Pyramidal cell regulation of interneuron survival sculpts cortical networks

Wong, Fong Kuan; Bercsényi, Kinga; Sreenivasan, Varun; Portalés, Adrián; Fernández-Otero, Marian; Marı́n, Oscar

doi:10.1038/s41586-018-0139-6

Cited by 240 publications

(337 citation statements)

References 57 publications

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“…Not only was the increased Pcdh-γ dependent cell death eliminated in Bax mutant animals, but these animals had ~ 40% increase in the numbers of surviving cINs compared to WT controls, identical to the effect of the Bax mutation in wild type animals. This observation is consistent with previous observation showing that ~40% of cIN are eliminated during the period of programmed cell death (Southwell et al 2012;Wong et al 2018). Moreover, the increased death of cINs after removal of Pcdh-γ function occurs precisely during the normal period of programmed cell death.…”

Section: Discussionsupporting

confidence: 94%

“…Here we have identified C-isoforms in the Pcdh-γ cluster as an essential molecular component that regulates programmed cell death among cINs. The fact that a cell surface adhesion protein plays a key role in this regulation suggests that interactions with other cells, possibly other cINs of the same age (Southwell et al 2012), or possibly excitatory pyramidal cells (Wong et al 2018), could be part of the logic to adjust the final number of these essential GABAergic cells for proper brain function. An understanding of the cell-cell interactions that use C-isoform Pcdh-γs to regulate cIN cell death should give fundamental insights into how the cerebral cortex forms and evolves.…”

Section: Discussionmentioning

confidence: 99%

“…In control experiments transplanting cIN precursors derived from Nkx2-1 Cre ;Ai14 embryos (but WT for the Pcdh-γ allele) alone, we observed that ~40% of the transplanted cIN population was eliminated between 6 and 21 DAT (Figure 10A-C). Therefore transplanted MGE cINs not only undergo programmed cell death during a period defined by their intrinsic cellular age but are also eliminated in a proportion that is strikingly similar to that observed during normal development (Wong et al 2018;Southwell et al 2012). Given these observations, we next asked how the presence of Pcdh-γ mutant cIN affected the survival of WT cIN in the transplantation setting.…”

Section: Loss Of Pcdh-γ Does Not Affect Cin Dispersion After Transplamentioning

confidence: 97%

“…Alterations in the number of cINs have been linked to epilepsy (F. Edward Dudek 2003), schizophrenia ((Beasley and Reynolds 1997;Hashimoto et al 2003;Enwright et al 2016) and autism (Gao and Penzes 2015;Giada Cellot 2014;Fatemi et al 2009). During mouse embryonic development, the brain produces an excess number of cINs, and ~ 40% of those are subsequently eliminated by apoptosis during early postnatal life, between postnatal day (P)1 and 15 (Southwell et al 2012;Wong et al 2018). What makes the death of these cells intriguing is its timing and location.…”

Section: Introductionmentioning

confidence: 99%

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Clustered γ-Protocadherins Regulate Cortical Interneuron Programmed Cell Death

Mancia¹,

Spatazza²,

Rakela³

et al. 2020

Preprint

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Cortical function critically depends on inhibitory/excitatory balance. Cortical inhibitory interneurons (cINs) are born in the ventral forebrain. After completing their migration into cortex, their final numbers are adjustedduring a period of postnatal development -by programmed cell death. The mechanisms that regulate cIN elimination remains controversial. Here we show that genes in the protocadherin (Pcdh)-γ gene cluster, but not in the Pcdh-α or Pcdh-β clusters, are required for the survival of cINs through a BAX-dependent mechanism. Surprisingly, the physiological and morphological properties of Pcdh-γ deficient and wild type cINs during cIN cell death were indistinguishable. Co-transplantation of wild type and Pcdh-γ deficient interneuron precursor cells demonstrate that: 1) the number of mutant cINs eliminated was much higher than that of wild type cells, but the proportion of mutant or WT cells undergoing cell death was not affected by their density; 2) the presence of mutant cINs increases cell death among wild-type counterparts, and 3) cIN survival is dependent on the expression of Pcdh-γ C3, C4, and C5. We conclude that Pcdh-γ, and specifically γC3, γC4, and γC5, play a critical role in regulating cIN survival during the endogenous period of programmed cIN death. SignificanceInhibitory cortical interneurons (cIN) in the cerebral cortex originate from the ventral embryonic forebrain. After a long migration, they come together with local excitatory neurons to form cortical circuits. These circuits are responsible for higher brain functions, and the improper balance of excitation/inhibition in the cortex can result in mental diseases. Therefore, an understanding of how the final number of cINs is determined is both biologically and, likely, therapeutically significant. Here we show that cell surface homophilic binding proteins belonging to the clustered protocadherin gene family, specifically three isoforms in the Pcdh-γ cluster, play a key role in the regulation cIN programmed cell death. Co-transplantation of mutant and wild-type cINs shows that Pcdh-γ genes have cell-autonomous and non-cell autonomous roles in the regulation of cIN cell death. This work will help identify the molecular mechanisms and cell-cell interactions that determine how the proper ratio of excitatory to inhibitory neurons is determined in the cerebral cortex.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Loss Of Pcdh-γ Does Not Affect Cin Dispersion After Transplamentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Clustered γ-Protocadherins Regulate Cortical Interneuron Programmed Cell Death

Mancia¹,

Spatazza²,

Rakela³

et al. 2020

Preprint

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“…Recent work from us and others highlighted the importance of Pten, another inhibitor of MTOR signaling that acts upstream of Tsc1, on establishing proper numbers of MGE-derived CINs in the cortex 28,29 . Therefore, we speculate that aberrant MTOR signaling in TS might lead to abnormalities in the development and function of MGE-derived CINs.…”

Section: Introductionmentioning

confidence: 99%

The Tuberous Sclerosis gene, Tsc1, represses parvalbumin+/fast-spiking properties in somatostatin-lineage cortical interneurons

Malik

Pai

Rubin

et al. 2019

Preprint

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Medial ganglionic eminence (MGE)-derived somatostatin (SST)+ and parvalbumin (PV)+ cortical interneurons (CINs), have characteristic molecular, anatomical and physiological properties. However, mechanisms regulating their diversity remain poorly understood. Here, we show that conditional loss of the Tuberous Sclerosis (TS) gene, Tsc1, which inhibits mammalian target of rapamycin (MTOR), causes a subset of SST+ CINs, to express PV and adopt fast-spiking (FS) properties, characteristic of PV+ CINs. These changes also occur when only one allele of Tsc1 is deleted, making these findings relevant to individuals with TS. Notably, treatment with rapamycin, which inhibits MTOR, reverses these changes in adult mice. These data reveal novel functions of MTOR signaling in regulating PV expression and FS properties, which may contribute to some neuropsychiatric symptoms observed in TS. Moreover, they suggest that CINs can exhibit properties intermediate between those classically associated with PV+ or SST+ CINs, which may be dynamically regulated by the MTOR signaling.

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Cortical Neuron Migration in Health and Disease

Javier‐Torrent,

Nguyen

2023

Neocortical Neurogenesis in Development and Evolution

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Pyramidal cell regulation of interneuron survival sculpts cortical networks

Cited by 240 publications

References 57 publications

Clustered γ-Protocadherins Regulate Cortical Interneuron Programmed Cell Death

Clustered γ-Protocadherins Regulate Cortical Interneuron Programmed Cell Death

The Tuberous Sclerosis gene, Tsc1, represses parvalbumin+/fast-spiking properties in somatostatin-lineage cortical interneurons

Cortical Neuron Migration in Health and Disease

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