Schizophrenia Research Forum - A Catalyst for Creative Thinking
Home Profile Membership/Get Newsletter Log In Contact Us
 For Patients & Families
What's New
Recent Updates
SRF Papers
Current Papers
Search All Papers
Search Comments
News
Research News
Conference News
Plain English
Forums
Current Hypotheses
Idea Lab
Online Discussions
Virtual Conferences
Interviews
Resources
What We Know
SchizophreniaGene
Animal Models
Drugs in Trials
Research Tools
Grants
Jobs
Conferences
Journals
Community Calendar
General Information
Community
Member Directory
Researcher Profiles
Institutes and Labs
About the Site
Mission
History
SRF Team
Advisory Board
Support Us
How to Cite
Fan (E)Mail
The Schizophrenia Research Forum web site is sponsored by the Brain and Behavior Research Foundation and was created with funding from the U.S. National Institute of Mental Health.
Research News
back to News Search
Safety Net: Perineuronal Nets Protect Interneurons Linked to Schizophrenia

17 May 2013. One of the focal points of schizophrenia research over the past decade has been abnormalities detected in a subgroup of prefrontal cortex interneurons distinguished by the fact that they contain the molecule parvalbumin. A new study published May 13 in the Proceedings of the National Academy of Sciences finds that these neurons appear to have protective shields against oxidative stress, suggesting a mechanism that could go awry in schizophrenia.

The study, led by Kim Do of the University of Lausanne, Switzerland, explored the function of neuron-swathing sheaths called “perineuronal nets” (PNNs) in mice. The researchers found that PNNs surrounding parvalbumin-containing (PV+) interneurons limited their levels of oxidative stress, and that degrading the PNNs led to increased oxidative stress and desynchronized brain activity.

The findings highlight the workings of PV+ interneurons, which have been implicated in schizophrenia by a number of studies. Postmortem studies have found that PV+ interneurons are low on GAD67, the enzyme that makes the inhibitory neurotransmitter γ-aminobutyric acid (GABA), as well as PV itself (Lewis et al., 2012). These inhibitory neurons emit rapid-fire action potentials and are key controllers of synchronous activity in the brain, including the γ waves linked to working memory which are affected by schizophrenia. Electroencephalogram (EEG) studies find degraded synchrony in schizophrenia, possibly reflecting weakened inhibitory signaling in the brain.

The new study suggests that the extracellular matrix molecules that comprise PNNs surrounding PV+ interneurons have a hand in compromising their function. Fewer PNNs have been found in a postmortem study of schizophrenia (see SRF related news story), and clues from other research have suggested that a PNN’s meshwork of protein and carbohydrate molecules provides more than just a place for a neuron to sit. PNNs have been suggested to stabilize synapses, to end critical periods during development (Kwok et al., 2011), and to offer a measure of protection against oxidative stress (Morawski et al., 2004). The new study supports the last idea and suggests that protection by PNNs is particularly important to PV+ interneurons, which may be more vulnerable to oxidative stress because their fast spiking comes with a high metabolic demand.

Oxidative stress-test
Intense firing in PV+ interneurons can generate reactive oxidative molecules within the cell. At sufficiently high levels, this can damage the cell’s innards, including its DNA. To guard against this, cells have other “antioxidant” molecules to sop up these reactive oxygen species. First authors Jan-Harry Cabungcal and Pascal Steullet explored their hypothesis that PNNs shield PV+ interneurons from oxidative stress using mice genetically engineered to be especially vulnerable to oxidative stress. These mice lacked a subunit of an enzyme called glutamate cysteine ligase (Gclm), which produces glutathione, an antioxidant. Gclm knockouts have lower than usual glutathione, akin to what Do and colleagues have previously found in schizophrenia (Do et al., 2000). Similarly, they have reported a genetic association between the GCLM gene and schizophrenia (Tosic et al., 2006), suggesting a role for oxidative stress in the disorder (see SRF related news story).

Using a product of DNA oxidation as a marker of oxidative stress, the researchers found higher levels of oxidative stress in neurons of the anterior cingulate cortex of Gclm knockouts compared to wild-type mice; however, the number of PV+ interneurons and PNNs detected were the same between the two groups at postnatal day 90. But growing up under chronic oxidative stress eventually took its toll: by postnatal day 180, the researchers counted fewer PV+ interneurons, but the same number of PNNs, compared to wild-type mice. This suggested to them that the lost PV+ interneurons may have been those without good PNNs.

The researchers found further support for this when they did a cell-by-cell accounting of how well oxidative stress correlated with the integrity of the PNN. For this experiment, they acutely increased oxidative stress further, using a dopamine reuptake inhibitor called GBR that increases reactive oxygen species, in addition to increasing extracellular dopamine. Under these conditions, the degree of DNA oxidation label was inversely correlated with PNN density (r = 0.42, P = 0.0032), which suggests that the better the PNN surrounding a cell, the less oxidative stress felt by the cell.

Stripping away the nets
The researchers also noticed that GBR treatment brought on a decrease in PNN label around PV+ interneurons in Gclm knockouts, but not in controls, suggesting that the PNN meshwork itself is sensitive to oxidative stress. This was further supported in a conditional knockout experiment using mice that lacked the glutathione-making enzyme only in PV+ interneurons: substantially lower numbers of both PV+ interneurons and PNNs were found, compared to wild-type mice. This indicates that oxidative stress inside a cell can degrade PV expression within the cell and PNN integrity outside of the cell, but it remains unclear whether PNN degradation comes before or after PV reduction.

Finally, the researchers stripped neurons of their PNNs with an enzyme called chondroitinase ABC (ChABC) injected in one side of the anterior cingulate cortex of Gclm knockouts. Following this with 11 days of GBR treatment, the researchers found a significant decrease in PV+ interneurons and a concomitant increase in oxidative stress marker in the ChABC injected side compared to the sham-injected hemisphere. The researchers did not find a decrease in calbindin and calretinin types of interneurons, however, which argues that PNNs are specific to the PV+ type of interneuron.

Taking brain slices from these animals, the researchers found that the rhythmic activity induced from ChABC-treated hemispheres was weaker: specifically, the power of oscillations in the frequency of the β and γ bands (13-28 Hz and 30-60 Hz, respectively) was decreased in the ChABC-treated hemispheres of GBR treated Gclm knockouts compared to the sham-injected hemispheres. The combination of PNN loss and oxidative stress seemed necessary to reduce oscillations in this range because when this experiment was done in wild-type mice, the ChABC-treated hemispheres had higher levels of β and γ oscillations.

Future work will have to assess whether these nets actually protect PV+ interneurons from oxidative stress in schizophrenia. Although a clear role for oxidative stress in schizophrenia is not yet settled, the findings illustrate how seemingly innocuous changes to extracellular matrix molecules can translate into widespread changes in brain activity.—Michele Solis.

Reference:
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 13. Abstract

 
Comments on News and Primary Papers
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...  Read more


View all comments by John Enwright

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...  Read more


View all comments by Sabina Berretta
View all comments by Harry Pantazopoulos

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...  Read more


View all comments by L. Elliot Hong
Submit a Comment on this News Article
Make a comment on this news article. 

If you already are a member, please login.
Not sure if you are a member? Search our member database.

*First Name  
*Last Name  
Affiliation  
Country or Territory  
*Login Email Address  
*Confirm Email Address  
*Password  
*Confirm Password  
Remember my Login and Password?  
Get SRF newsletter with recent commentary?  
 
Enter the code as it is shown below:
This code helps prevent automated registrations.

I recommend the Primary Papers

Please note: A member needs to be both registered and logged in to submit a comment.

Comment:

(If coauthors exist for this comment, please enter their names and email addresses at the end of the comment.)

References:


SRF News
SRF Comments
Text Size
Reset Text Size
Email this pageEmail this page

Share/Bookmark
Copyright © 2005- 2014 Schizophrenia Research Forum Privacy Policy Disclaimer Disclosure Copyright