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Life or death: developing cortical interneurons make their own decision

2012; Springer Nature; Volume: 31; Issue: 23 Linguagem: Inglês

10.1038/emboj.2012.290

1460-2075

Juan Song, Kimberly M. Christian, Guo‐li Ming, Hongjun Song,

Photoreceptor and optogenetics research

Have you seen?16 October 2012free access Life or death: developing cortical interneurons make their own decision Juan Song Juan Song Institute for Cell Engineering, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA Search for more papers by this author Kimberly M Christian Kimberly M Christian Institute for Cell Engineering, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA Search for more papers by this author Guo-li Ming Guo-li Ming Institute for Cell Engineering, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA Search for more papers by this author Hongjun Song Corresponding Author Hongjun Song Institute for Cell Engineering, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA Search for more papers by this author Juan Song Juan Song Institute for Cell Engineering, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA Search for more papers by this author Kimberly M Christian Kimberly M Christian Institute for Cell Engineering, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA Search for more papers by this author Guo-li Ming Guo-li Ming Institute for Cell Engineering, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA Search for more papers by this author Hongjun Song Corresponding Author Hongjun Song Institute for Cell Engineering, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA Search for more papers by this author Author Information Juan Song1, Kimberly M Christian1, Guo-li Ming1 and Hongjun Song 1 1Institute for Cell Engineering, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA *Correspondence to: [email protected] The EMBO Journal (2012)31:4373-4374https://doi.org/10.1038/emboj.2012.290 There is an Article (October 2012) associated with this Have you seen?. PDFDownload PDF of article text and main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info During nervous system development, programmed cell death is considered as an essential adaptive process. The mechanism by which the number of mature neurons is determined in the central nervous system is not well understood. In a recent Nature paper, Southwell et al (2012) demonstrate that cortical GABAergic interneuron cell death is intrinsically determined without the need to compete for extrinsic survival signals derived from other cell types. Programmed cell death is evolutionarily conserved throughout the animal kingdom and affects both neurons and glia of the developing central (CNS) and peripheral nervous system (PNS) (Buss et al, 2006). Significant cell death also occurs during multiple stages of adult neurogenesis (Ming and Song, 2011). How neuronal population size is optimized to build mature circuits is a fundamental question in developmental neurobiology. Classic studies in the PNS led to the ‘neurotrophic factor hypothesis’, namely, neurons are overproduced and compete for limited amounts of survival-promoting factors from targets (Levi-Montalcini and Angeletti, 1968; Barde et al, 1983; Figure 1). In the developing CNS, Southwell et al (2012) made the interesting discovery that cortical interneurons self-regulate their number independent of survival factors released from other cell types. Figure 1.Neuronal number control in the developing nervous system. In the developing PNS, neurons compete for survival factors, such as neurotrophins, provided by targeted cells as a means of attaining optimal innervation. In the developing CNS, there are two proposed models for interneuron cell death. (1) ‘Individual autonomous’ model: interneuron cell death is intrinsically determined within each interneuron precursor in a manner independent from their interactions with other cells; each cell has a probability of Pi to survive; (2) ‘Population autonomous’ model: developing interneurons compete for limited survival signals produced by other interneurons born around the same time; individual neurons affect each other and the population as a whole has a probability of Pi to survive. Download figure Download PowerPoint To characterize developmental cell death of cortical interneurons, Southwell et al (2012) examined GAD67-GFP knock-in mice in vivo and primary interneuron precursor culture in vitro. Interestingly, prominent interneuron death occurs in culture during the same window when cortical interneuron number declines by ∼30% in vivo, suggesting that interneuron death can be independent of extrinsic niche components. This developmental cell death depends on Bcl-2 associated X (Bax) and occurs uniformly across all interneuron subtypes. To corroborate their findings, they characterized interneuron death in a series of elegant transplantation experiments. First, they transplanted embryonic interneuron precursors from medial ganglionic eminence into the postnatal neocortex and showed death of transplanted interneurons occurs at a cellular age similar to that of endogenous interneurons, suggesting a timing mechanism regulated by the intrinsic maturation state. Second, they transplanted various numbers of embryonic interneuron precursors and found that a similar fraction of transplanted interneurons survive. Third, they transplanted interneurons lacking TrkB, a neurotrophin receptor primarily expressed in the CNS, and found similar rates of cell death. These results provide strong evidence that interneuron death is not determined through competition for extrinsic survival signals. Is it then possible that transplanted interneurons compete with endogenous neurons to survive? They transplanted DsRed-expressing interneuron precursors into GAD67-GFP mice and observed equal numbers of endogenous interneurons in both recipient and control hemispheres. Together, these studies show that isochronic interneurons regulate their own numbers in vitro, in developing cortex in vivo, or after transplantation. An intrinsic regulatory mechanism is in sharp contrast to the ‘neurotrophic factor hypothesis’ based largely on PNS studies. There have been hints of fundamental differences in the CNS. For example, brain-derived neurotrophic factor (BDNF) is the most widely expressed neurotrophin in the CNS, but its elimination fails to affect neuronal numbers in most CNS areas (Ernfors et al, 1994). In a study using engineered embryonic stem cells, TrkB (although not TrkA and TrkC) does not trigger neuronal death and it was proposed that cell–cell contact and synaptic transmission control CNS neuronal survival (Nikoletopoulou et al, 2010). The intriguing findings by Southwell et al (2012) raise more questions. First, two models have been proposed to explain cell intrinsic regulation of interneuron death in developing cortex (Figure 1). In the ‘individual-autonomous’ model, interneuron death is intrinsically determined within each precursor; in the ‘population-autonomous’ model, developing interneurons of the same age compete for limited survival signals produced by other interneurons. How to differentiate these two models experimentally? One possibility is to co-transplant a mixture of normal interneurons from GAD67-GFP mice with isochronic Bax KO interneurons. If the ‘individual’ model holds true, then the number of surviving GFP+ neurons should be in proportion to total transplanted GFP+ cells. If the ‘population’ model is correct, then fewer GFP+ interneurons are expected to survive because of absence of cell death in the Bax KO population. Second, what are underlying cellular and molecular mechanisms? In the ‘individual’ model, is it epigenetically or transcriptionally regulated, analogous to intrinsically programmed differentiation of embryonic CNS neural stem cells (Okano and Temple, 2009)? In the ‘population’ model, how do interneurons achieve targeted communication with other interneurons? One possibility is via gap junctions between neocortical interneurons (Druga, 2009). A recent study showed that gap junctions allow selective communication between developing sister excitatory neurons to promote lineage-dependent microcircuit assembly in the neocortex (Yu et al, 2012). Interneurons also form reciprocal synaptic connections. Future genetic and pharmacological studies can test these possibilities. Another striking finding of Southwell et al (2012) is that mouse neocortex has the capacity to maintain 35% more interneurons. What are the consequences of adding more neurons in the brain? Southwell et al (2012) performed patch-clamp recordings and found that transplanted interneurons are successfully integrated into the cortical circuitry. Interestingly, only the frequency, not the amplitude, of inhibitory events onto pyramidal neurons is increased, but not in proportion to the density of transplanted interneurons. Thus, cortical inhibition may arise through homeostatic regulation of synaptic strength and number, instead of interneuron population size. These findings have important implications for cell replacement therapy. Given that the regulation in both number and properties of cortical interneurons under many physiological and pathological conditions, such as ageing, Alzheimer's diseases, chronic stress, schizophrenia and other severe psychiatric illnesses, and epilepsy, the findings by Southwell et al (2012) have significant implications for developmental neurobiology, neural plasticity and regenerative medicine. Acknowledgements JS is supported by a postdoctoral fellowship from MSCRF; GLM is supported by NIH (HD069184, NS048271) and Dr Miriam and Sheldon G Adelson Medical Research Foundation; HJS is supported by NIH (NS047344, ES021957, MH087874) and SFARI. Conflict of Interest The authors declare that they have no conflict of interest. References Barde YA, Edgar D, Thoenen H (1983) New neurotrophic factors. Annu Rev Physiol 45: 601–612CrossrefPubMedWeb of Science®Google Scholar Buss RR, Sun W, Oppenheim RW (2006) Adaptive roles of programmed cell death during nervous system development. 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Nature 486: 113–117CrossrefCASPubMedWeb of Science®Google Scholar Previous ArticleNext Article Read MoreAbout the coverClose modalView large imageVolume 31,Issue 23,November 28, 2012Love Dust - Produced in the hindwing of a male butterfly ( Tirumala formosa), pheromone transfer particles called "love dust" are transferred to the female antennae during courtship. Adult male butterflies actively search for particular phanerogams to obtain pyrrolizidine alkaloids for the synthesis of this pheromone. The SEM image on the front cover was captured by Kei Hashimoto of the RIKEN Yokohama Institute, Japan. Volume 31Issue 2328 November 2012In this issue FiguresReferencesRelatedDetailsLoading ...