VIRAL TOOLS FOR BIDIRECTIONAL REMODELLING OF NEURAL EXTRACELLULAR MATRIX IN HEALTH AND DISEASE

The neural extracellular matrix (ECM) of the central nervous system (CNS) is a key regulator of perisomatic GABAergic transmission, synaptic plasticity, neuronal excitability, network oscillations, memory formation, and cognitive flexibility. Its principal components—hyaluronic acid, chondroitin sulfate proteoglycans, link proteins (HAPLN1–4), and tenascins—form highly organized structures such as perineuronal nets. Following CNS injury or disease, the ECM undergoes biphasic remodeling, with acute degradation followed by chronic, region-specific reorganization and often excessive accumulation. This pathological dysregulation of ECM integrity can impair regeneration and contribute to epilepsy, cognitive decline, and central insulin resistance, highlighting the ECM as a compelling therapeutic target. To enable precise manipulation of ECM structure and function in vivo, we developed a suite of adeno-associated viral (AAV) tools for bidirectional ECM remodeling. These include AAVs that drive shRNA-mediated depletion of ECM components or their regulatory proteases, enabling controlled loss-of-function approaches with defined spatial and temporal resolution. Complementary strategies involve overexpression of native or dominant-negative link proteins to stabilize ECM assembly or promote its disassembly, revealing, for example, a critical role of ECM integrity in constraining memory engram size. Finally, targeted ECM degradation can be achieved via AAV-mediated expression of ECM-degrading proteases. Notably, neuronal overexpression of ADAMTS5 in the hippocampus efficiently cleaves aggrecan-rich perineuronal nets, rescues synaptic plasticity, and improves cognitive performance in aged mice. Together, these viral tools provide a versatile platform for elucidating ECM physiology and for opening new therapeutic avenues to restore neural plasticity in CNS disorders.