Journal
JOURNAL OF COMPARATIVE NEUROLOGY
Volume 489, Issue 4, Pages 449-466Publisher
WILEY
DOI: 10.1002/cne.20647
Keywords
parvalbumin; somatostatin; interneuron; GAD-67
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Funding
- NICHD NIH HHS [P30 HD15052] Funding Source: Medline
- NIMH NIH HHS [MH65299] Funding Source: Medline
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We have previously shown that in adult mice with a null mutation in the urokinase-type plasminogen activator receptor (uPAR) gene, maintained on a C57BL/6J/129Sv background, there is a selective loss of GABAergic interneurons in anterior cingulate and parietal cortex, with the parvalbumin-expressing subpopulation preferentially affected. Here, we performed a more detailed anatomical analysis of uPAR(-/-) mutation on the congenic C57BL/6J background. With glutamic acid decarboxylase-67 and gamma-aminobutyric acid (GABA) immunostaining, there is a similar region-selective loss of cortical interneurons in the congenic uPAR(-/-) mice from the earliest age examined (P21). In contrast, the loss of parvalbumin-immunoreactive cells is observed only in adult cortex, and the extent of this loss is less than in the mixed background. Moreover, earlier in development, although there are normal numbers of parvalbumin cells in the uPAR(-/-) cortex, fewer cells coexpress GABA, suggesting that the parvalbumin subpopulation migrates appropriately to the cortex, but does not differentiate normally. Among the other forebrain regions examined, only the adult hippocampus shows a loss of GABAergic interneurons, although the somatostatin, rather than the parvalbumin, subpopulation contributes to this loss. The data suggest that uPAR function is necessary for the normal development of a subpopulation of GABAergic neurons in the telencephalon. It is likely that the late-onset parvalbumin phenotype is due to the effects of an altered local environment on selectively vulnerable neurons and that the extent of this loss is strain dependent. Thus, an interplay between complex genetic factors and the environment may influence the phenotypic impact of the uPAR mutation both pre- and postnatally.
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