Losing the sugar coating: Potential impact of perineuronal net abnormalities on interneurons in schizophrenia

In the paper

“Our group has shown marked decreases of PNNs in several brain regions of subjects diagnosed with SZ (Mauney et al., 2013; Pantazopolous et al., 2014; Pantazopoulos et al., 2010).”

What the sources say

• Not checked yetcites Mauney et al., 2013 source
• Not checked yetcites Pantazopolous et al., 2014
• Not checked yetcites Pantazopoulos et al., 2010 source

In the paper

“In particular, decreases of PNNs have been detected in the amygdala, entorhinal cortex and prefrontal cortex.”

• Also stated in: § 2. PERINEURONAL NET ABNORMALITIES IN SCHIZOPHRENIA · plain

  “Lower numbers of WFA-labeled PNNs were detected in the amygdala, entorhinal and prefrontal cortex (Mauney et al., 2013; Pantazopoulos et al., 2010).”

What the sources say

• Not checked yetcites Mauney et al., 2013 source
• Not checked yetcites Pantazopoulos et al., 2010 source

In the paper

“The distribution of these changes matches closely not only the normal distribution of WFA-labeled PNNs, but also that of GABAergic interneurons expressing PVB (Pantazopoulos et al., 2010).”

What the sources say

• Not checked yetcites Pantazopoulos et al., 2010 source

In the paper

“This result confirms the association of WFA-labeled PNNs with PVB-positive neurons, yet indicates that about a third of these PNNs ensheaths other neuronal populations. Among these are interneurons expressing somatostatin (Fig. 4; unpublished data), a particular interesting neuronal population in light of their expression of the voltage-gated potassium channel subunit Kv3, which may confer them”

In the paper

“Our results show that only approximately 54% of aggrecan-labeled PNNs were co-labeled with WFA.”

What the sources say

• Not checked yetcites Pantazopolous et al., 2014

In the paper

“Numbers of PNN immunolabeled for CS-6 (Pantazopolous et al., 2014), WFA, and v0/v1 isoforms of the CSPG versican were normal in this nucleus (Fig. 3; unpublished data).”

What the sources say

• Not checked yetcites Pantazopolous et al., 2014

In the paper

“In contrast, decreases of CS-6 immunoreactive PNNs were detected broadly across several amygdala nuclei, including the lateral, basal, accessory basal, cortical, and medial nuclei.”

What the sources say

• Not checked yetcites Pantazopolous et al., 2014

In the paper

“Remarkably, the central nucleus of the amygdala appears to be spared by these abnormalities in SZ.”

What the sources say

• Not checked yetcites Pantazopolous et al., 2014

In the paper

“Our results show marked reductions of aggrecan- and CS6-positive PNNs in the amygdala SZ subjects (effect size, aggrecan g=−0.82; 3B3 g= −1.71) (Fig. 5).”

What the sources say

• Not checked yetcites Pantazopolous et al., 2014

In the paper

“Recent findings from our group show that decreases of PNNs in the amygdala of subjects with SZ are accompanied by marked reductions of glial cells expressing aggrecan and CS6 sulfation (Pantazopoulos, submitted for publication).”

What the sources say

• Not checked yetcites Pantazopoulos, submitted for publication

In the paper

“Several studies in rodent, human and non-human primates have shown that a large population of WFA-labeled PNNs ensheaths fast-firing inhibitory interneurons expressing the calcium binding protein parvalbumin (PVB) and Kv3.1b, a subunit of voltage gated potassium channels typically expressed in fast-firing neurons (Brauer et al., 1993; Hartig et al., 1995; Morris and Henderson, 2000; Pantazopoulos”

What the sources say

• Not checked yetcites Brauer et al., 1993 source
• Not checked yetcites Hartig et al., 1995 source
• Not checked yetcites Morris and Henderson, 2000

In the paper

“Their components include chondroitin sulfate proteoglycans (CSPGs), hyaluronan, tenascin-R, link proteins, Reelin and semaphorin 3A (Carulli et al., 2013b; Deepa et al., 2006; Dick et al., 2013; Matthews et al., 2002; Vo et al., 2013a).”

What the sources say

• Not checked yetcites Carulli et al., 2013b
• Not checked yetcites Deepa et al., 2006 source
• Not checked yetcites Dick et al., 2013 source

In the paper

“Among these, GABAergic neurons undoubtedly represent one of the largest populations in several brain regions, including several cortical areas, striatum, hippocampus, inferior colliculus, septum and amygdala (Foster et al., 2014; Hartig et al., 1994; Lee et al., 2012; Pantazopoulos et al., 2006; Seeger et al., 1996; Shah and Lodge, 2013).”

What the sources say

• Not checked yetcites Foster et al., 2014 source
• Not checked yetcites Hartig et al., 1994 source
• Not checked yetcites Pantazopoulos et al., 2006 source

In the paper

“Perineuronal nets (PNNs) were shown to be markedly altered in subjects with schizophrenia.”

What the sources say

• Not checked yetcites Mauney et al., 2013 source
• Not checked yetcites Pantazopoulos et al., 2010 source

In the paper

“Long believed to be responsible primarily for structural support, PNNs have in recent years come to the forefront of neuroscience research as critical elements regulating synaptic functions and plasticity during development and adulthood (Beurdeley et al., 2012; Dityatev et al., 2010; Gogolla et al., 2009; Gundelfinger et al., 2010; Pizzorusso et al., 2002; Xue et al., 2014; Yamada and Jinno, 2013”

What the sources say

• Not checked yetcites Beurdeley et al., 2012 source
• Not checked yetcites Dityatev et al., 2010 source
• Not checked yetcites Pizzorusso et al., 2002 source

In the paper

“PNNs gradually mature in an experience-dependent manner during late stages of postnatal development, overlapping with the prodromal period/age of onset of schizophrenia.”

• Also stated in: § 3.2 PNN Regulation of Synaptic Plasticity and Learning · hedged

  “Relevant to the pathophysiology of SZ, in human and non-human primates these events span across adolescence and early adulthood, potentially coinciding with the prodromal period and onset of SZ (Hensch, 2004; Penn, 2001; Sturman and Moghaddam, 2011).”

What the sources say

• Not checked yetcites Hensch, 2004 source
• Not checked yetcites Penn, 2001 source
• Not checked yetcites Sturman and Moghaddam, 2011

In the paper

“Emerging evidence from human postmortem studies highlights the involvement of PNNs in schizophrenia (SZ) (Mauney et al., 2013; Pantazopolous et al., 2014; Pantazopoulos et al., 2010).”

What the sources say

• Not checked yetcites Mauney et al., 2013 source
• Not checked yetcites Pantazopolous et al., 2014
• Not checked yetcites Pantazopoulos et al., 2010 source

In the paper

“More recent evidence indicates that WFA-labeled PNNs are associated with more heterogeneous neuronal phenotypes than previously thought, including several subgroups of interneurons, a small subset of cortico-cortical pyramidal cells, spinal cord motor neurons and cerebellum Purkinje cells (Ajmo et al., 2008; Brauer et al., 1995; Bruckner et al., 1993; Gati and Lendvai, 2013; Hartig et al., 1995;”

What the sources say

• Not checked yetcites Ajmo et al., 2008 source
• Not checked yetcites Brauer et al., 1995 source
• Not checked yetcites Bruckner et al., 1993 source

In the paper

“We integrate these considerations with results from recent genetic studies showing genetic susceptibility for schizophrenia associated with genes encoding for PNN components, matrix-regulating molecules and immune system factors.”

• Also stated in: § 4. POTENTIAL CAUSES OF PNN ABNORMALITIES · plain

  “Our findings, together with recent findings from genetic studies showing that several vulnerability genes for SZ encode PNN components and enzymes involved in ECM remodeling (Buxbaum et al., 2008; Cichon et al., 2011; Dow et al., 2011; Groszewska et al., 2011; Ripke and Consortium, 2011; Ripke et al., 2013; Ripke and Schizophrenia Working Group of the Psychiatric Genomics, 2014; Rybakowski et al.,”

What the sources say

• Not checked yetcites Buxbaum et al., 2008 source
• Not checked yetcites Cichon et al., 2011 source
• Not checked yetcites Ripke et al., 2013 source

In the paper

“Furthermore, given the role of PNNs in regulating the trafficking of glutamate receptors (Frischknecht et al., 2009; Sinagra et al., 2005), it is possible that PNN loss may contribute to a decrease of NMDA receptors on PVB-expressing neurons neurons reported in the prefrontal cortex of subjects with SZ (Bitanihirwe et al., 2009).”

What the sources say

• Not checked yetcites Bitanihirwe et al., 2009 source

In the paper

“We suggest that a similar disruption of inhibitory activity may occur in subjects with SZ in brain regions affected by PNN abnormalities, such as the amygdala, entorhinal cortex and prefrontal cortex (Mauney et al., 2013; Pantazopolous et al., 2014; Pantazopoulos et al., 2010).”

What the sources say

• Not checked yetcites Mauney et al., 2013 source
• Not checked yetcites Pantazopolous et al., 2014
• Not checked yetcites Pantazopoulos et al., 2010 source

In the paper

“Second, PNNs divide the neuronal surface into multiple compartments, which control the diffusion of neurotransmitter receptors laterally within the plasma membrane (Fawcett, 2009; Frischknecht et al., 2009).”

What the sources say

• Not checked yetcites Fawcett, 2009 source
• Not checked yetcites Frischknecht et al., 2009 source

In the paper

“In animal models, increased activity from the amygdala has been shown to result in decreased GABA neurons in sector CA2/3 of the hippocampus, thus potentially contributing to hippocampal abnormalities in this region in SZ (Benes and Berretta, 2000, 2001; Berretta et al., 2004; Heckers and Benes, 2005; Konradi et al., 2011; Wang et al., 2011).”

What the sources say

• Not checked yetcites Benes and Berretta, 2000
• Not checked yetcites Berretta et al., 2004 source

In the paper

“Relevant to the pathophysiology of several psychiatric disorders, Reelin plays a key role in these latter mechanisms, interacting with integrins to regulate NMDA receptor subunit composition (Campo et al., 2009).”

What the sources say

• Not checked yetcites Campo et al., 2009 source

In the paper

“Thus, PNN disruption may impact the activity of intrinsic circuitry and consequent information outflow.”

In the paper

“PNNs form perisynaptic condensations of organized ECM, which become an integral component of the functional synaptic complex.”

What the sources say

• Not checked yetcites Dityatev and Schachner, 2006
• Not checked yetcites Frischknecht and Gundelfinger, 2012 source

In the paper

“As discussed, these are predominantly represented by GABAergic neurons, including, but not restricted to, those expressing PVB and somatostatin (Adams et al., 2001; Brauer et al., 1993; Bruckner et al., 1993; Hartig et al., 1995; Hartig et al., 2001; Haunso et al., 1999; Morris and Henderson, 2000; Pantazopoulos et al., 2006; Wintergerst et al., 1996) (Pantazopoulos et al., unpublished”

What the sources say

• Not checked yetcites Adams et al., 2001 source
• Not checked yetcites Brauer et al., 1993 source
• Not checked yetcites Hartig et al., 1995 source

In the paper

“In the prefrontal cortex, PNN degradation may affect gamma oscillatory activity originating from interneurons expressing parvalbumin (Carter et al., 1998; Kim and Webster, 2010; Lewis and Gonzalez-Burgos, 2008; Manoach et al., 1999; Spencer, 2008; Uhlhaas and Singer, 2010; Woo et al., 2010).”

What the sources say

• Not checked yetcites Carter et al., 1998 source
• Not checked yetcites Lewis and Gonzalez-Burgos, 2008
• Not checked yetcites Spencer, 2008 source

In the paper

“In the mammalian brain, the composition and properties of the ECM undergo a profound transformation during late postnatal development (Fawcett, 2009; Gundelfinger et al., 2010; Lander et al., 1997).”

What the sources say

• Not checked yetcites Fawcett, 2009 source
• Not checked yetcites Gundelfinger et al., 2010 source
• Not checked yetcites Lander et al., 1997 source

In the paper

“These findings show that PNN abnormalities in SZ impact several distinct PNNs phenotypes and neuronal populations, many likely to correspond to interneurons.”

In the paper

“A juvenile form of ECM, supportive of neurogenesis, cell migration, axonal outgrowth and synaptogenesis, is substituted by an adult form, which predominantly restricts plasticity (Bandtlow and Zimmermann, 2000; Faissner et al., 2010; Fawcett, 2009; Galtrey and Fawcett, 2007).”

What the sources say

• Not checked yetcites Bandtlow and Zimmermann, 2000 source
• Not checked yetcites Faissner et al., 2010 source
• Not checked yetcites Fawcett, 2009 source

In the paper

“Notable examples are interactions of ECM molecules with ‘neuronal activity-regulated pentraxin’ (Narp) complexes and integrins, shown to regulate AMPA and NMDA receptor subunit composition, synaptic clustering and homeostatic synaptic scaling in GABAergic neurons (Campo et al., 2009; Chang et al., 2010; Cingolani et al., 2008; Dityatev et al., 2010; Frischknecht and Gundelfinger, 2012).”

What the sources say

• Not checked yetcites Campo et al., 2009 source
• Not checked yetcites Chang et al., 2010 source
• Not checked yetcites Cingolani et al., 2008 source

In the paper

“Consistently, PNN enzymatic digestion results in increased excitability of interneurons (Dityatev et al., 2007).”

What the sources say

• Not checked yetcites Dityatev et al., 2007 source

In the paper

“Relevant to the pathophysiology of SZ, in human and non-human primates these events span across adolescence and early adulthood, potentially coinciding with the prodromal period and onset of SZ (Hensch, 2004; Penn, 2001; Sturman and Moghaddam, 2011).”

What the sources say

• Not checked yetcites Hensch, 2004 source
• Not checked yetcites Penn, 2001 source
• Not checked yetcites Sturman and Moghaddam, 2011

In the paper

“Notably, this mechanism was shown to depend on GABAergic transmission, pointing at the interactions between inhibitory interneurons and PNNs in plastic mechanisms.”

What the sources say

• Not checked yetcites Gogolla et al., 2009 source

In the paper

“Specifically, Gogolla and coworkers demonstrated that PNNs in the amygdala are necessary to protect fear-related memories from full erasure following extinction (Gogolla et al., 2009).”

What the sources say

• Not checked yetcites Gogolla et al., 2009 source

In the paper

“Thus, these findings raise the possibility that decreased CSPG synthesis in glial cells may contribute PNN reductions in SZ.”

In the paper

“Further support for the neuroprotective properties of PNNs comes from postmortem findings on older subjects, showing that neurons enveloped by PNNs contain less of the lysosomal pigment lipofucsin, which accumulates as a consequence of oxidative processes (Morawski et al., 2004).”

What the sources say

• Not checked yetcites Morawski et al., 2004 source

In the paper

“Our findings, together with recent findings from genetic studies showing that several vulnerability genes for SZ encode PNN components and enzymes involved in ECM remodeling (Buxbaum et al., 2008; Cichon et al., 2011; Dow et al., 2011; Groszewska et al., 2011; Ripke and Consortium, 2011; Ripke et al., 2013; Ripke and Schizophrenia Working Group of the Psychiatric Genomics, 2014; Rybakowski et al.,”

What the sources say

• Not checked yetcites Buxbaum et al., 2008 source
• Not checked yetcites Cichon et al., 2011 source
• Not checked yetcites Dow et al., 2011 source

In the paper

“Consistent with this possibility, altered fear learning, and related activity of the PFC and amygdala, has been reported in subjects with SZ (Holt et al., 2012; Holt et al., 2009).”

What the sources say

• Not checked yetcites Holt et al., 2012 source
• Not checked yetcites Holt et al., 2009 source

In the paper

“Emerging evidence shows that PNNs may play a key role in protecting neurons from oxidative stress, such as it may be caused by a decrease of glutathione, a key brain antioxidant found to be decreased in SZ (Cabungcal et al., 2013; Gawryluk et al., 2011; Suttkus et al., 2014).”

What the sources say

• Not checked yetcites Cabungcal et al., 2013 source
• Not checked yetcites Gawryluk et al., 2011 source
• Not checked yetcites Suttkus et al., 2014 source

In the paper

“In addition, recently reported genetic vulnerabilities for CSPG genes, including PTPRZ1 and neurocan (Buxbaum et al., 2008; Muhleisen et al., 2012; Ripke and Schizophrenia Working Group of the Psychiatric Genomics, 2014), may contribute to decrease CSPG synthesis in SZ.”

What the sources say

• Not checked yetcites Buxbaum et al., 2008 source
• Not checked yetcites Muhleisen et al., 2012 source
• Not checked yetcites Ripke and Schizophrenia Working Group of the Psychiatric Genomics, 2014 source

In the paper

“However, PNNs may in turn be vulnerable to oxidative stress, as shown in mice with a genetic redox dysregulation (Cabungcal et al., 2013).”

What the sources say

• Not checked yetcites Cabungcal et al., 2013 source

In the paper

“In particular, PNN components such as aggrecan, tenascin-R, and link proteins are essential for this protection (Suttkus et al., 2014).”

What the sources say

• Not checked yetcites Suttkus et al., 2014 source

In the paper

“In the visual cortex, where this process has been most extensively studied, PNN maturation around PVB-expressing neurons closes the critical period for ocular dominance (Pizzorusso et al., 2002).”

What the sources say

• Not checked yetcites Pizzorusso et al., 2002 source

In the paper

“Similarly, and particularly relevant to findings in SZ, PNN maturation in the amygdala determines the transition from juvenile to adult forms of emotion-related plasticity (Gogolla et al., 2009; Xue et al., 2014).”

What the sources say

• Not checked yetcites Gogolla et al., 2009 source
• Not checked yetcites Xue et al., 2014 source

In the paper

“Consistent with this hypothesis, a recent gene expression profiling study of the superior temporal gyrus in subjects with SZ showed altered mRNA expression of MMPs and ADAMTSs, including MMP16 (Pietersen et al., 2014).”

What the sources say

• Not checked yetcites Pietersen et al., 2014 source

In the paper

“First, converging results from several recent genetic association and genome-wide association studies indicate that genes encoding for a number of metzincin metalloproteases may represent vulnerability factors for SZ.”

What the sources say

• Not checked yetcites Bespalova et al., 2012 source
• Not checked yetcites Dow et al., 2011 source
• Not checked yetcites McGrath et al., 2013 source

In the paper

“We suggest that altered expression of members of the metzincin family of metalloproteases may contribute to a disruption of PNNs in SZ.”

In the paper

“These abnormalities may result from complex interactions of genetic vulnerabilities of genes encoding for CSPGs, metalloproteases and immune system molecules with environmental factors leading to stress and immune system activation”

In the paper

“In turn, these may result in a disruption of cognitive and emotional processing.”

In the paper

“Second, PNN integrity and expression of metalloproteases are markedly affected by stress and immune responses (Fillman et al., 2014; Franklin et al., 2008; Gray et al., 2008; Medina-Flores et al., 2004).”

What the sources say

• Not checked yetcites Fillman et al., 2014 source
• Not checked yetcites Franklin et al., 2008 source
• Not checked yetcites Gray et al., 2008 source

In the paper

“Emerging evidence supports the intriguing idea that the ECM, both in its developmental and adult forms, is constantly remodeled in response to a broad variety of stimuli, which in adulthood include learning and memory, stress, and immune system activation (Frischknecht and Gundelfinger, 2012).”

What the sources say

• Not checked yetcites Frischknecht and Gundelfinger, 2012 source

In the paper

“For instance, ADAMTSs are known to cleave multiple PNN components including the CSPGs aggrecan, brevican, neurocan, versican, and phosphacan (Fig. 2) (Porter et al., 2005; Tauchi et al., 2012).”

What the sources say

• Not checked yetcites Porter et al., 2005 source
• Not checked yetcites Tauchi et al., 2012 source

In the paper

“Notably, altered expression of MMPs and ADAMTS was found to be associated with PNN reduction (Gray et al., 2008).”

What the sources say

• Not checked yetcites Gray et al., 2008 source

In the paper

“Thus, expression of several metalloproteases may be altered in subjects with SZ as a result of genetic predisposition.”

In the paper

“Similar disruption of MMP3 and MMP9 activity in the hippocampus results in disruption of spatial memory and avoidance learning (Nagy et al., 2007; Wright et al., 2007).”

What the sources say

• Not checked yetcites Nagy et al., 2007 source
• Not checked yetcites Wright et al., 2007 source