Measuring the Maturity of the Fast-Spiking Interneuron Transcriptional Program in Autism, Schizophrenia, and Bipolar Disorder
Open accessAbstract
BACKGROUND: Emerging evidence suggests that fast-spiking (FS) interneurons are disrupted in multiple neuropsychiatric disorders including autism, schizophrenia, and bipolar disorder. FS cells, which are the primary source of synaptic inhibition, are critical for temporally organizing brain activity, regulating brain maturation, and modulating critical developmental periods in multiple cortical systems. Reduced expression of parvalbumin, a marker of mature FS cells, has been reported in individuals with schizophrenia and bipolar disorder and in mouse models of schizophrenia and autism. Although these results suggest that FS cells may be immature in neuropsychiatric disease, this possibility had not previously been formally assessed. METHODS: This study used time-course global expression data from developing FS cells to create a maturation index that tracked with the developmental age of purified cortical FS cells. The FS cell maturation index was then applied to global gene expression data from human cortex to estimate the maturity of the FS cell developmental program in the context of various disease states. Specificity of the index for FS cells was supported by a highly significant correlation of maturation index measurements with parvalbumin expression levels that withstood correction for multiple covariates. CONCLUSIONS: Results suggest the FS cell developmental gene expression program is immature in autism, schizophrenia, and bipolar disorder. More broadly, the current study indicates that cell-type specific maturation indices can be used to measure the maturity of developmental programs even in data from mixed cell types such as those found in brain homogenates.
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The dorsolateral prefrontal cortex of young patients already has low expression levels of parvalbumin and GAD67, and the gene expression pattern in parvalbumin interneurons of schizophrenia individuals resembles that of non-mature cells.
“The DLPFC of young patients already has low expression levels of parvalbumin and GAD67 (Hoftman et al., 2013), and gene expression pattern in PVI of schizophrenia individuals resembles that of non-mature cells (Gandal et al., 2012).”
From Redox dysregulation, neuroinflammation, and NMDA receptor hypofunction: A “central hub” in schizophrenia pathophysiology? (2016) · cites this paper as Gandal et al., 2012
PV cINs exert strong inhibitory control over local networks and their dysfunction is implicated in Dravet syndrome, focal epilepsy, ASD, and schizophrenia.
“These neurons exert a strong level of inhibitory control over local networks and their disfunction has been directly implicated in neurological and neuropsychiatric disorders, including Dravet syndrome, focal epilepsy, ASD and schizophrenia 31–34.”
From Viral manipulation of functionally distinct interneurons in mice, non-human primates and humans (2020) · cites this paper as [33]
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- Authors
- Gandal, M. J., Nesbitt, A. M., McCurdy, R. M., & Alter, M. D.
- Affiliations
- University of Pennsylvania (US)
- Institute of Molecular and Cell Biology (SG)
- Corresponding author
- Alter, Mark D.
- ORCID
- Gandal, Michael J.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2012-08-24
- Volume
- 7
- Issue
- 8
- Pages
- e41215
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3427326
- OpenAlex
- W2030277241
- Cited by
- 67
- References
- 35
- Citations by year
- 2025: 3 · 2024: 2 · 2023: 3 · 2022: 7 · 2021: 8 · 2020: 5 · 2019: 5 · 2018: 9 · 2017: 5 · 2016: 4 · 2015: 4 · 2014: 5 · 2013: 7
- FWCI
- 3.65
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Simons Foundation Autism Research Initiative
- National Institute of Mental Health (1K08MH08228-01A2, K08MH080228)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- fast-spiking interneurons, parvalbumin, neuronal maturation, maturation index, autism spectrum disorder, schizophrenia, bipolar disorder, cortical gene expression, inhibitory interneurons, human cortex
- MeSH terms
- Autistic Disorder, Bipolar Disorder, Humans, Schizophrenia, Linear Models, Prefrontal Cortex, Oligonucleotide Array Sequence Analysis, Neuropsychiatry
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