Regionalized loss of parvalbumin interneurons in the cerebral cortex of mice with deficits in GFRα1 signaling

Alison J. Canty, Jule Dietze, Michael Harvey, Hideki Enomoto, Jeffrey Milbrandt, Carlos F. Ibáñez

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

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 receptorGFRα1 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 GFRα1 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.Wepropose that GFRα1 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.

Original languageEnglish
Pages (from-to)10695-10705
Number of pages11
JournalJournal of Neuroscience
Volume29
Issue number34
DOIs
StatePublished - Aug 26 2009

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