Chondroitin sulfate proteoglycans (CSPGs) are a main component of the brain extracellular matrix (ECM). Findings from our group, recently published in the Archives of General Psychiatry, point to substantial abnormalities affecting CSPGs in the amygdala and entorhinal cortex of subjects with schizophrenia, but not bipolar disorder. Marked increases of glial cells expressing CSPGs were not accompanied by astrocytosis, suggesting schizophrenia-specific anomalous regulation of CSPG expression. Concurrent reductions of perineuronal nets, CSPG-enriched ECM aggregates surrounding distinct neuronal populations, point to altered CSPG content in the ECM. CSPG functions, such as regulation of neuronal migration, stabilization of synaptic connectivity, maintenance of neuronal networks, neuronal microenvironment and volume transmission, bear direct relevance to the pathophysiology of schizophrenia. These functions, together with the magnitude of CSPG changes (419-1560%) in amygdala and entorhinal cortex of subjects with schizophrenia, point to a pivotal role for a disruption of glial-ECM-neuronal interactions in the pathogenesis of this disease. The main goal of the postmortem and in vitro studies proposed here is to test the hypothesis that molecular pathways regulating CSPGs may be altered in schizophrenia, causing CSPG accumulation in astrocytes and abnormal CSPG expression in extracellular matrix perineuronal aggregates. These studies are organized in four specific aims, designed to test interrelated aspects of this model.
Specific Aim 1 will test the hypothesis that, in schizophrenia, increased CSPG-positive glial cells in medial temporal lobe regions correspond to astrocytes, as suggested by previous results.
Specific Aim 2 will test the hypothesis that the molecular pathways regulating CSPG synthesis and secretion into the ECM are disrupted in the medial temporal lobe of subjects with schizophrenia.
Specific Aim 3 will test the hypothesis that CSPG expression within the ECM may be reduced, resulting in CSPGs-impoverished perineuronal nets surrounding parvalbumin-expressing neurons. In vitro manipulations on cultured human astrocytes will be used in Specific Aim 4 to test dynamically the potential of growth factors and secretory carrier membrane proteins, investigated in Specific Aim 2, to cause CSPG accumulation in human astrocytes and decreased CSPG secretion into the extracellular space.
In Specific Aims 1, 2 and 3, a group of subjects with bipolar disorder will be included to test whether CSPG abnormalities are specific to schizophrenia or represent a shared feature among major psychoses. The relevance of the proposed studies resides in their potential of uncovering an as yet unknown and distinctive aspect of the pathophysiology of SZ, affecting brain regions known to play an important role in this disease. We put forward that extracellular matrix/glial abnormalities may represent a unifying factor contributing to disturbances of neuronal migration, synaptic connectivity, and GABAergic, glutamatergic and dopaminergic neurotransmission in schizophrenia.

Public Health Relevance

The relevance of the proposed studies resides in their contribution to the understanding of the molecular mechanisms and cellular populations involved in extracellular matrix abnormalities in schizophrenia, a novel and potentially distinctive aspect of the pathophysiology of this disease. Such abnormalities may affect a broad range of developmental and adult neural functions such as neuronal migration, neurotransmission and synaptic plasticity. Set in the context of the medial temporal lobe role in emotion and perceptual processing, a disruption of such functions may play a key role in the pathophysiology of some of the main symptoms of schizophrenia, such as flat affect, social and cognitive impairment, delusional thinking and anxiety.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH086522-03
Application #
8371238
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Meinecke, Douglas L
Project Start
2010-12-01
Project End
2015-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
3
Fiscal Year
2013
Total Cost
$379,200
Indirect Cost
$139,200
Name
Mclean Hospital
Department
Type
DUNS #
046514535
City
Belmont
State
MA
Country
United States
Zip Code
02478
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Sethi, Manveen K; Zaia, Joseph (2017) Extracellular matrix proteomics in schizophrenia and Alzheimer's disease. Anal Bioanal Chem 409:379-394
Pantazopoulos, Harry; Wiseman, Jason T; Markota, Matej et al. (2017) Decreased Numbers of Somatostatin-Expressing Neurons in the Amygdala of Subjects With Bipolar Disorder or Schizophrenia: Relationship to Circadian Rhythms. Biol Psychiatry 81:536-547
Sorg, Barbara A; Berretta, Sabina; Blacktop, Jordan M et al. (2016) Casting a Wide Net: Role of Perineuronal Nets in Neural Plasticity. J Neurosci 36:11459-11468
Pantazopoulos, Harry; Berretta, Sabina (2016) In Sickness and in Health: Perineuronal Nets and Synaptic Plasticity in Psychiatric Disorders. Neural Plast 2016:9847696
Sonntag, Kai-C; Tejada, George; Subburaju, Sivan et al. (2016) Limited predictability of postmortem human brain tissue quality by RNA integrity numbers. J Neurochem 138:53-9
Pantazopoulos, H; Markota, M; Jaquet, F et al. (2015) Aggrecan and chondroitin-6-sulfate abnormalities in schizophrenia and bipolar disorder: a postmortem study on the amygdala. Transl Psychiatry 5:e496
Berretta, Sabina; Pantazopoulos, Harry; Markota, Matej et al. (2015) Losing the sugar coating: potential impact of perineuronal net abnormalities on interneurons in schizophrenia. Schizophr Res 167:18-27
Berretta, Sabina; Heckers, Stephan; Benes, Francine M (2015) Searching human brain for mechanisms of psychiatric disorders. Implications for studies on schizophrenia. Schizophr Res 167:91-7
Mauney, Sarah A; Athanas, Katina M; Pantazopoulos, Harry et al. (2013) Developmental pattern of perineuronal nets in the human prefrontal cortex and their deficit in schizophrenia. Biol Psychiatry 74:427-35

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