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Cited by 95Schizophrenia research and treatmentNeuroscience and Neuropharmacology ResearchTryptophan and brain disorders

Perineuronal nets and schizophrenia: The importance of neuronal coatings

Open access
Bitanihirwe, Byron K.Y., Woo, Tsung-Ung W.·2014·Neuroscience & Biobehavioral Reviews
DOI 10.1016/j.neubiorev.2014.03.018PMC PMC4447499
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Abstract

Schizophrenia is a complex brain disorder associated with deficits in synaptic connectivity. The insidious onset of this illness during late adolescence and early adulthood has been reported to be dependent on several key processes of brain development including synaptic refinement, myelination and the physiological maturation of inhibitory neural networks. Interestingly, these events coincide with the appearance of perineuronal nets (PNNs), reticular structures comprised of components of the extracellular matrix that coat a variety of cells in the mammalian brain. Until recently, the functions of the PNN had remained enigmatic, but are now considered to be important in development of the central nervous system, neuronal protection and synaptic plasticity, all elements which have been associated with schizophrenia. Here, we review the emerging evidence linking PNNs to schizophrenia. Future studies aimed at further elucidating the functions of PNNs will provide new insights into the pathophysiology of schizophrenia leading to the identification of novel therapeutic targets with the potential to restore normal synaptic integrity in the brain of patients afflicted by this illness.

Verified 2026-10-06 · 4 references not checked yet

Integrity signals

Registry

Crossref · 10.1016/j.neubiorev.2014.03.018

Cites

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Statistics

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Claims the paper makes

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  • Findingcitation

    In human prefrontal cortex, PNN counts rise across the peripubertal years and continue into late adolescence and early adulthood.

    “we have recently shown that the number of PNNs in the human prefrontal cortex also increases through the peripubertal period until late adolescence and early adulthood (Mauney et al., 2013)”
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  • Premisecitation

    Evidence links PNNs to ion homeostasis near neurons with high activity.

    “PNNs have been implicated in ion homeostasis around highly active neurons”
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    • cites Bruckner et al., 1993 source

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  • Premisecitation

    Parvalbumin interneurons are critical for higher brain functions such as cognition and perception through regulation of gamma band neural synchrony.

    “which are critical for the integrity of various higher brain functions, such as cognition and perception, via regulation of gamma band neural synchrony”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Gonzalez-Burgos and Lewis, 2008

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  • Premisecitation

    Malfunctioning synaptic communication inside and across brain regions may produce schizophrenia symptoms by disrupting cognitive and perceptual circuitry.

    “the symptoms associated with schizophrenia may arise from a malfunctioning synaptic communication within and between brain regions, leading to a functional disruption of the circuitry that underlies many of the cognitive and perceptive functions (Uhlhaas, 2013)”
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    • cites Uhlhaas, 2013 source

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  • Premisecitation

    Genes encoding PNN structural constituents and regulators of PNN formation have been linked to schizophrenia.

    “recent evidence linking genes encoding structural constituents of PNNs and those that regulate their formation to schizophrenia”
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    • cites Buxbaum et al., 2008 source

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    Premisenone given

    PNNs are important in central nervous system development, neuronal protection, and synaptic plasticity.

    “important in development of the central nervous system, neuronal protection and synaptic plasticity”
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    Premisecitation

    PNNs ensheath mature CNS neurons and their axons and dendrites but are excluded from synaptic contact sites, creating lattice-like holes.

    “PNNs represent well-organized components of the extracellular matrix (ECM) that ensheath many mature central nervous system (CNS) neurons and their axons and dendritic processes, but which are excluded from sites of synaptic contact, thereby creating “holes” that give these structures their lattice-like appearance”
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    Premisecitation

    PNNs function in developmental processes including closure of the critical period and synaptic stability/plasticity.

    “PNNs appear to function in a multitude of key physiological processes during development, including the closure of the critical period”
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    Premisecitation

    For the last twenty years, the neurodevelopmental theory has dominated schizophrenia research.

    “the neurodevelopmental theory of schizophrenia (Murray and Lewis, 1987; Weinberger, 1987) has been the dominant paradigm for schizophrenia research over the past two decades”
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    Premisecitation

    The neural ECM differs from non-neural ECM by having low fibrous proteins and high GAGs and PGs.

    “the neural ECM, in contrast, is composed of low levels of fibrous proteins, high amount of GAGs (Novak and Kaye, 2000) as well as PGs”
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    Premisecitation

    PNNs have been tied to neuroprotection.

    “PNNs have been implicated in ion homeostasis around highly active neurons (Bruckner et al., 1993; Bruckner et al., 1996a; Bruckner et al., 1996b; Hartig et al., 1999; Hartig et al., 2001; Hobohm et al., 1998) and neuroprotection”
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    Premisenone given

    PNNs are reticular extracellular matrix structures that coat various cells in the mammalian brain.

    “perineuronal nets (PNNs), reticular structures comprised of components of the extracellular matrix that coat a variety of cells in the mammalian brain”
    Quote in the paperSubstantial claim

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    Premisecitation

    ChABC-induced enhancement of object recognition is reversible; memory gradually returns to control levels over 8 weeks, suggesting reoccurring PNNs restore control plasticity.

    “ChABC induced enhancement of object recognition was reversible. Notably, over the course of 8 weeks, memory gradually returned to control levels, suggesting that reoccurring PNNs gradually restore control plasticity levels (Romberg et al., 2013)”
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    Premisecitation

    Trimming whiskers during the first month of life lowers aggrecan-positive PNNs surrounding parvalbumin cells in layer IV of mouse barrel cortex and extends the critical period.

    “sensory deprivation by whisker trimming within the first 30 days of birth was found to decrease the number of aggrecan-positive PNNs around parvalbumin-expressing cells in layer IV of the mouse barrel cortex and prolong the critical period (McRae et al., 2007)”
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    Interpretationcitation

    PNNs appear linked to particular striatal circuit components and are important for controlling striatal activity.

    “These findings suggest that PNNs are associated with specific elements of striatal circuits and play a key role in regulating the function of this important structure (Lee et al., 2012)”
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    Premisecitation

    In adult mice, removing sensory input leaves aggrecan expression unchanged, which suggests that established PNNs do not need normal sensory input for upkeep.

    “Sensory deprivation in adult mice, however, did not alter aggrecan expression, indicating that once established, maintenance of PNNs does not require normal sensory input (McRae et al., 2007)”
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    Premisecitation

    In mouse visual cortex slices, blocking glutamate receptors and presynaptic N- and P/Q-type calcium channels left PNN growth unchanged, which suggests that neuronal activity is necessary for PNN development but glutamatergic transmission is not.

    “blockage of glutamate receptors and presynaptic N- and P/Q-type calcium channels (both implicated in glutamate release) did not affect PNN growth, indicating that neuronal activity is required but that glutamatergic neurotransmission is not essential for PNN development (Dityatev et al., 2007)”
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    Interpretationcitation

    PNNs prevent extinction from erasing fear.

    “it was suggested that PNNs prevent extinction from erasing fear”
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    Interpretationcitation

    PNNs appear to shield newly learned fear memories from being erased by extinction, so extinction memories can coexist with the original fear memory.

    “These findings indicate that PNNs are actively involved in protecting the acquisition of fear memories from extinction-induced erasure, allowing extinction memories to coexist with previously acquired fear memories”
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    Premisecitation

    Otx2 signals maturation of parvalbumin-containing GABAergic interneurons, contributing to opening and possibly closure of the critical period.

    “this homeoprotein signals the maturation of the parvalbumin-containing GABAergic interneurons, which contributes to the opening and possibly also the closure of the critical period”
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    Premisecitation

    In cats, developmental sensory deprivation lowers aggrecan expression, whereas adult deprivation does not.

    “where aggrecan expression decreases after sensory deprivation during development but not in adulthood (Sur et al., 1988)”
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    Premisecitation

    ChABC depletion of PNNs enhances object recognition and facilitates long-term depression in perirhinal cortex.

    “a depletion of PNNs in animals following localized digestion with ChABC was shown to result in enhanced object recognition, in addition to a facilitation of long-term depression in the perirhinal cortex”
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    Premisecitation

    Human PNNs occur in the entorhinal cortex, amygdala, hippocampus, visual and prefrontal cortices, and motor and somatosensory cortex.

    “in humans, PNNs have also been found to be present in a variety of brain regions, including entorhinal cortex (Pantazopoulos et al., 2010), amygdala (Pantazopoulos et al., 2008; Pantazopoulos et al., 2010), hippocampus (Lendvai et al., 2013), motor and somatosensory cortex (Hausen et al., 1996), visual cortex (Mauney et al., 2013; Murakami et al., 1994; Seeger et al., 1996) and prefrontal cortex (”
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    Premisecitation

    The dopamine hypothesis of schizophrenia stems from evidence that antipsychotic drugs block dopamine D2 receptors and dopamine-releasing drugs worsen symptoms.

    “The dopamine hypothesis of schizophrenia stems from the body of work suggesting that the major antipsychotic drugs act by blocking dopamine D2 receptors and that dopamine-releasing drugs worsen schizophrenia symptoms (Snyder, 1976)”
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    Transgenic animals lacking brevican exhibit disruptions in the perinodal net and deficits in nerve conduction.

    “transgenic animals lacking the CSPG brevican have been reported to exhibit disruptions in the perinodal-net in addition to deficits in nerve conduction (Bekku et al., 2010)”
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    Interpretationcitation

    PNNs might shield fast-spiking parvalbumin cells from oxidative stress, thereby averting the electrophysiological problems seen in schizophrenia.

    “Together these findings highlight the possible role of PNNs in protecting the fast-spiking parvalbumin cells against oxidative stress, which in turn prevents the electrophysiological deficits associated with schizophrenia.”
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    Premisecitation

    Tutor song deprivation decreases percentage of parvalbumin-positive neurons and relative staining intensity of parvalbumin and PNNs.

    “shifting the vocal critical period with tutor song deprivation decreased the percentage of neurons that were parvalbumin positive and the relative staining intensity of both parvalbumin and PNNs (Balmer et al., 2009)”
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    Premisecitation

    PNN deficit in mice preferentially affects parvalbumin-containing inhibitory interneurons and reduces beta and gamma neural oscillations.

    “PNN deficit within these mice preferentially affected parvalbumin-containing inhibitory interneurons with a concomitant reduction in neural oscillations in the beta and gamma frequency bands (Cabungcal et al., 2013)”
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    Premisecitation

    Human post-mortem studies show disease-specific reduction in PNN density and altered expression of genes regulating PNNs/ECM in amygdala, olfactory epithelium, entorhinal cortex, superior temporal cortex, and prefrontal cortex in schizophrenia.

    “a number of human post-mortem brain studies have revealed a disease-specific reduction in the density of PNNs as well as altered expression of genes that regulate PNNs and ECM in key brain structures associated with schizophrenia, including the amygdala, olfactory epithelium, entorhinal cortex, superior temporal cortex and prefrontal cortex”
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    • cites Mauney et al., 2013 source

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    • cites Pietersen et al., 2014a

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    • Rests on an assumption: Postmortem reductions in PNN density in schizophrenia reflect antemortem disease-related changes rather than artifacts of tissue processing, medication, or death.

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    Premisecitation

    Parvalbumin interneurons express Kv3.1b potassium channel subunits that produce rapidly repolarizing action potentials and contribute to the fast-spiking phenotype.

    “These neurons express specific potassium channel subunits, such as Kv3.1b, which produce rapidly repolarizing action potentials”
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    Premisecitation

    Patients with schizophrenia show parvalbumin neuron deficits, cortical gamma synchrony abnormalities, and information-processing problems, especially in working memory and executive function.

    “schizophrenia is associated with deficits in parvalbumin neurons (Bitanihirwe et al., 2009; Hashimoto et al., 2003), abnormalities in cortical gamma synchrony”
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    Premisecitation

    Gamma band oscillation frequency may increase with mild PNN deficit but decrease compared to controls under additional oxidative stress.

    “the frequency of gamma band oscillations may actually be increased in mice with a mild PNN deficit (ChABC treatment alone) while the frequency of gamma band oscillations is decreased (compared to controls) once more oxidative stress is placed on the system”
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    Premisecitation

    RPTPβ-overexpressing transgenic animals display schizophrenia-like behavioral deficits, including reduced sensorimotor gating, hyperactivity, and working memory impairment.

    “Finally, these animals also demonstrated schizophrenia-like behavioral deficits, including reduced sensory motor gating, hyperactivity and working memory impairment, indicating that enhanced RPTPβ signaling can contribute to schizophrenia phenotypes (Takahashi et al., 2011a).”
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    Premisecitation

    Intra-ventral hippocampal ChABC removal of PNNs in rats increases dopamine neuron population activity and hyperresponsiveness to amphetamine locomotor effects.

    “rats treated with intra-ventral hippopcampal ChABC to remove PNNs not only exhibited an increase in dopamine neuron population activity, as shown by a significantly greater firing rate of putative pyramidal neurons throughout the ventral hippocampus, but were also hyper responsive to the locomotor stimulating effects of amphetamine (Shah and Lodge, 2013)”
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    Premisecitation

    A deficit in synaptic pruning has long been proposed to contribute to schizophrenia onset.

    “In light of the fact that PNNs are known to play a role in regulating developmental synaptic pruning in the cerebral cortex and that synaptic pruning deficit has long been speculated to contribute to the onset of schizophrenia (McGlashan and Hoffman, 2000; Feinberg, 1982; Keshavan et al., 1994)”
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    Interpretationcitation

    Hippocampal PNN loss by itself appears able to raise hippocampal activity and produce the dopamine hyperfunction thought to cause positive symptoms in schizophrenia.

    “Together these data suggest that a loss of hippocampal PNNs is sufficient, in and of itself, to augment hippocampal activity and induce the dopamine system hyperfunction purported to underlie the positive symptoms of schizophrenia”
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    • Rests on an assumption: Findings from animal models of PNN manipulation and distribution can be generalized to human schizophrenia pathophysiology.

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    Premisecitation

    NgR is present in PNN-encapsulated neurons and binds CSPGs.

    “Finally, Nogo receptor (NgR), which binds myelin-associated proteins that inhibit axonal growth, such as the Nogo proteins, is expressed in PNN-encapsulated neurons (Ye and Miao, 2013) and also binds CSPGs (Dickendesher et al., 2012).”
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    Premisecitation

    Layer 3 pyramidal cells in schizophrenia show reduced spine numbers.

    “This is an interesting observation in light of the finding of reduction in spine number on layer 3 pyramidal cells in schizophrenia (Glantz and Lewis, 2000; Sweet et al., 2009).”
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    Interpretationcitation

    These changes may alter synaptic signal transmission by affecting neuronal synchronization, neuron-glia communication, and synaptic and extrasynaptic volume transmission, including dopamine.

    “Such changes could affect the efficacy of signal transmission at synapses by altering neuronal synchronization and neuron-glia communication but also by affecting synaptic and extrasynaptic volume transmission (Fuxe et al., 2013; Sykova, 2005), a notable example being dopamine (Fuxe et al., 2013).”
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    Premisecitation

    Phosphacan is involved in CNS development, including neuronal migration, axon outgrowth, synapse formation, synaptic activity, and myelin formation.

    “The spatiotemporal expression pattern of phosphacan within the CNS suggests potential roles for this protein in various developmental processes, including cell migration (Maeda et al., 1996), neurite growth (Garwood et al., 2003), synaptogenesis (Haunso et al., 1999), synaptic function (Murai et al., 2002), and myelination (Harroch et al., 2000)(Garwood et al., 2001)”
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    Interpretationreasoning

    PNNs are integral to the synapse and appear specialized to monitor and adapt to extracellular changes.

    “These lattice-like structures represent an integral part of the synapse and appear to be specialized to monitor and adapt according to the dynamic changes in the extracellular environment.”
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    Premisecitation

    PNNs sit directly on neuronal surfaces, allowing them to modulate neuronal physiology and strongly influence synaptic formation, plasticity, and stabilization in the brain.

    “One such piece of the schizophrenia puzzle involves PNNs, whose location directly on the surface of neurons places them in a unique position to not only modulate neuronal physiology but to also exert a strong influence on synaptic formation, plasticity and stabilization in the brain (Kwok et al., 2008; Kwok et al., 2011; McRae and Porter, 2012; Wang and Fawcett, 2012).”
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    Premisecitation

    Multiple sclerosis resembles schizophrenia in clinical course, age of onset, and immunological profile.

    “a neurological condition that shares a similar clinical course, age of onset and immunological profile to patients with schizophrenia (Stevens, 1988).”
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  • The paper relies on this without support.

    Findings from animal models of PNN manipulation and distribution can be generalized to human schizophrenia pathophysiology.

    “Because of the critical function of PNNs in synaptic plasticity, disruption of these structures may contribute to the neuronal circuitry dysfunction associated with neurological and psychiatric diseases”

  • The paper relies on this without support.

    Postmortem reductions in PNN density in schizophrenia reflect antemortem disease-related changes rather than artifacts of tissue processing, medication, or death.

    “a number of human post-mortem brain studies have revealed a disease-specific reduction in the density of PNNs as well as altered expression of genes that regulate PNNs and ECM in key brain structures associated with schizophrenia”

  • The paper relies on this without support.

    PNNs regulate developmental synaptic pruning in the cerebral cortex.

    “In light of the fact that PNNs are known to play a role in regulating developmental synaptic pruning in the cerebral cortex”

  • The paper relies on this without support.

    MMPs and ADAMTSs are the two families of endogenous extracellular metalloproteinases that cleave ECM components.

    “Two families of endogenous, extracellular metalloproteinases cleave ECM components: matrix metalloproteinase (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs).”

  • The paper relies on this without support.

    ECM components are normally turned over by cleavage.

    “Because cleavage of ECM components is part of their normal turnover process, a dysregulation in this process may be a prerequisite for neurological disease.”

  • The paper relies on this without support.

    Several CNS developmental processes—neuronal migration, axon outgrowth, synapse formation, synaptic activity, and myelination—are affected in schizophrenia.

    “all processes that have been postulated to be affected in schizophrenia.”

  • The paper relies on this without support.

    Schizophrenia-like behavioral deficits in RPTPβ-overexpressing animals correspond to schizophrenia phenotypes in humans.

    “indicating that enhanced RPTPβ signaling can contribute to schizophrenia phenotypes”
7 of 7

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Cites

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Research works printed but not linked: 1

  1. Golgi, 1898, Intorno alla struttura delle cellule nervose, Boll. Soc. Med. Chir. Pavia, 13, 1

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Authors
Bitanihirwe, B. K. Y., & Woo, T.-U. W.
Affiliations
  • University of Zurich (CH)
  • Beth Israel Deaconess Medical Center (US)
Corresponding author
Woo, Tsung-Ung W.
ORCID
Venue
Neuroscience & Biobehavioral Reviews
Publisher
Elsevier BV
Published
2014-09
Volume
45
Pages
85-99
ISSN
0149-7634 (ISSN-L)
DOI
10.1016/j.neubiorev.2014.03.018
PMC
PMC4447499
OpenAlex
W2050848379
Semantic Scholar
2ec5e797d34003fe803c80cc7e477ebb801ec3f3
Cited by
95
References
284
Citations by year
2026: 5 · 2025: 6 · 2024: 6 · 2023: 5 · 2022: 6 · 2021: 9 · 2020: 9 · 2019: 21 · 2018: 5 · 2017: 9 · 2016: 7 · 2015: 5 · 2014: 2
FWCI
1.06
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuroscience & Biobehavioral Reviews (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institutes of Health
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Keywords
perineuronal nets, schizophrenia, extracellular matrix, synaptic connectivity, synaptic plasticity, brain development, myelination, inhibitory neural networks, synaptic refinement, neuroprotection, therapeutic target
MeSH terms
Animals, Central Nervous System, Extracellular Matrix, Humans, Neuronal Plasticity, Neurons, Schizophrenia

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