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Cabungcal JH, Steullet P, Morishita H, Kraftsik R, Cuenod M, Hensch TK, Do KQ. Perineuronal nets protect fast-spiking interneurons against oxidative stress. Proc Natl Acad Sci U S A. 2013 May 28 ; 110(22):9130-5. Pubmed Abstract

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Primary Papers: Perineuronal nets protect fast-spiking interneurons against oxidative stress.

Comment by:  John Enwright
Submitted 30 May 2013
Posted 30 May 2013

Multiple studies have demonstrated various roles of perineuronal nets (PNNs) in normal neuronal functions such as regulating synaptic plasticity, ion homeostasis, and critical period closure (Karetko and Skangiel-Kramska, 2009). Furthermore, in subjects with schizophrenia, PNNs have been shown to be disrupted (Pantazopoulos et al., 2010), and other studies have reported evidence of elevated oxidative stress in schizophrenia (Gawryluk et al., 2011). The findings in this paper suggesting a link between the two is intriguing.

A specific population of neurons—cortical fast-spiking, parvalbumin (PV)-positive inhibitory neurons—may be especially vulnerable to oxidative stress. These same neurons are thought to be critical in the generation of γ oscillations, which are thought to underlie working memory, and are disrupted in schizophrenia (Lewis and Sweet, 2009). Interestingly, the authors report altered γ power (a measure of the strength of γ oscillations) and reductions in the number of PV cells after prolonged periods of oxidative stress, but without alterations in PNNs. However, it is unclear if the reduction in PV cell number is due to cell death or reduced PV expression, and why this level of oxidative stress is not sufficient to alter PNNs. Under conditions of more pronounced oxidative stress (the GCLM knockout mice that have been treated for 10 days with GBR), alterations in PNNs become apparent. Furthermore, an interesting correlation between the levels of oxidative stress and decreased PNN labeling is apparent. Together, these data suggest that PNNs may be both neuroprotective and affected by high levels of oxidative stress. It would be interesting to know if the decreased PNN labeling is due to loss of only the glycosaminoglycans (which WFA labels) or a more complete alteration in PNN structure (e.g., loss of core structural proteins such as the lecticans and link proteins). Perhaps the most interesting data are those that show direct alterations of PNNs (by use of chondroitinase ABC to dissolve PNNs) further increase vulnerability to oxidative stress (measured by loss of PV cells, increased levels of an oxidative stress marker, and alteration in oscillatory power).

This study suggests an important link between two seemingly (up to this point) unrelated observations (altered PNNs and elevated oxidative stress) seen in schizophrenia and argues for a specific role of PNNs in the pathogenesis of the disease. While the 70 percent reduction in glutathione in the GCLM knockout mice is sufficient to double levels of oxidative stress, PV cell number (at least in young adults) and PNN labeling are not affected. The authors suggest that the cumulative effects of oxidative stress, instead of the absolute levels, are critical to the alterations reported. It would be interesting to know how the levels of oxidative stress in this study compare to oxidative stress levels seen in human subjects and if correlations exist among oxidative stress, PV, and PNNs in the same human postmortem tissue. Such information would further enhance the findings reported here, as the combination of GBR and GCLM knockouts may induce levels of oxidative stress that are much higher than those seen in postmortem tissue (where PNNs, PV levels, and oxidative stress are altered). It will also be interesting to learn whether increased oxidative stress or decreased PNNs are the more critical “upstream factor” in such a potential pathogenic cascade, or if both alterations in the disease state are consequences of a common upstream factor. Overall, the authors propose an interesting and plausible interaction between PNNs and oxidative stress and provide evidence for a potential role of the PNN in the pathogenesis of schizophrenia.


Karetko M, Skangiel-Kramska J. Diverse functions of perineuronal nets. Acta Neurobiol Exp. 2009; 69: 564-577. Abstract

Pantazopoulos H, Woo TW, Lim MP, Lange N, Berretta S. Extracellular Matrix-Glial Abnormalities in the Amygdala and Entorhinal Cortex of Subjects Diagnosed With Schizophrenia. Arch Gen Psychiatry 2010; 67(2): 155-166. Abstract

Gawryluk JW, Wang JF, Andreazza AC, Shao L, Young LT. Decreased levels of glutathione, the major brain antioxidant, in post-morterm prefrontal cortex from patients with psychiatric disorders. Int J Neuropsychopharmacol. 2011; 14(1): 123-30. Abstract

Lewis DA, Sweet RA. Schizophrenia from a neural circuitry perspective: advancing toward rational pharmacological therapies. The Journal of Clinical Investigation 2008; 119(4): 706-716. Abstract

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Primary Papers: Perineuronal nets protect fast-spiking interneurons against oxidative stress.

Comment by:  Sabina BerrettaHarry Pantazopoulos
Submitted 30 May 2013
Posted 3 June 2013
  I recommend this paper

This elegant study explores the relationships among three potential key factors in the pathophysiology of schizophrenia, i.e., abnormalities affecting neurons expressing parvalbumin, perineuronal nets, and oxidative stress/glutathione reduction.

Perineuronal nets are new players in the field of schizophrenia; in fact, their role in normal brain functions has only recently come to the forefront of neuroscience. These specialized extracellular matrix structures form around the somata, dendrites, and proximal segment of the axon of distinct neuronal populations during late postnatal development (Brückner et al., 2006; Galtrey and Fawcett, 2007). Their activity-driven maturation stabilizes successful synaptic connections and, at least in some brain regions, culminates with the closure of critical periods of development and instatement of adult plastic modalities (Pizzorusso et al., 2002; Gogolla et al., 2009). Perineuronal net adult functions include regulation of glutamatergic receptor within the postsynaptic specialization and availability to the neuron of growth factors, non-cell autonomous homeoproteins, and other factors diffusing through the extracellular space (Frischknecht et al., 2009; Maeda, 2010; Beurdeley et al., 2012). Their multifold relevance to the pathophysiology of schizophrenia resides in recent findings showing that marked perineuronal nets decrease in several brain regions of people with schizophrenia, predominant association with parvalbumin-expressing neurons, interactions with glutamatergic, GABAergic, and dopaminergic neurotransmitter systems, and maturation during late development periods, potentially coinciding with developmental stages leading to the clinical manifestations of schizophrenia (Frischknecht et al., 2009; Pantazopoulos et al., 2010; Berretta, 2012; Mauney et al., 2013).

Lack of perineuronal nets may thus contribute to several key aspects of the pathophysiology of schizophrenia. Perineuronal net abnormalities may be postulated to disrupt preservation of successful sets of synaptic connections and internalization of factors necessary to the maintenance of mature neuronal properties (Beurdeley et al., 2012). They may impact on glutamatergic receptor functional availability in parvalbumin-expressing neurons and these neurons' electrophysiological properties, impairing their ability to modulate the outflow of information from projection neurons and to drive γ-oscillatory rhythms (Bitanihirwe et al., 2009; Frischknecht et al., 2009; Shah and Lodge, 2013).

The results by Cabungcal and colleagues support several of these possibilities and add a novel and exciting dimension to the potential role of perineuronal nets in schizophrenia. The emerging model suggests that perineuronal nets may counteract the intrinsic vulnerability of parvalbumin-expressing neurons by acting as a shield, protecting them against oxidative stress. Despite this protective effect, perineuronal nets are here also shown to be damaged by oxidative stress, which in schizophrenia may result, at least in part, from a reduction of glutathione expression. Thus, during the course of the disease, oxidative stress may weaken perineuronal nets and eventually impact on parvalbumin-expressing neurons. Alternatively, it may be postulated that failure to form functional perineuronal nets during development, perhaps due to developmental and/or genetic factors, may deprive parvalbumin-expressing neurons of their protective shield, enhancing their vulnerability to the effects of glutathione reduction/oxidative stress, and ultimately resulting in neurochemical and functional damage to these neurons. In either case, these models represent compelling, testable hypotheses on the potential pathophysiological links among glutathione reduction, parvalbumin-expressing neuron abnormalities, and perineuronal net decreases in schizophrenia. Testing these hypotheses will provide important insight into the pathophysiology of schizophrenia.


Berretta S, 2012. Extracellular matrix abnormalities in schizophrenia. Neuropharmacology. Abstract

Beurdeley M, Spatazza J, Lee HH, Sugiyama S, Bernard C, Di Nardo AA, Hensch TK, Prochiantz A, 2012. Otx2 binding to perineuronal nets persistently regulates plasticity in the mature visual cortex. J Neurosci 32, 9429-9437. Abstract

Bitanihirwe BK, Lim MP, Kelley JF, Kaneko T, Woo TU, 2009. Glutamatergic deficits and parvalbumin-containing inhibitory neurons in the prefrontal cortex in schizophrenia. BMC Psychiatry 9, 71. Abstract

Brückner G, Szeoke S, Pavlica S, Grosche J, Kacza J, 2006. Axon initial segment ensheathed by extracellular matrix in perineuronal nets. Neuroscience 138, 365-375. Abstract

Frischknecht R, Heine M, Perrais D, Seidenbecher CI, Choquet D, Gundelfinger ED, 2009. Brain extracellular matrix affects AMPA receptor lateral mobility and short-term synaptic plasticity. Nat Neurosci. Abstract

Galtrey CM, Fawcett JW, 2007. The role of chondroitin sulfate proteoglycans in regeneration and plasticity in the central nervous system. Brain Res Rev 54, 1-18. Abstract

Gogolla N, Caroni P, Luthi A, Herry C, 2009. Perineuronal nets protect fear memories from erasure. Science 325, 1258-1261. Abstract

Maeda N, 2010. Structural variation of chondroitin sulfate and its roles in the central nervous system. Cent Nerv Syst Agents Med Chem 10, 22-31. Abstract

Mauney SA, Athanas KM, Pantazopoulos H, Shaskan N, Passeri E, Berretta S, Woo T-UW, 2013. Developmental pattern of perineuronal nets in the human prefrontal cortex and their deficit in schizophrenia. Biological Psychiatry in press.

Pantazopoulos H, Woo T-UW, Lim MP, Lange N, Berretta S, 2010. Extracellular Matrix-Glial Abnormalities in the Amygdala and Entorhinal Cortex of Subjects Diagnosed With Schizophrenia. Arch Gen Psychiatry 67, 155-166. Abstract

Pizzorusso T, Medini P, Berardi N, Chierzi S, Fawcett JW, Maffei L, 2002. Reactivation of ocular dominance plasticity in the adult visual cortex. Science 298, 1248-1251. Abstract

Shah A, Lodge DJ, 2013. A loss of hippocampal perineuronal nets produces deficits in dopamine system function: relevance to the positive symptoms of schizophrenia. Transl Psychiatry 3, e215. Abstract

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Primary Papers: Perineuronal nets protect fast-spiking interneurons against oxidative stress.

Comment by:  L. Elliot Hong
Submitted 4 June 2013
Posted 4 June 2013

Neural cells in the central nervous system are supported by extracellular structures organized by chondroitin sulphate proteoglycans, also called perineuronal nets (PNNs). This paper by Cabungcal et al., centered on the PNNs, offers a novel mechanism that could potentially integrate several currently somewhat segregated pathophysiologies, i.e., oxidative stress, neural plasticity, excessive dopamine, parvalbumin (PV)-positive GABAergic interneurons, and neural oscillations, all of which have been associated with schizophrenia.

The study showed that degradation of mature PNNs in mice renders PV-immunoreactive cells in the anterior cingulate cortex more vulnerable to chronic oxidative stress. Decrease in PV cells, in turn, leads to reduced local neural oscillations in the β and γ frequency range. The authors also demonstrated that PNNs and PV-interneurons are both sensitive to excessive oxidative stress; immature PV cells in early development may have less PNN protection, and these cells are particularly vulnerable to oxidative stress; and finally, older, but not younger, mice exposed to chronic oxidative stress and low glutathione have reduced PV cells and impaired neural oscillations. A more detailed summary of these findings is already provided by Michele Solis at this Forum.

If increased oxidative stress degrades the extracellular chondroitin sulphate proteoglycans in schizophrenia patients, as suggested by these intriguing sets of innovative animal experiments, what could be the consequences that are relevant to the clinical pathophysiology seen in schizophrenia patients? Intact extracellular chondroitin sulphate proteoglycans play critical roles in neural development. Prior to the maturation of PNNs, neural networks have high levels of plasticity. Lack of completely matured PNNs allows many essential neuroplasticity functions such as organization of ocular dominance (Pizzorusso et al., 2002), permanent extinction of fear memory (Gogolla et al., 2009), and elongation of axons (Snow et al., 1990) to occur. Experimentally removing the PNN has been associated with reactivation of these fundamental plasticity processes (Pizzorusso et al., 2002; Gogolla et al., 2009). In that case, one could extrapolate that oxidative stress-induced PNN erosion may lead to inappropriate reactivation or delayed closure of certain brain plasticity, which could lead to the often observed or postulated plasticity abnormalities in schizophrenia.

Another striking functional demonstration of PNN and oxidative stress by Cabungcal et al. is the interaction between PNN and dopamine-induced oxidative stress on neural oscillations. Pharmacologically removed PNN without additional oxidative stress is associated with increased power in β and γ frequency neural oscillations. However, with the presence of dopamine-induced oxidative stress, removing PNN leads to reduced PV immunoreactive cells and reduced power in β and γ frequency neural oscillations. This is fascinating. Both significantly higher γ band and significantly lower γ band synchronization have been reported in schizophrenia patients, an inconsistency rarely addressed in the literature, perhaps due to the unclear underlying mechanisms. This work by Cabungcal et al. provides one potentially new mechanism to help rethink the underlying dynamics leading to these clinical neural oscillation dysfunctions.


Pizzorusso T, Medini P, Berardi N, Chierzi S, Fawcett JW, Maffei L. Reactivation of ocular dominance plasticity in the adult visual cortex. Science. 2002 Nov 8;298(5596):1248-51. Abstract

Snow DM, Steindler DA, Silver J. Molecular and cellular characterization of the glial roof plate of the spinal cord and optic tectum: a possible role for a proteoglycan in the development of an axon barrier. Dev Biol. 1990 Apr;138(2):359-76. Abstract

Gogolla N, Caroni P, Lüthi A, Herry C. Perineuronal nets protect fear memories from erasure. Science. 2009 Sep 4;325(5945):1258-61. Abstract

View all comments by L. Elliot Hong