Biology subjects

Frischknecht, R.

Publications and source records attributed to Frischknecht, R..

5 recordsLinked to original sources

bioRxiv2024

Activity-dependent extracellular proteolytic cascade remodels ECM to promote structural plasticity

The brains perineuronal extracellular matrix (ECM) is a crucial factor in maintaining the stability of mature brain circuitry. However, how is activity-induced synaptic plasticity achieved in the adult brain with a dense ECM? We hypothesized that neuronal activity induces cleavage of ECM components, creating space for synaptic rearrangements. To test this hypothesis, we investigated neuronal activity-dependent proteolytic cleavage of brevican, a prototypical perineuronal ECM proteoglycan, and its importance of this process for functional and structural synaptic plasticity in the rat hippocampus ex vivo. Our findings revealed that chemical long-term potentiation (cLTP) triggers a rapid brevican cleavage through the activation of an extracellular proteolytic cascade involving proprotein convertases and ADAMTS-4 and ADAMTS-5. This process is dependent on NMDA receptors and requires astrocytes. Interestingly, the extracellular full-length brevican increases upon cLTP, indicating a simultaneous secretion of ECM components. Interfering with cLTP-induced brevican cleavage did not impact the early LTP but prevented formation of new dendritic protrusions. Collectively, these results reveal a mechanism of activity-dependent ECM remodeling and suggest that ECM degradation is essential for structural synaptic plasticity.

neuroscience↗

bioRxiv2024

Anisotropic Articular Cartilage Biofabrication based on Decellularized Extracellular Matrix

Tissue-engineered grafts that mimic articular cartilage show promise for treating cartilage injuries. However, engineering cartilage cell-based therapies to match zonal architecture and biochemical composition remains challenging. Decellularized articular cartilage extracellular matrix (dECM) has gained attention for its chondro-inductive properties, yet dECM-based bioinks have limitations in mechanical stability and printability. This study proposes a rapid light-based bioprinting method using a tyrosine-based crosslinking mechanism, which does not require chemical modifications of dECM and thereby preserves its structure and bioactivity. Combining this resin with Filamented Light (FLight) biofabrication enables the creation of cellular, porous, and anisotropic dECM scaffolds composed of aligned microfilaments. Specifically, we investigate the effects of various biopolymer compositions (i.e., hyaluronic acid, collagen I, and dECM) and inner architecture (i.e., bulk light vs FLight) on immune response and cell morphology, and we investigate their influence on nascent ECM production and long-term tissue maturation. Our findings highlight the importance of FLight scaffolds in directing collagen deposition resembling articular cartilage structure and promoting construct maturation, and they emphasize the superiority of biological-rich dECM over single-component materials for engineering articular cartilage, thereby offering new avenues for the development of effective cartilage tissue engineering strategies.

bioengineering↗

bioRxiv2022

Small leucine-rich proteoglycans inhibit CNS regeneration by modifying the structural and mechanical properties of the lesion environment

Extracellular matrix (ECM) deposition after central nervous system (CNS) injury leads to inhibitory scarring in mammals, whereas it facilitates axon regeneration in the zebrafish. However, the molecular basis of these different fates is not understood. Here, we identify small leucine-rich proteoglycans (SLRPs) as a causal factor in regeneration failure. We demonstrate that the SLRPs Chondroadherin, Fibromodulin, Lumican, and Prolargin are enriched in human, but not zebrafish, CNS lesions. Targeting SLRPs to the zebrafish injury ECM inhibits axon regeneration and functional recovery. Mechanistically, we find that SLRPs confer structural and mechanical properties to the lesion environment that are adverse to axon growth. Our study reveals SLRPs as previously unknown inhibitory ECM factors in the human CNS that impair axon regeneration by modifying tissue mechanics and structure. ONE SENTENCE SUMMARYComposition, structural organization, and mechanical properties of the injury ECM direct central nervous system regeneration.

neuroscience↗

bioRxiv2020

Removal of the extracellular matrix biases auditory cortical layer dynamics towards supragranular corticocortical integration

In the adult vertebrate brain, enzymatic removal of the extracellular matrix (ECM) is increasingly recognized to promote learning, memory recall, and restorative plasticity. However, the underlying impact of local removal of the ECM on cortical circuit processing is still not understood. Here, we removed the ECM in the primary auditory cortex (ACx) of adult Mongolian gerbils using local injections of hyaluronidase (HYase). Using laminar current-source density (CSD) analysis, we found layer-specific changes of the spatiotemporal synaptic activity patterns. Applying multitaper spectral analysis and time-domain conditional Granger causality (GC) measures, we found increased stimulus-evoked oscillatory power in the beta band (25-36 Hz) selectively within infragranular layers Vb and enhanced supragranular synaptic activity. Our findings reveal new insights on how ECM modulation affects the sensory integration via altered translaminar cortical network dynamics with a supragranular lead of the columnar response profile.

neuroscience↗

bioRxiv2019

Dopamine modulates the integrity of the perisynaptic extracellular matrix at excitatory synapses

In the brain, Hebbian-type and homeostatic forms of plasticity are affected by neuromodulators like dopamine (DA). Modifications of the perisynaptic extracellular matrix (ECM), controlling functions and mobility of synaptic receptors as well as diffusion of transmitters and neuromodulators in the extracellular space, are crucial for the manifestation of plasticity. Mechanistic links between synaptic activation and ECM modifications are largely unknown. Here, we report that neuromodulation via D1-type DA receptors can induce targeted ECM proteolysis specifically at excitatory synapses of rat cortical neurons via proteases ADAMTS-4 and -5. We show that receptor activation induces increased proteolysis of brevican (BC) and aggrecan, two major constituents of the adult ECM, in vivo and in vitro. ADAMTS immunoreactivity is detected near synapses, and shRNA-mediated knockdown reduced BC cleavage. We outline a molecular scenario how synaptic activity and neuromodulation are linked to ECM rearrangements via increased cAMP levels, NMDA receptor activation, and intracellular calcium signaling.

neuroscience↗