Looking Inside the Matrix: Perineuronal Nets in Plasticity, Maladaptive Plasticity and Neurological Disorders

The integrity of the central nervous system (CNS) matrix is crucial for its proper function. Loss of the lattice-like structure compromise synaptic stability and can lead to the disruption of the excitatory/inhibitory balance, astrocytosis, maladaptive plasticity and neuronal death. Perineuronal nets (PNNs) in the extracellular matrix (ECM) provide synaptic integration and control the functional wiring between neurons. These nets are significantly modified during CNS disorders, such as neurodegenerative, cerebrovascular and inflammatory diseases. The breakdown or the modification of PNNs could be due to the activity of matrix metalloproteinases (MMPs) or to the deposition of proteoglycans, glycoproteins, and hyaluronic acid. The expression and the activity of ECM-degrading enzymes can be regulated with tissue inhibitors of MMPs or via transcriptional and epigenetic silencing or enhancement (i.e. via histone deacetylases). The identification of molecules and mechanisms able to modify these processes will be essential for a new perspective on brain functioning in health and disease, leading to a target-directed approach with drugs directly interfering with the molecular mechanism underlying neurological disorders.