Scientific Understanding of Consciousness
Interneuron Developent Cell Death Intrinsically Determined
Nature, 491, 109–113, (01 November 2012)
Intrinsically determined cell death of developing cortical interneurons
Neuroscience Graduate Program, University of California, San Francisco, California 94143, USA
Derek G. Southwell, Daniel L. Jones, Scott C. Baraban & Arturo Alvarez-Buylla
Departments of Neuroscience and Neurosurgery, and the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research; University of California, San Francisco, California 94143, USA
Derek G. Southwell, Mercedes F. Paredes, Rui P. Galvao, Daniel L. Jones, Joy Y. Sebe, Yunshuo Tang, Scott C. Baraban & Arturo Alvarez-Buylla
Medical Scientist Training Program, University of California, San Francisco, California 94143, USA
Derek G. Southwell & Yunshuo Tang
Department of Neurology, University of California, San Francisco, California 94143, USA
Mercedes F. Paredes
Department of Otolaryngology, Coleman Memorial Laboratory and W.M. Keck Foundation Center for Integrative Neuroscience, University of California, San Francisco, California 94143, USA
Robert C. Froemke
Instituto Cavanilles, Universidad de Valencia, CIBERNED, Valencia 46071, Spain
Clara Alfaro-Cervello & Jose M. Garcia-Verdugo
Biomedical Sciences Graduate Program, University of California, San Francisco, California 94143, USA
Department of Psychiatry and the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, California 94143, USA
John L. Rubenstein
Cortical inhibitory circuits are formed by GABA-secreting interneurons, a cell population that originates far from the cerebral cortex in the embryonic ventral forebrain. Given their distant developmental origins, it is intriguing how the number of cortical interneurons is ultimately determined. One possibility, suggested by the neurotrophic hypothesis is that cortical interneurons are overproduced, and then after their migration into cortex the excess interneurons are eliminated through a competition for extrinsically derived trophic signals. Here we characterize the developmental cell death of mouse cortical interneurons in vivo, in vitro and after transplantation. We found that 40% of developing cortical interneurons were eliminated through Bax (Bcl-2-associated X)-dependent apoptosis during postnatal life. When cultured in vitro or transplanted into the cortex, interneuron precursors died at a cellular age similar to that at which endogenous interneurons died during normal development. Over transplant sizes that varied 200-fold, a constant fraction of the transplanted population underwent cell death. The death of transplanted neurons was not affected by the cell-autonomous disruption of TrkB (tropomyosin kinase receptor B), the main neurotrophin receptor expressed by neurons of the central nervous system. Transplantation expanded the cortical interneuron population by up to 35%, but the frequency of inhibitory synaptic events did not scale with the number of transplanted interneurons. Taken together, our findings indicate that interneuron cell death is determined intrinsically, either cell-autonomously or through a population-autonomous competition for survival signals derived from other interneurons.
Our findings suggest that interneuron cell death is regulated by intrinsically defined mechanisms. When interneuron precursors were cultured in vitro or heterochronically transplanted, they died when they reached a cellular age equivalent to that of endogenous interneurons during the peak of endogenous interneuron cell death. This suggests that interneuron cell death is timed by the expression of a maturational program intrinsic to interneurons, rather than the developmental state of the cortex itself. Similarly, the extent of interneuron cell death seems to be intrinsically defined: across a range of transplant sizes, a constant fraction of the transplanted interneurons died in the recipient cortex, even when the transplant size was significantly below the number of interneurons that the cortex could support. Interneuron cell death is therefore unlikely to follow from intercellular competition for limiting survival signals derived from other cell types.
We propose two mechanisms that may govern the developmental cell death of cortical interneurons. In the first, which we refer to as ‘cell-autonomous’, interneuron cell death is intrinsically determined within each embryonic interneuron precursor. In this model, interneuron precursors would be individually destined to die in a manner independent from their interactions with other cell types. For example, the production of interneurons could occur with a certain rate of error such that a fraction of defective interneuron precursors cannot survive past a certain cellular age. Similarly, a fixed fraction of interneuron precursors may be cell-autonomously programmed to die during a specific stage of their development. Alternatively, in a ‘population-autonomous’ mechanism, developing interneurons may require and compete for limiting survival signals produced by other isochronic interneurons. These neurotrophic signals, which may be obtained through cell–cell contact, synaptic transmission or neurotrophin signalling independent of TrkB, would be present in a quantity that scales to the number of isochronic developing interneurons. Either a cell-autonomous or population-autonomous mechanism could explain why cell death occurred at a constant rate across broad range of interneuron transplant sizes, and also why the survival of endogenous interneurons was not affected by the transplantation of additional interneurons.
Interneurons have a critical role in cortical physiology, and their dysfunction has been implicated in neurological disorders such as epilepsy, schizophrenia and Alzheimer’s disease. The detailed examination of interneuron cell death is thus expected to yield new insights into cortical development, the pathophysiology of brain disorders and the therapeutic application of neuronal transplantation.
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