Abstract
The extracellular matrix (ECM) plays a key role in synaptogenesis and the regulation of synaptic functions in the central nervous system. Recent studies revealed that in addition to dopaminergic and serotoninergic neuromodulatory systems, microglia also contribute to the regulation of ECM remodeling. In the present work, we investigated the physiological role of microglia in the remodeling of perineuronal nets (PNNs), predominantly associated with parvalbumin-immunopositive (PV+) interneurons, and the perisynaptic ECM around pyramidal neurons in the hippocampus. Adult mice were treated with PLX3397 (pexidartinib), as the inhibitor of colony-stimulating factor 1 receptor (CSF1-R), to deplete microglia. Then, confocal analysis of the ECM and synapses was performed. Although the elimination of microglia did not alter the overall number or intensity of PNNs in the CA1 region of the hippocampus, it decreased the size of PNN holes and elevated the expression of the surrounding ECM. In the neuropil area in the CA1 str. radiatum, the depletion of microglia increased the expression of perisynaptic ECM proteoglycan brevican, which was accompanied by the elevated expression of presynaptic marker vGluT1 and the increased density of dendritic spines. Thus, microglia regulate the homeostasis of pre- and postsynaptic excitatory terminals and the surrounding perisynaptic ECM as well as the fine structure of PNNs enveloping perisomatic—predominantly GABAergic—synapses.
Highlights
The neural extracellular matrix (ECM) constitutes the non-cellular component of brain tissue, contributing up to 20% of the organ’s total volume [1]
We have identified an interaction between microglia and the perisynaptic ECM in the hippocampus of healthy young mice, as evidenced by the increase in perisynaptic Bcan after microglia depletion
Our findings indicate that this interaction is essential for the maintenance of the perisomatic ECM with the fine structure of perineuronal nets (PNNs)
Summary
The neural extracellular matrix (ECM) constitutes the non-cellular component of brain tissue, contributing up to 20% of the organ’s total volume [1]. The composition of the brain ECM varies, but in general, the core constituents are the glycan hyaluronic acid and chondroitin sulfate proteoglycans (CSPGs) of the lectican family such as aggrecan, brevican (Bcan), neurocan, and versican (Vcan). These CSPGs are linked to a hyaluronic acid backbone and these links are stabilized via hyaluronan and proteoglycan link proteins (HAPLN1-4). PNNs are assumed to stabilize neuronal circuits during development and support the function of established synaptic connections [8,9]. The precise molecular mechanisms are still elusive and currently under investigation
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