Structural and Functional Modulation of Perineuronal Nets: In Search of Important Players with Highlight on Tenascins

Abstract

The extracellular matrix (ECM) of the brain plays a crucial role in providing optimal conditions for neuronal function. Interactions between neurons and a specialized form of ECM, perineuronal nets (PNN), are considered a key mechanism for the regulation of brain plasticity. Such an assembly of interconnected structural and regulatory molecules has a prominent role in the control of synaptic plasticity. In this review, we discuss novel ways of studying the interplay between PNN and its regulatory components, particularly tenascins, in the processes of synaptic plasticity, mechanotransduction, and neurogenesis. Since enhanced neuronal activity promotes PNN degradation, it is possible to study PNN remodeling as a dynamical change in the expression and organization of its constituents that is reflected in its ultrastructure. The discovery of these subtle modifications is enabled by the development of super-resolution microscopy and advanced methods of image analysis.

Keywords: extracellular matrix; mechanotransduction; neurogenesis; perineuronal nets; super-resolution microscopy; synaptic plasticity; tenascin-C.

Figure 1

Scheme of perineuronal net structure and assembly. (A) Different cell types that are producing PNN components and associated regulatory molecules. (B) Schematic representation of the neuronal cell surface depicting a section of the simplified perineuronal net structure and its assembly, showing constituents and associated molecules. (C) Graphical representation of various molecular structures used in the above scheme. HA—hyaluronic acid; MMPs—matrix metalloproteinases; ADAMTS—a disintegrin and metalloproteinase with thrombospondin motifs; TA—tenascin assembly; EGF—epidermal growth factor; FN III—fibronectin type III (Created with Biorender.com).

Figure 2

Distribution of TnC and its relation to other ECM components. (A) Confocal image of triple staining for PNN (visualized by WFA in green), TnC (red) and neurons (NeuroTrace Nissl stain in blue) in the lateral deep cerebellar nucleus of a 3 month old mouse. Close apposition of PNN and TnC is indicated by the white arrow. (B) Expected interactions of TnC with proteoglycans and postsynaptic receptors taking into account their proximity [35,36,37,38,40,41,42,43]. L-VDCC–L type voltage dependent Ca²⁺ channel (Created with Biorender.com).

Figure 3

Hypothetical block diagram that illustrates the possible pathways of PNN remodeling towards synaptic plasticity and the role of enriched environment, including the involvement of tenascin C. LTP—long-term potentiation; L-VDCC-L—type voltage dependent Ca²⁺ channel; CSPG—chondroitin sulfate proteoglycans; MMP-9—matrix metalloproteinase 9; ADAMTS—a disintegrin and metalloproteinase with thrombospondin motifs. The dashed line indicates that direct evidence is still lacking (Created in Biorender.com).

Figure 4

An original SIM image of PNN in the hippocampus (left), and an enlarged image window with a schematic representation of the main PNN constituents and associated molecules (enlisted in the bottom) and their simplified relations (right). The schematic representation emphasizes that only the lecticans, fluorescently labeled with WFA as the PNN marker, form the observable and analyzable PNN topography.