Perineuronal nets in brain physiology and disease

doi:10.1016/j.semcdb.2018.09.011

Seminars in Cell & Developmental Biology

Volume 89, May 2019, Pages 125-135

https://doi.org/10.1016/j.semcdb.2018.09.011 Get rights and content

Abstract

Perineuronal nets (PNNs) in the brain are condensed glycosaminoglycan-rich extracellular matrix structures with heterogeneous composition yet specific organization. They typically assemble around a subset of fast-spiking interneurons that are implicated in learning and memory. Owing to their unique structural organization, PNNs have neuroprotective capacities but also participate in signal transduction and in controlling neuronal activity and plasticity. In this review, we define PNN structure in detail and describe its various biochemical and physiological functions. We further discuss the role of PNNs in brain disorders such as schizophrenia, bipolar disorder, Alzheimer disease and addictions. Lastly, we describe therapeutic approaches that target PNNs to alter brain physiology and counter brain dysfunction.

Introduction

The extracellular matrix (ECM) represents 10–20% of the brain volume [1]. In this matrix, glycosaminoglycans (GAGs) play a crucial structural role with hyaluronan (HA) being the major component [2]. Three different ECM compartments exist in the central nervous system (CNS): basement membrane, diffuse matrix and condensed matrix [3]. Basement membrane is a sheet-like layer made with collagen and laminin that forms a border between endothelial and parenchymal tissue. Diffuse matrix is present in the neural interstitials of brain parenchyma while condensed matrix called perineuronal nets (PNNs) forms around a subset of neurons. These two matrices are further enriched in proteoglycans (PGs).

PNNs were discovered over a century ago by Camillo Golgi but their components and organization are still not fully understood. They are rather heterogeneous structures that enwrap cell bodies and dendrites leaving holes for synaptic contacts. The most common histological technique to detect PNNs is by using the lectin Wisteria floribunda agglutinin (WFA) which recognizes the N-acetylgalactosamine of sugar chains present in the majority (>80%) of PNNs. WFA histology has revealed PNNs throughout the brain but mostly around fast-spiking parvalbumin interneurons (PV cells), which are highly active neurons that need a specialized microenvironment. In order to probe PNN function, loss of function experiments typically use chondroitinase ABC (ChABC), which is an enzyme that degrades chondroitin sulfate GAGs down to their disaccharide building blocks. This enzyme can be injected directly into the brain and has revealed the importance of PNNs in PV cell activity, in learning and memory and in certain pathologies.

In this review, we provide a description of known PNN components and subsequent variations that lead to its great heterogeneity. We illustrate how PNNs act as a physical barrier, interact with signaling molecules and regulate neuronal activity. We also describe its role in various brain functions and its ensuing implication in several brain disorders. Finally, we survey approaches to change PNN expression, which include not only ChABC but also genetic models and more precise molecular tools. Ongoing research into PNNs promises to further our understanding of brain physiology and animal behavior and provide us with novel therapeutics.

Section snippets

Overview of PNN components

Cerebral ECM is composed of highly diverse GAGs, PGs and proteins that condense through specific interactions around certain neurons to form PNNs. The backbone of PNNs is formed by long GAG chains of HA to which are attached hyaluronan- and proteoglycan-binding link proteins (Hapln) that mediate interaction with PGs. These PGs are further connected by tenascin family proteins. While these numerous interactions form a condensed mesh, PNNs remain dynamic through modulations notably by secreted

Ion buffering

PNNs are composed of a combination of negative charges which form a polyanionic environment around neurons [6]. This particular microenvironment interacts more precisely with positive ions and can act as a reservoir. PNNs are typically found around highly active neurons and are thought to facilitate high neuron spike frequencies by providing ion sorting on the neuronal surface [42]. Negative charges at the extracellular surface can generate an ion concentration gradient across the membrane and

Brain disorders

As they are often associated with PV cells vital for proper brain development and function, PNNs have become the subject of intense focus for understanding disease mechanisms and for repairing dysfunction (reviewed in [95,96]). PV cells not only drive plasticity critical periods needed for processing sensory information but also periods during which complex motor and cognitive functions are instilled. They regulate firing of local principal neurons but also drive γ-band oscillations between

Concluding remarks

PNNs exert several physiological functions such as ion buffering, physical barrier and signal transduction that influence synaptic plasticity and neuronal activity. Attesting to their vital importance, environmental or genetic disruption of PNN assembly may lead to pathologies such as schizophrenia, bipolar disorder and addictions. On the other hand, changes in PNN assembly can happen in response to altered brain activity as a consequence of brain injury, addiction behaviors or neurogenerative

Funding

This work was supported by the European Research Council (ERC-2013-ADG-339379; HOMEOSIGN) and by the Agence Nationale de la Recherche (ANR-15-CE16-0010; P2N2).

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Perineuronal nets in brain physiology and disease

Abstract

Introduction

Section snippets

Overview of PNN components

Ion buffering

Brain disorders

Concluding remarks

Funding

Neurosci. Lett.

J. Biol. Chem.

Biochim. Biophys. Acta (BBA) – Gen. Subj.

J. Biol. Chem.

J. Biol. Chem.

Exp. Neurol.

J. Biol. Chem.

J. Biol. Chem.

Structure

Neuroscience

J. Biol. Chem.

J. Clin. Neurosci.

Mol. Cell. Neurosci.

Curr. Opin. Chem. Biol.

Brain Res.

Exp. Neurol.

Matrix Biol.

J. Biol. Chem.

FEBS Lett.

Brain Res.

Brain Res.

Neuroscience

J. Chem. Neuroanat.

J. Biol. Chem.

Neuron

Cell

Cell Rep.

Cell.

Mol. Cell. Neurosci.

Mol. Cell. Neurosci.

Brain Res.

Prog. Brain Res.

Neuron

Matrix Biol.

Neuron

Neuron

Neuron.

Neuroscience

Biol. Psychiatry

Hyaluronic acid and hyaluronic acid-binding proteins in brain extracellular matrix

Anat. Embryol.

Pathophysiology of the brain extracellular matrix: a new target for remyelination

Nat. Rev. Neurosci.

Aggrecan glycoforms contribute to the molecular heterogeneity of perineuronal nets

J. Neurosci.

Chondroitin sulphate proteoglycans: preventing plasticity or protecting the CNS?

J. Anat.

Perineuronal nets provide a polyanionic, glia-associated form of microenvironment around certain neurons in many parts of the rat brain

Glia

Composition of perineuronal nets in the adult rat cerebellum and the cellular origin of their components

J. Comp. Neurol.

Tau pathology promotes the reorganization of the extracellular matrix and inhibits the formation of perineuronal nets by regulating the expression and the distribution of hyaluronic acid synthases

J. Alzheimers Dis.

In vitro modeling of perineuronal nets: hyaluronan synthase and link protein are necessary for their formation and integrity

J. Neurochem.

Lecticans: organizers of the brain extracellular matrix

Cell. Mol. Life Sci.

The versican C-type lectin domain recognizes the adhesion protein tenascin-R

Proc. Natl. Acad. Sci. U.S.A.

Chondroitin sulfate proteoglycans in neural development and regeneration

Curr. Opin. Neurobiol.