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Perineuronal Nets: Old Structures, New Functions.

B. Tewari,Lata Chaunsali,Harald Sontheimer

Published 2026 in The Neuroscientist

ABSTRACT

Perineuronal nets (PNNs) are morphologically distinct aggregates of extracellular matrix that predominantly ensheath fast-spiking GABAergic neurons in the brain. Discovered in the late 19th century by Camilo Golgi, PNNs have emerged as an important stabilizing structure of synapses during development. Particularly in the somatosensory cortex, PNNs ensure that activity-dependent wiring of sensory maps remains stable throughout life. While for decades, the study of PNNs has been focused almost exclusively on their role in development, recent research on PNNs in neurologic diseases has identified novel functions for PNNs and has provided compelling evidence that disruption of PNNs can be a major contributor to diseases such as epilepsy, glioma, and Alzheimer disease. Studies of PNNs in disease also provided a wealth of information on the dynamic remodeling of PNNs in the normal and diseased brain and the potential ability to modulate disease etiology or presentation by targeting PNNs. In this literature review, we focus on recently identified functions of PNNs in the healthy brain and how alterations in PNNs are causally associated with neurologic diseases, including epilepsy, glioma, and Alzheimer disease. Specific novel functions discussed in greater detail include the regulation of neuronal firing via 1) altered membrane capacitance, 2) electrostatic ion filtering, and 3) aiding astrocytic clearance of Glu and K+ at tripartite synapses.

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