TY - JOUR
T1 - Intrinsically determined cell death of developing cortical interneurons
AU - Southwell, Derek G.
AU - Paredes, Mercedes F.
AU - Galvao, Rui P.
AU - Jones, Daniel L.
AU - Froemke, Robert C.
AU - Sebe, Joy Y.
AU - Alfaro-Cervello, Clara
AU - Tang, Yunshuo
AU - Garcia-Verdugo, Jose M.
AU - Rubenstein, John L.
AU - Baraban, Scott C.
AU - Alvarez-Buylla, Arturo
N1 - Funding Information:
Acknowledgements We thank Y. Yanagawa for GAD67–GFP mice, L. Reichardt for TrkB mutant mice and R. Romero for technical contributions. D.G.S. and M.F.P. were supported by training grants from the California Institute for Regenerative Medicine. J.Y.S. was supported by a fellowship from the National Institute of Neurologic Disorders and Stroke (F32NS061497). This work was supported by the California Institute for Regenerative Medicine (A.A.-B., TR2-01749), the John G. Bowes Research Fund (A.A.-B.), the Spanish Ministry of Science and Innovation (J.M.G-V., SAF-2008-01274), and the National Institutes of Health (J.L.R., S.C.B. and A.A.-B., R01 NS071785; A.A.-B., R01 NS048528).
PY - 2012/11/1
Y1 - 2012/11/1
N2 - Cortical inhibitory circuits are formed by γ-aminobutyric acid (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.
AB - Cortical inhibitory circuits are formed by γ-aminobutyric acid (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.
UR - http://www.scopus.com/inward/record.url?scp=84868353325&partnerID=8YFLogxK
U2 - 10.1038/nature11523
DO - 10.1038/nature11523
M3 - Article
C2 - 23041929
AN - SCOPUS:84868353325
SN - 0028-0836
VL - 491
SP - 109
EP - 113
JO - Nature
JF - Nature
IS - 7422
ER -