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The Journal of Neuroscience, August 26, 2009, 29(34):10695-10705; doi:10.1523/JNEUROSCI.2658-09.2009

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Development/Plasticity/Repair
Regionalized Loss of Parvalbumin Interneurons in the Cerebral Cortex of Mice with Deficits in GFR{alpha}1 Signaling

Alison J. Canty,1 Jule Dietze,1 Michael Harvey,2 Hideki Enomoto,3 Jeffrey Milbrandt,4 and Carlos F. Ibáñez1

1Department of Neuroscience, Division of Molecular Neurobiology, and 2Department of Neuroscience, Division of Brain Research, Karolinska Institute, S-171 77 Stockholm, Sweden, 3Laboratory for Neuronal Differentiation and Regeneration, RIKEN Center for Developmental Biology, Kobe 650-0047, Japan, and 4Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110

Correspondence should be addressed to Carlos F. Ibáñez at the above address. Email: carlos.ibanez{at}ki.se

Inhibitory interneurons are crucially important for cerebral cortex function and behavior. The mechanisms controlling inhibitory interneuron diversification and allocation to distinct cortical areas remain poorly understood. GDNF (glial cell line-derived neurotrophic factor) and its receptor GFR{alpha}1 have been implicated in the development of GABAergic precursors but, because of the early lethality of null mutants, their roles in postnatal maturation and function of cortical interneurons are unknown. "cis-only" mutant mice lack GFR{alpha}1 only in cells that do not express the RET signaling receptor subunit and survive to adulthood. At birth, both null mutants and cis-only mice showed a specific loss of GABAergic interneurons in rostro- and caudolateral cortical regions but not in more medial areas. Unexpectedly, the adult cortex of cis-only mice displayed a complete loss of parvalbumin (PV)-expressing GABAergic interneurons in discrete regions (PV holes) interspersed among areas of normal PV cell density. PV holes predominantly occurred in the visual and frontal cortices, and their size could be affected by neuronal activity. Consistent with deficits in cortical inhibitory activity, these mice showed enhanced cortical excitability, increased sensitivity to epileptic seizure, and increased social behavior. We propose that GFR{alpha}1 signaling guides the development of a subset of PV-expressing GABAergic interneurons populating discrete regions of the cerebral cortex and may thus contribute to the diversification and allocation of specific cortical interneuron subtypes.

Received June 7, 2009; revised July 13, 2009; accepted July 16, 2009.

Correspondence should be addressed to Carlos F. Ibáñez at the above address. Email: carlos.ibanez{at}ki.se






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