Extracellular Matrix (ECM)-Regulated Molecular Switches: Tissue Inhibitors of Metalloproteinases in Synaptic Formation and Neuropathic Diseases

Synaptic formation, the cornerstone of neurological function, underpins complex behaviors and cognitive processes, with structural/functional aberrations implicated in neurodevelopmental disorders and neurodegenerative pathologies. Synaptogenesis involves dynamic interplay between cell adhesion molecules (CAMs) and extracellular matrix (ECM) components, which collectively regulate neuronal connectivity and plasticity. Matrix metalloproteinases (MMPs) and their endogenous inhibitors, tissue inhibitors of metalloproteinases (TIMPs), emerge as critical regulators of these processes through ECM remodeling and modulation of cell surface receptor signaling. This review synthesizes current understanding of ECM-TIMP-MMP axes in synaptic development, highlighting their dual roles in physiological plasticity and pathological disruption across neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease), neuro-oncological disorders, and neuroinflammatory conditions. By dissecting the context-dependent functions and therapeutic implications of TIMP family members in synaptic maintenance and disease progression, this work provides a conceptual framework for advancing TIMP-based neurotherapeutic strategies and a theoretical basis for future exploration of TIMP as a potential therapeutic target for neurological disorders.