A loss of hippocampal perineuronal nets produces deficits in dopamine system function: relevance to the positive symptoms of schizophrenia
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Deficits in parvalbumin containing interneurons are a consistent observation in animal models and schizophrenia patients. These neurons are surrounded by chondroitin sulfate proteoglycans, forming perineuronal nets, thought to support the high firing frequencies observed in these neurons. A loss of perineuronal nets has been observed post mortem in human schizophrenia patients, however, whether this contributes to the symptoms of schizophrenia is not known. Here we directly examine the effects of chondroitinase ABC degradation of ventral hippocampal (vHipp) perineuronal nets, and demonstrate that this results in an enhanced hippocampal activity and significant increase in dopamine neuron population activity. In addition, chondroitinase-treated rats display an augmented locomotor response to amphetamine, consistent with the enhanced response to psychomotor stimulants observed in schizophrenia patients. Taken together, these data demonstrate that a loss of vHipp perineuronal nets is sufficient, in and of itself, to induce aberrant hippocampal and dopamine system function consistent with that observed in rodent models and schizophrenia patients.
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Localized PNN destruction reproduces functional abnormalities reminiscent of schizophrenia.
“whereas localized PNN destruction reproduces functional abnormalities reminiscent of SZ.9”
From Aggrecan and chondroitin-6-sulfate abnormalities in schizophrenia and bipolar disorder: a postmortem study on the amygdala (2015) · cites this paper as [9]
In a rodent model, PNN enzymatic degradation in the ventral hippocampus resulted in increased activity of pyramidal neurons, postulated to result from disruption of GABAergic neuronal activity following PNN loss.
“In this study, PNN enzymatic degradation in the ventral hippocampus resulted in increased activity of pyramidal neurons, postulated to result from disruption of GABAergic neuronal activity following PNN loss (Shah and Lodge, 2013).”
From Losing the sugar coating: Potential impact of perineuronal net abnormalities on interneurons in schizophrenia (2015) · cites this paper as Shah and Lodge, 2013
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)”
From Perineuronal nets and schizophrenia: The importance of neuronal coatings (2014) · cites this paper as Shah and Lodge, 2013
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”
From Perineuronal nets and schizophrenia: The importance of neuronal coatings (2014) · cites this paper as Shah and Lodge, 2013
Offspring of rat dams exposed to methylazoxymethanol acetate have lower levels of brevican and phosphacan throughout ventral hippocampus.
“the offspring of rat dams exposed to the DNA-alkylating agent methylazoxymethanol acetate had significantly lower levels of the PNN proteins brevican and phosphacan throughout the ventral hippocampus (Shah and Lodge, 2013)”
From Perineuronal nets and schizophrenia: The importance of neuronal coatings (2014) · cites this paper as Shah and Lodge, 2013
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References 55 · Cited by 87
- Authors
- Shah, A., & Lodge, D. J.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- Corresponding author
- Lodge, D J
- ORCID
- Lodge, D J
- Venue
- Translational Psychiatry
- Published
- 2013-01-15
- Volume
- 3
- Issue
- 1
- Pages
- e215-e215
- ISSN
- 2158-3188 (ISSN-L)
- PMC
- PMC3566725
- OpenAlex
- W2167030444
- Cited by
- 87
- References
- 55
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 6 · 2023: 7 · 2022: 9 · 2021: 8 · 2020: 5 · 2019: 4 · 2018: 9 · 2017: 3 · 2016: 9 · 2015: 10 · 2014: 11 · 2013: 1
- FWCI
- 7.31
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc-nd
- www.springer.com/tdm (unspecified)
- Locations
- Translational Psychiatry (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Alliance for Research on Schizophrenia and Depression
- National Institutes of Health (5r01mh090067-10, MH090067)
- National Institute of Mental Health (R01: MH090067)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- perineuronal nets, chondroitin sulfate proteoglycans, parvalbumin interneurons, ventral hippocampus, dopaminergic system, schizophrenia, positive symptoms, chondroitinase ABC, amphetamine response, locomotor activity, hippocampal activity
- MeSH terms
- Amphetamine, Analysis of Variance, Animals, Disease Models, Animal, Dopamine, Hippocampus, Immunohistochemistry, Interneurons, Male, Methylazoxymethanol Acetate, Parvalbumins, Chondroitin Sulfate Proteoglycans, Schizophrenia, Rats, Sprague-Dawley, Chondroitin ABC Lyase, Rats
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