Orchestrating the Matrix: The Role of Glial Cells and Systemic Signals in Perineuronal Net Dynamics

Abstract

Perineuronal nets (PNNs) are specialized, dense extracellular matrix structures that enmesh the cell bodies and dendrites of specific neurons, most notably inhibitory interneurons. Increasing evidence indicates that PNNs serve not merely as passive scaffolds but play an active and essential role in modulating synaptic plasticity and circuit physiology. They critically influence the timing of sensory system critical periods, as well as processes underlying learning, memory, and higher cognitive functions. Furthermore, dysregulation of PNN density and architecture have been associated with conditions like autism, neurodevelopmental disorders, schizophrenia and Alzheimer's disease. Since they are extensively involved in brain function, we discuss the multitude of regulatory factors that govern the formation, maturation, and remodeling of PNNs. In particular, we focus on both molecular and cellular brain-intrinsic mechanisms, highlighting the potential contributions of microglia and astrocyte derived factors. Additionally, we consider the influence of long-range signaling cues, including the metabolic status and peripheral hormones. Analysing this complex network of interactors, we try to highlight the role of PNNs beyond neural plasticity and brain function, in a broader whole-body physiological perspective.

Keywords: Astrocytes; Extracellular matrix; Glycosaminoglycan; Metabolism; Microglia; Perineuronal nets; Plasticity.

Fig. 1

Functional roles of PNNs across multiple brain regions. Regional specificity of PNN-mediated control of neural plasticity is suggestive of the action of complex regulatory networks both in postnatal development and in adulthood. The cartoon of the mouse brain was created with Brainrender [43] and adapted for illustration purposes

Fig. 2

Regulation of PNNs during development and adulthood. Molecular and physiological factors promoting circuit maturation during postnatal development are involved in the accumulation of PNNs. During adulthood, events requiring plasticity, like memory formation and consolidation, affect PNN maintenance and function. Notably, PNNs integrate both brain-intrinsic and systemic cues, such as nutrition and hormonal landscape

Fig. 3

Regulation of PNNs by glial cells. Microglia and astrocytes influence PNN development and stability both in physiological and in pathological conditions. Microglia is mostly associated with clearance of ECM molecules while astrocytes with their production. Both cell types are involved in regulation of PNNs by matrix metalloproteases and in synaptic homeostasis