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Pyramidal cell regulation of interneuron survival sculpts cortical networks
Open accessAbstract
Complex neuronal circuitries such as those found in the mammalian cerebral cortex have evolved as balanced networks of excitatory and inhibitory neurons. Although the establishment of appropriate numbers of these cells is essential for brain function and behaviour, our understanding of this fundamental process is limited. Here we show that the survival of interneurons in mice depends on the activity of pyramidal cells in a critical window of postnatal development, during which excitatory synaptic input to individual interneurons predicts their survival or death. Pyramidal cells regulate interneuron survival through the negative modulation of PTEN signalling, which effectively drives interneuron cell death during this period. Our findings indicate that activity-dependent mechanisms dynamically adjust the number of inhibitory cells in nascent local cortical circuits, ultimately establishing the appropriate proportions of excitatory and inhibitory neurons in the cerebral cortex.
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“Moreover, preventing programmed cell death in pyramidal cells by genetically ablating the proapoptotic Bcl-2 family members Bax and Bak (Lindsten et al., 2000) from these cells is sufficient to abolish the programmed cell death of cortical interneurons (Wong et al., 2018).”
From Development and Functional Diversification of Cortical Interneurons (2018) · cites this paper as Wong et al., 2018
In the citing paper
“Consistent with this idea, increasing or decreasing the excitability of pyramidal cells using DREADDs during the period of interneuron programmed cell death respectively enhances or diminishes the survival of cortical interneurons (Wong et al., 2018).”
From Development and Functional Diversification of Cortical Interneurons (2018) · cites this paper as Wong et al., 2018
In the citing paper
“First, long-term Ca2+ imaging experiments in vivo indicate that activity levels at the onset of the cell death period predict the fate of interneurons (Wong et al., 2018).”
From Development and Functional Diversification of Cortical Interneurons (2018) · cites this paper as Wong et al., 2018
In the citing paper
“This process seems to impact all classes of interneurons (Denaxa et al., 2018; Priya et al., 2018; Wong et al., 2018) (Figure 6A).”
From Development and Functional Diversification of Cortical Interneurons (2018) · cites this paper as Wong et al., 2018
In the citing paper
“This is consistent with the observation that interneuron cell death occurs progressively in vivo, with early-born infragranular layer interneurons disappearing before late-born supragranular layer interneurons (Wong et al., 2018).”
From Development and Functional Diversification of Cortical Interneurons (2018) · cites this paper as Wong et al., 2018
In the citing paper
“In other words, interneurons with relatively low levels of activity immediately before the period of interneuron cell death have an increased probability of undergoing apoptosis.”
From Development and Functional Diversification of Cortical Interneurons (2018) · cites this paper as Wong et al., 2018
In the citing paper
“it is perhaps not surprising that these cells play a critical role in the survival of cortical interneurons (Figure 6B).”
From Development and Functional Diversification of Cortical Interneurons (2018) · cites this paper as Wong et al., 2018
In the citing paper
“Second, experimentally increasing the activity of pyramidal cells (which increases interneuron survival) non-cell autonomously represses the expression of PTEN in interneurons (Wong et al., 2018).”
From Development and Functional Diversification of Cortical Interneurons (2018) · cites this paper as Wong et al., 2018
In the citing paper
“Interestingly, PTEN levels rise in cortical interneurons during the period of programmed cell death in a temporal pattern that coincides with the normal development of interneurons, transiently increasing first in infragranular layer interneurons and, subsequently, in superficial layer interneurons (Wong et al., 2018).”
From Development and Functional Diversification of Cortical Interneurons (2018) · cites this paper as Wong et al., 2018
In the citing paper
“First, genetic deletion of PTEN from postmitotic MGE-derived interneurons dramatically increases their survival (Wong et al., 2018).”
From Development and Functional Diversification of Cortical Interneurons (2018) · cites this paper as Wong et al., 2018
In the citing paper
“This observation is in line with previous findings that the excitatory identity controls the survival and wiring of local interneurons60,61.”
From Layer 4 of mouse neocortex differs in cell types and circuit organization between sensory areas (2019) · cites this paper as [61]
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Metadata
- Authors
- Wong, F. K., Bercsenyi, K., Sreenivasan, V., Portalés, A., Fernández-Otero, M., & Marín, O.
- Affiliations
- King's College London (GB)
- Venue
- Nature
- Published
- 2018-05
- Volume
- 557
- Issue
- 7707
- Pages
- 668-673
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6207348
- OpenAlex
- W2803681151
- Cited by
- 286
- References
- 60
- Citations by year
- 2026: 25 · 2025: 33 · 2024: 37 · 2023: 37 · 2022: 42 · 2021: 41 · 2020: 26 · 2019: 35 · 2018: 9
- FWCI
- 10.20
- Type
- journal article
- Language
- en
- Open access
- green
- kclpure.kcl.ac.uk
- Licence
- other-oa
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (King's College London) (publishedVersion, other-oa)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Research Explorer (The University of Manchester) (submittedVersion, other-oa)
- Funders
- Wellcome Trust (103714/Z/14/Z, 103714MA)
- European Commission (H2020)
- Horizon 2020 Framework Programme
- Medical Research Council (MR/N026063/1)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
- Keywords
- pyramidal neurons, excitation-inhibition balance, cortical development, postnatal development, neuronal cell death, activity-dependent regulation, inhibitory interneurons, excitatory synaptic input
- MeSH terms
- Animals, Cell Count, Cell Survival, Cerebral Cortex, Female, Interneurons, Male, Neural Pathways, Cell Death, Pyramidal Cells, PTEN Phosphohydrolase, Mice
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