Extracellular matrix and perineuronal nets in neural plasticity, memory, and epileptogenesis

Abstract

In the mature brain, the extracellular matrix (ECM) molecules derived from neurons and glia accumulate in spatially distinct extracellular compartments, including a diffuse interstitial matrix and condensed perineuronal nets (PNNs), where they regulate receptor mobility, ion homeostasis, cell-surface signaling, structural stabilization, and experience-dependent synaptic remodeling. PNNs, in particular, assemble around selected neuronal populations - most prominently parvalbumin-positive fast-spiking interneurons - and thereby couple extracellular molecular architecture to inhibitory control, critical-period closure, and the long-term precision of network activity. These properties place ECM and PNNs at the intersection of developmental maturation, synaptic plasticity, memory-related stabilization, and pathological circuit remodeling. These principles are directly relevant to epilepsy. If ECM and PNNs normally stabilize synaptic organization, preserve inhibitory interneuron function, regulate extracellular space, and constrain maladaptive rewiring, then their disruption is positioned to lower the threshold for persistent hyperexcitability and aberrant network synchronization. For instance, hyaluronan deficiency alters neuronal activity and can produce seizures. However, the biological mechanisms and specific contributions of ECM and PNN in epilepsy still need to be further elucidated. Therefore, the purpose of the study is to systematically elaborate on the similarities and differences between ECM and PNN in terms of plasticity, memory, the biological mechanisms of neurological diseases, especially in the context of epilepsy.