Perineuronal Net Alterations Following Early-Life Stress: Are Microglia Pulling Some Strings?

Abstract

The extracellular matrix plays a key role in synapse formation and in the modulation of synaptic function in the central nervous system. Recent investigations have revealed that microglia, the resident immune cells of the brain, are involved in extracellular matrix remodeling under both physiological and pathological conditions. Moreover, the dysregulation of both innate immune responses and the extracellular matrix has been documented in stress-related psychopathologies as well as in relation to early-life stress. However, the dynamics of microglial regulation of the ECM and how it can be impacted by early-life adversity have been understudied. This brief review provides an overview of the recent literature on this topic, drawing from both animal model and human post mortem studies. Direct and indirect mechanisms through which microglia may regulate the extracellular matrix-including perineuronal nets-are presented and discussed in light of the interactions with other cell types.

Keywords: early-life stress; extracellular matrix; microglia; parvalbumin interneurons; perineuronal nets.

Figure 1

Cell-type enrichment analysis of PNN components in the dorsolateral prefrontal cortex (dlPFC) of healthy subjects. Heatmap showing the expression levels of PNN canonical components derived from post mortem dlPFC samples from 34 neurotypical individuals (16M/18F) (Maitra et al., 2023) [68]. The OPC cluster highly expresses VCAN, PTPRZ1 and TNR. Microglia cells barely express—if at all—canonical PNN components such as VCAN, ACAN, BCAN and TNR. The processed dataset by Maitra et al. (2023) [68], including the cluster annotations, was downloaded through the UCSC Cell Browser with the following link: https://cells.ucsc.edu/?ds=dlpfc-mdd (accessed on 30 June 2024) Using the R package Seurat [67] (v. 4.1.1, R version 4.1 [69]), the matrix.mtx, features.tsv, barcodes.tsv and meta.tsv files were loaded into a Seurat object. Only neurotypical subjects (n = 34) were included in the following analysis. The heatmap was generated using Seurat’s DoHeatmap function with default parameters and the following set of genes inputted as features to include: NCAN, VCAN, BCAN, ACAN, PTPRZ1, CSPG4, TNR, HAPLN1, HAPLN2, HAPLN3, HAPLN4. All the PNN components were derived from Tanti et al. (2022) [3]. The expression values (normalized expression) of each marker were scaled and are presented as z-scores in the colour bar of the heatmap. Expression is grouped by broad cell types. A darker colour (blue) indicates higher levels of expression. Abbreviations: Ast, Astrocytes; End, Endothelial cells; ExN, Excitatory neurons; InN, Inhibitory neurons; Mic, Microglia; Mix, Mixed expression profile; Oli, oligodendrocytes; OPCs, Oligodendrocyte precursor cells; PNN, Perineuronal net.

Figure 2

Microglial interactions with other glia cells that are pertinent to ECM-PNN regulation. Inhibitory neurons release GABA, cytokines (e.g., IL33) and chemokines (e.g., CX3CL1). The receptors for these molecules are highly expressed by microglia. The interplay between these neuronal ligands and microglial receptors initiates different signaling cascades that culminate in the engulfment of ECM-PNN components. Furthermore, non-neural cells such as astrocytes can affect the interaction between microglia and PNNs through the release of IL33. Microglia also synthesize and release enzymes such as MMP2, MMP9 and Cathepsin S that indirectly modulate the integrity of PNNs. Finally, microglia secrete several pro-inflammatory and anti-inflammatory cytokines and chemokines. These molecules can robustly regulate OPC proliferation, maturation and survival.