Perineuronal nets as regulators of parvalbumin interneuron function: Factors implicated in their formation and degradation

Abstract

The brain extracellular matrix (ECM) has garnered increasing attention as a fundamental component of brain function in a predominantly “neuron‐centric” paradigm. Particularly, the perineuronal nets (PNNs), a specialized net‐like structure formed by ECM aggregates, play significant roles in brain development and physiology. PNNs enwrap synaptic junctions in various brain regions, precisely balancing new synaptic formation and long‐term stabilization, and are highly dynamic entities that change in response to environmental stimuli, especially during the neurodevelopmental period. They are found mainly surrounding parvalbumin (PV)‐expressing GABAergic interneurons, being proposed to promote PV interneuron maturation and protect them against oxidative stress and neurotoxic agents. This structural and functional proximity underscores the crucial role of PNNs in modulating PV interneuron function, which is critical for the excitatory/inhibitory balance and, consequently, higher‐level behaviours. This review delves into the molecular underpinnings governing PNNs formation and degradation, elucidating their functional interactions with PV interneurons. In the broader physiological context and brain‐related disorders, we also explore their intricate relationship with other molecules, such as reactive oxygen species and metalloproteinases, as well as glial cells. Additionally, we discuss potential therapeutic strategies for modulating PNNs in brain disorders.

Degradation of Perineuronal Nets in the Ventral Hippocampus of Adult Rats Recreates an Adolescent-Like Phenotype of Stress Susceptibility

“…PNNs typically consist of a hyaluronate backbone that connects CSPGs to the cell surface along with glycoproteins, such as tenascin-R and link proteins ( 45 ). These structures are crucial in protecting PVIs from potential harm and facilitating their activity states ( 17 , 46 ).…”

“…During adolescence, PVIs exhibit higher plasticity in terms of excitatory drive and functional activity ( 3 , 15 ), which renders them particularly vulnerable to stress-induced damage ( 2 ). The period of vulnerability for PVIs persists until adulthood and the full emergence of perineuronal nets (PNNs), a glycosaminoglycan extracellular matrix ( 16 , 17 ) surrounding the PVIs, which coincides with their maturation ( 18 ). PNNs act as a physical barrier that offers stability to glutamatergic inputs and shields PVIs from oxidative and metabolic damage ( 19 , 20 ).…”