Developmental vulnerability of synapses and circuits associated with neuropsychiatric disorders
Open accessAbstract
Psychiatric and neurodegenerative disorders, including intellectual disability, autism spectrum disorders (ASD), schizophrenia (SZ), and Alzheimer's disease, pose an immense burden to society. Symptoms of these disorders become manifest at different stages of life: early childhood, adolescence, and late adulthood, respectively. Progress has been made in recent years toward understanding the genetic substrates, cellular mechanisms, brain circuits, and endophenotypes of these disorders. Multiple lines of evidence implicate excitatory and inhibitory synaptic circuits in the cortex and hippocampus as key cellular substrates of pathogenesis in these disorders. Excitatory/inhibitory balance – modulated largely by dopamine – critically regulates cortical network function, neural network activity (i.e. gamma oscillations) and behaviors associated with psychiatric disorders. Understanding the molecular underpinnings of synaptic pathology and neuronal network activity may thus provide essential insight into the pathogenesis of these disorders and can reveal novel drug targets to treat them. Here, we discuss recent genetic, neuropathological, and molecular studies that implicate alterations in excitatory and inhibitory synaptic circuits in the pathogenesis of psychiatric disorders across the lifespan.
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Evidence for ECM/PNN pathology in psychiatric disorders supports the hypothesis that ECM/PNN abnormalities may contribute to a critical pathological component shared by psychiatric disorders, i.e., disruption of synaptic functions.
“Evolving in parallel with our understanding of these functions, evidence for ECM/PNN pathology in psychiatric disorders supports the intriguing hypothesis that ECM/PNN abnormalities may contribute to a critical pathological component shared by psychiatric disorders, i.e., disruption of synaptic functions (e.g.Penzes et al., 2013;Duman, 2014;Xu et al., 2014).”
From Casting a Wide Net: Role of Perineuronal Nets in Neural Plasticity (2016) · cites this paper as Penzes et al., 2013
The Introduction and Conclusions (page numbers unavailable) describe disrupted synaptic function as a potential shared feature of several psychiatric disorders. They do not link that disruption to ECM/PNN pathology or abnormalities, so the ECM/PNN-specific hypothesis is not supported by this source. (LLM, conf=0.85)
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Widespread expression of ErbB2, ErbB3 and ErbB4 in non-human primate brain
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Gao, R., & Penzes, P. (2015) · Current Molecular Medicine · doi:10.2174/1566524015666150303003028 · Cited by 516 · see citing works
“Such imbalances may arise from problems in initial neural circuit formation or maintenance, as many of the genes derived from linkage and association studies code for proteins involved with these processes [4, 11].”
BackgroundSelf-citationEngineered In Vitro Disease Models
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Casting a Wide Net: Role of Perineuronal Nets in Neural Plasticity
Sorg, B. A., Berretta, S., Blacktop, J. M., Fawcett, J. W., Kitagawa, H., Kwok, J. C. F., & Miquel, M. (2016) · The Journal of Neuroscience · doi:10.1523/jneurosci.2351-16.2016 · Cited by 454 · see citing works
Wnts in adult brain: from synaptic plasticity to cognitive deficiencies
Oliva, C. A., Vargas, J. Y., & Inestrosa, N. C. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2013.00224 · Cited by 162 · see citing works
GABAergic mechanisms regulated by miR-33 encode state-dependent fear
Jovasevic, V., Corcoran, K. A., Leaderbrand, K., Yamawaki, N., Guedea, A. L., Chen, H. J., Shepherd, G. M. G., & Radulovic, J. (2015) · Nature Neuroscience · doi:10.1038/nn.4084 · Cited by 88 · see citing works
Control of dendritic spine morphological and functional plasticity by small GTPases.
Woolfrey, K. M., & Srivastava, D. P. (2016) · Neural Plasticity · doi:10.1155/2016/3025948 · Cited by 76 · see citing works
Khanal, P., & Hotulainen, P. (2021) · Cells · doi:10.3390/cells10092392 · Cited by 60 · see citing works
- Authors
- Penzes, P., Buonanno, A., Passafaro, M., Sala, C., & Sweet, R. A.
- Affiliations
- Northwestern University (US)
- Section on Molecular Neurobiology Eunice Shriver Kennedy NICHD National Institutes of Health Program of Developmental Neurobiology Bethesda Maryland USA
- University of Milan (IT)
- University of Pittsburgh (US)
- Corresponding author
- Penzes, Peter
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2013-05-22
- Volume
- 126
- Issue
- 2
- Pages
- 165-182
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- PMC
- PMC3700683
- OpenAlex
- W2031695523
- Cited by
- 125
- References
- 216
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 8 · 2023: 4 · 2022: 7 · 2021: 11 · 2020: 11 · 2019: 3 · 2018: 13 · 2017: 10 · 2016: 17 · 2015: 15 · 2014: 11 · 2013: 5
- FWCI
- 1.63
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01 BX000452)
- Istituto Italiano di Tecnologia
- National Institutes of Health (MH 071316, MH071533)
- National Institute on Aging (AG027224, R01AG027224)
- National Institute of Mental Health (MH071533, MH 071316, MH097216, R01MH097216, R01MH071533, R56MH071316, R01MH071316)
- National Institute of Child Health and Human Development
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
- Keywords
- neuropsychiatric disorders, intellectual disability, autism spectrum disorder, schizophrenia, Alzheimer's disease, excitation-inhibition balance, synaptic circuits, dopamine, gamma oscillations, hippocampus, developmental vulnerability, neuropathology, therapeutic target
- MeSH terms
- Animals, Mental Disorders, Brain, Humans, Nerve Net, Nervous System Diseases, Synapses
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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