. Otx2 is crucial for parvalbumin and PNN maturation and a positive feedback loop between these parameters has been described. Collectively, these data indicate an important role of brevican, neurocan, tenascin-C and tenascin-R in regulating the interplay between PNNs, inhibitory interneurons, synaptic distribution as well as Otx2 in the V1.

neuroscience↗

bioRxiv2020

Extracellular matrix supports excitation-inhibition balance in neuronal networks by stabilizing inhibitory synapses

Maintaining the balance between excitation and inhibition is essential for the appropriate control of neuronal network activity. Sustained excitation-inhibition (E-I) balance relies on the orchestrated adjustment of synaptic strength, neuronal activity and network circuitry. While growing evidence indicates that extracellular matrix (ECM) of the brain is a crucial regulator of neuronal excitability and synaptic plasticity, it remains unclear whether and how ECM contributes to neuronal circuit stability. Here we demonstrate that the integrity of ECM supports the maintenance of E-I balance by retaining inhibitory connectivity. Depletion of ECM in mature neuronal networks preferentially decreases the density of inhibitory synapses and the size of individual inhibitory postsynaptic scaffolds. After ECM depletion, inhibitory synapse strength homeostatically increases via the reduction of presynaptic GABAB receptors. However, the inhibitory connectivity reduces to an extent that inhibitory synapse scaling is no longer efficient in controlling neuronal network activity. Our results indicate that the brain ECM preserves the balanced network state by stabilizing inhibitory synapses. Significance statementThe question how the brains extracellular matrix (ECM) controls neuronal plasticity and network activity is key for an appropriate understanding of brain functioning. In this study, we demonstrate that ECM depletion much more strongly affects the integrity of inhibitory than excitatory synapses in vitro and in vivo. We revealed that by retaining inhibitory connectivity, ECM ensures the efficiency of inhibitory control over neuronal network activity. Our work significantly expands our current state of knowledge about the mechanisms of neuronal network activity regulation. Our findings are similarly relevant for researchers working on the physiological regulation of neuronal plasticity in vitro and in vivo and for researchers studying the remodeling of neuronal networks upon brain injury, where prominent ECM alterations occur.

neuroscience↗

bioRxiv2020

Loss of the extracellular matrix molecule tenascin-C leads to absence of reactive gliosis and promotes anti-inflammatory cytokine expression in an autoimmune glaucoma mouse model

Previous studies demonstrated that retinal damage correlates with a massive remodeling of extracellular matrix (ECM) molecules and reactive gliosis. However, the functional significance of the ECM in retinal neurodegeneration is still unknown. In the present study, we used an intraocular pressure (IOP) independent experimental autoimmune glaucoma (EAG) mouse model to examine the role of the ECM glycoprotein tenascin-C (Tnc). Wild type (WT ONA) and Tnc knockout (KO ONA) mice were immunized with an optic nerve antigen (ONA) homogenate and control groups (CO) obtained sodium chloride (WT CO, KO CO). IOP was measured weekly and electroretinographies were recorded at the end of the study. 10 weeks after immunization, we analyzed retinal ganglion cells (RGCs), glial cells and the expression of different cytokines in retina and optic nerve tissue in all four groups. IOP and retinal function was comparable in all groups. Although less severe in KO ONA, WT and KO mice displayed a significant loss of RGCs after immunization. Compared to KO ONA, a significant reduction of {beta}III-tubulin stained axons and oligodendrocyte markers was noted in the optic nerve of WT ONA. In retinal and optic nerve slices, we found an enhanced GFAP+ staining area of astrocytes in immunized WT. In retinal flat-mounts, a significantly higher number of Iba1+ microglia was found in WT ONA, while a lower number of Iba1+ cells was observed in KO ONA. Furthermore, an increased expression of the glial markers Gfap, Iba1, Nos2 and Cd68 was detected in retinal and optic nerve tissue of WT ONA, whereas comparable levels were observed in KO ONA post immunization. In addition, pro-inflammatory Tnfa expression was upregulated in WT ONA, but downregulated in KO ONA. Vice versa, a significantly increased anti-inflammatory Tgfb expression was measured in KO ONA animals. Collectively, this study revealed that Tnc plays an important role in glial and inflammatory response during retinal neurodegeneration. Our results provide evidence that Tnc is involved in glaucomatous damage by regulating retinal glial activation and cytokine release. Thus, this transgenic EAG mouse model offers for the first time the possibility to investigate IOP-independent glaucomatous damage in direct relation to ECM remodeling.

neuroscience↗