1. Increased dopaminergic innervation in the brain of conditional mutant mice overexpressing Otx2: effects on locomotor behavior and seizure susceptibility.
- Author
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Tripathi PP, Di Giovannantonio LG, Sanguinetti E, Acampora D, Allegra M, Caleo M, Wurst W, Simeone A, and Bozzi Y
- Subjects
- Animals, Brain physiopathology, Cell Count, Dopamine Plasma Membrane Transport Proteins metabolism, Kainic Acid, Male, Mice, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Transgenic, Neural Pathways physiology, Otx Transcription Factors genetics, Parvalbumins metabolism, Proto-Oncogene Proteins c-fos metabolism, Proto-Oncogene Proteins c-jun metabolism, RNA, Messenger metabolism, Brain cytology, Brain physiology, Dopamine metabolism, Dopaminergic Neurons physiology, Motor Activity physiology, Otx Transcription Factors metabolism, Seizures physiopathology
- Abstract
The homeobox-containing transcription factor Otx2 controls the identity, fate and proliferation of mesencephalic dopaminergic (mesDA) neurons. Transgenic mice, in which Otx2 was conditionally overexpressed by a Cre recombinase expressed under the transcriptional control of the Engrailed1 gene (En1(Cre/+); tOtx2(ov/+)), show an increased number of mesDA neurons during development. In adult mice, Otx2 is expressed in a subset of neurons in the ventral tegmental area (VTA) and its overexpression renders mesDA more resistant to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-HCl (MPTP) neurotoxin. Here we further investigated the neurological consequences of the increased number of mesDA neurons in En1(Cre/+); tOtx2(ov/+) adult mice. Immunohistochemistry for the active, glycosylated form of the dopamine transporter (glyco-Dat) showed that En1(Cre/+); tOtx2(ov/+) adult mice display an increased density of mesocortical DAergic fibers, as compared to control animals. Increased glyco-Dat staining was accompanied by a marked hypolocomotion in En1(Cre/+); tOtx2(ov/+) mice, as detected in the open field test. Since conditional knockout mice lacking Otx2 in mesDA precursors (En1(Cre/+); Otx2(floxv/flox) mice) show a marked resistance to kainic acid (KA)-induced seizures, we investigated the behavioral response to KA in En1(Cre/+); tOtx2(ov/+) and control mice. No difference was observed between mutant and control mice, but En1(Cre/+); tOtx2(ov/+) mice showed a markedly different c-fos mRNA induction profile in the cerebral cortex and hippocampus after KA seizures, as compared to controls. Accordingly, an increased density of parvalbumin (PV)-positive inhibitory interneurons was detected in the deep layers of the frontal cortex of naïve En1(Cre/+); tOtx2(ov/+) mice, as compared to controls. These data indicate that Otx2 overexpression results in increased DAergic innervation and PV cell density in the fronto-parietal cortex, with important consequences on spontaneous locomotor activity and seizure-induced gene expression. Our results strengthen the notion that Otx2 mutant mouse models are a powerful genetic tool to unravel the molecular and behavioral consequences of altered development of the DAergic system., (Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2014
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