Intrinsically determined cell death of developing cortical interneurons

Southwell, Derek G.; Paredes, Mercedes F.; Galvão, Rui P.; Jones, Daniel L.; Froemke, Robert C.; Sebe, Joy Y.; Alfaro-Cervelló, Clara; Tang, Yunshuo; García‐Verdugo, José Manuel; Rubenstein, John L.R.; Baraban, Scott C.; Alvarez-Buylla, Arturo

doi:10.1038/nature11523

Cited by 315 publications

(415 citation statements)

References 24 publications

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“…Reductions in GAD67 + cells have also been observed in vivo, and it is possible in vitroderived cells undergo a similar process of programmed cell death (Southwell et al, 2012). It is also possible that some interneuron subtypes require excitatory input for survival and maturation, rendering monocultures suboptimal for survival and function of GABAergic neurons (Close et al, 2012;De Marco Garcia et al, 2011).…”

Section: Discussionmentioning

confidence: 87%

Single-Cell Profiling of an In Vitro Model of Human Interneuron Development Reveals Temporal Dynamics of Cell Type Production and Maturation

Close¹,

Yao²,

Miller³

et al. 2017

Neuron

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SummaryGABAergic interneurons are essential for neural circuit function and their loss or dysfunction is implicated in human neuropsychiatric disease. In vitro methods for interneuron generation hold promise for studying human cellular and functional properties and ultimately therapeutic cell replacement. We describe here a protocol for generating cortical interneurons from hESCs and analyze the properties and maturation timecourse of cell types using single-cell RNAseq. We find that the cell types produced mimic in vivo temporal patterns of neuron and glial production, with immature progenitors and neurons observed early and mature cortical neurons and glial cell types produced late. By comparing the transcriptomes of immature interneurons to more mature neurons, we identified genes important for human interneuron differentiation. Many of these genes were previously implicated in neurodevelopmental and neuropsychiatric disorders. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. HHS Public Access

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Section: Discussionmentioning

confidence: 87%

Single-Cell Profiling of an In Vitro Model of Human Interneuron Development Reveals Temporal Dynamics of Cell Type Production and Maturation

Close¹,

Yao²,

Miller³

et al. 2017

Neuron

View full text Add to dashboard Cite

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“…8A-M). These caspase 3+ cells had a neuron-like appearance, as cleaved caspase 3 was expressed both in soma and processes (Southwell et al, 2012). There were also more caspase 3+ cells in the hGFAP-Cre; COUP-TFI flox/flox and hGFAP-Cre; COUP-TFI flox/flox ; COUP-TFII flox/+ compound conditional mutant SVZ compared with controls ( Fig.…”

Section: Defective Migration Of Coup-tfi/coup-tfii-deficient Svz Cellsmentioning

confidence: 77%

Transcription factors COUP-TFI and COUP-TFII are required for the production of granule cells in the mouse olfactory bulb

et al. 2015

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Neural stem cells (NSCs) persist in the adult mammalian subventricular zone (SVZ) of the lateral ventricle. Primary NSCs generate rapidly dividing intermediate progenitor cells, which in turn generate neuroblasts that migrate along the rostral migratory stream (RMS) to the olfactory bulb (OB). Here, we have examined the role of the COUP-TFI and COUP-TFII orphan nuclear receptor transcription factors in mouse OB interneuron development. We observed that COUP-TFI is expressed in a gradient of low rostral to high caudal within the postnatal SVZ neural stem/progenitor cells. COUP-TFI is also expressed in a large number of migrating neuroblasts in the SVZ and RMS, and in mature interneurons in the OB. By contrast, very few COUP-TFII-expressing (+) cells exist in the SVZ-RMS-OB pathway. Conditional inactivation of COUP-TFI resulted in downregulation of tyrosine hydroxylase expression in the OB periglomerular cells and upregulation of COUP-TFII expression in the SVZ, RMS and OB deep granule cell layer. In COUP-TFI/ COUP-TFII double conditional mutant SVZ, cell proliferation was increased through the upregulation of the proneural gene Ascl1. Furthermore, COUP-TFI/II-deficient neuroblasts had impaired migration, resulting in ectopic accumulation of calretinin (CR)+ and NeuN+ cells, and an increase in apoptotic cell death in the SVZ. Finally, we found that most Pax6+ and a subset of CR+ granular cells were lost in the OB. Taken together, these results suggest that COUP-TFI/II coordinately regulate the proliferation, migration and survival of a subpopulation of Pax6+ and CR+ granule cells in the OB.

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“…(34)(35)(36). Once a ceiling of enhanced inhibitory tone is reached, transplantation of greater numbers of interneuron progenitors no longer increases synaptic inhibition (37). We transplanted dissociated MGE cells from β-actin-GFP mouse embryonic day (E) 13 into the dorsal hippocampus of WT postnatal day (P) 2 mouse pups.…”

Section: Significancementioning

confidence: 99%

Bidirectional homeostatic plasticity induced by interneuron cell death and transplantation in vivo

Howard

Rubenstein

Baraban

2013

Proc. Natl. Acad. Sci. U.S.A.

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Chronic changes in excitability and activity can induce homeostatic plasticity. These perturbations may be associated with neurological disorders, particularly those involving loss or dysfunction of GABA interneurons. In distal-less homeobox 1 (Dlx1 −/− ) mice with late-onset interneuron loss and reduced inhibition, we observed both excitatory synaptic silencing and decreased intrinsic neuronal excitability. These homeostatic changes do not fully restore normal circuit function, because synaptic silencing results in enhanced potential for long-term potentiation and abnormal gamma oscillations. Transplanting medial ganglionic eminence interneuron progenitors to introduce new GABAergic interneurons, we demonstrate restoration of hippocampal function. Specifically, miniature excitatory postsynaptic currents, input resistance, hippocampal long-term potentiation, and gamma oscillations are all normalized. Thus, in vivo homeostatic plasticity is a highly dynamic and bidirectional process that responds to changes in inhibition.excitatory/inhibitory balance | gamma frequency oscillations | LTP | neural transplantation P rolonged changes in activity levels induce bidirectional changes in neuronal excitability and synaptic activity known as homeostatic plasticity (1, 2). This phenomenon has been described well at excitatory synapses and functions to maintain activity within a preferred dynamic range. Maintaining excitatory/inhibitory synaptic balance is critical for neuronal information processing and a potential problem when confronted with aberrant states of excitability, such as those associated with autism, schizophrenia, Alzheimer's disease, or epilepsy (3-12).Chronic manipulation of synaptic input and/or action potential (AP) output rates in cortical and hippocampal cell cultures induces homeostatic synaptic scaling, in which the amplitude and then the frequency of pyramidal neuron miniature excitatory postsynaptic currents (mEPSCs) increase when activity is lowered or decrease when activity is raised (13-16). Recent studies have begun to reveal the underlying molecular mechanisms of homeostatic synaptic changes, including the AMPA receptor subunits, synapse-associated calcium-binding proteins, and intracellular signaling cascades involved (14,17,18). Changes to activity also trigger homeostatic plasticity of inhibitory synaptic transmission (19)(20)(21)(22)(23). Homozygous deletion of glutamate decarboxylase 1 (Gad1), the rate-limiting enzyme in the synthesis of GABA, reduced miniature inhibitory postsynaptic current (mIPSC) amplitudes in cultured hippocampal neurons but also blocked further homeostatic changes to mIPSCs. This suggests a key role for regulation of Gad1 expression in inhibitory homeostatic plasticity (23). Intrinsic excitability is also homeostatically regulated by activity. Changes in input resistance (Rin) and voltage-activated K + and Na + channel number (24-27), and in Na + channel compartmentalization (28, 29), have been described following manipulations that chronically alter neuronal activity...

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Intrinsically determined cell death of developing cortical interneurons

Cited by 315 publications

References 24 publications

Single-Cell Profiling of an In Vitro Model of Human Interneuron Development Reveals Temporal Dynamics of Cell Type Production and Maturation

Single-Cell Profiling of an In Vitro Model of Human Interneuron Development Reveals Temporal Dynamics of Cell Type Production and Maturation

Transcription factors COUP-TFI and COUP-TFII are required for the production of granule cells in the mouse olfactory bulb

Bidirectional homeostatic plasticity induced by interneuron cell death and transplantation in vivo

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