Combined loss of brevican, neurocan, tenascin-C and tenascin-R leads to impaired fear retrieval due to perineuronal net loss
Year: 2025
Type: article
Abstract: In conditions such as neurodegenerative diseases, posttraumatic stress disorder (PTSD), addiction and spinal cord injuries, restricted synaptic plasticity hinders the formation of new neuronal connections, preventing the compensation and treatment of adverse behaviors. Perineuronal nets (PNNs) significantly restrict synaptic plasticity by inhibiting synapse formation. The digestion of PNNs has been associated with short-term cognitive improvements and reduced long-term memory, offering potential therapeutic benefits in PTSD. This study investigates the correlation between PNNs and fear memory processes in extracellular matrix (ECM) mutant mice, particularly focusing on the amygdala-medial prefrontal cortex (mPFC) circuit, which is crucial for fear memory generation and maintenance. Fear conditioning was conducted on mice lacking four key ECM-molecules: brevican, neurocan, tenascin-C and tenascin-R (4x KO). These mice exhibited severe impairments in memory consolidation, as evident by their inability to retrieve previously learned fear memories, coupled with reduced PNN density and disturbed synaptic integrity along their PNNs. Additionally, changes in neural activity in the basolateral amygdala (BL) and reductions in VGAT\(^{+}\) synaptic puncta in the amygdala-mPFC circuit were observed. In contrast, tenascin single KOs showed intact fear behavior and memory compared to their control groups. Impaired fear memory consolidation can be advantageous in certain conditions, such as PTSD, making the 4x KO mice an intriguing model for future fear conditioning studies and highlighting brevican, neurocan, Tnc, and Tnr as compelling targets for further investigation. This study underscores the significance of ECM regulation for synaptic organization and the potential of PNN modulation as a therapeutic target for fear memory-related conditions.
Authors: Müller-Bühl, Cornelius (Dr. rer. nat.), Pakusch, Johanna (M. Sc.), Bader, Verian (Dr. rer. nat.), Winklhofer, Konstanze (Prof. Dr.), Mark, Melanie Danelle (Prof. Dr. phil.), Faissner, Andreas (Prof. Dr.)
Institution: Ruhr University Bochum
Language: English
Topic: Memory and Neural Mechanisms
Subfield: Cognitive Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
Awards: GRK 2862: Monoaminerge neuronale Netze & Krankheiten, EXC 2033: RESOLV (Ruhr Explores Solvation), G1799309044, G1991299991, G199205490, G274347230, G2843511416, G3134524351, Frühe Schritte der Biogenese mitochondrialer Innenmembranproteine: Die Rolle zytosolischer Faktoren bei Synthese, Targeting und Qualitätskontrolle, SFB 1280: Extinktionslernen, FOR 2848: Architektur und Heterogenität der inneren mitochondrialen Membran auf der Nanoskala, G4070988349, Inhibition der Myelin Regeneration durch Tenascin Proteine und das assoziierte Matrisom, G4841108212, G4940545991, Regulation der Synapsen Entwicklung, Funktion und Plastizität durch die Extrazelluläre Matrix (EZM) des Nervensystems
OpenAlex ID: W7111487354
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