Increased dopaminergic innervation in the brain of conditional mutant mice overexpressing Otx2: Effects on locomotor behavior and seizure susceptibility

P. P. Tripathi, L. G. Di Giovannantonio, E. Sanguinetti, D. Acampora, M. Allegra, M. Caleo, W. Wurst, A. Simeone, Y. Bozzi

Research output: Contribution to journalArticlepeer-review

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 ( En1Cre/+; tOtx2ov/+), 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 En1Cre/+; tOtx2ov/+ adult mice. Immunohistochemistry for the active, glycosylated form of the dopamine transporter (glyco-Dat) showed that En1Cre/+; tOtx2ov/+ 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 En1Cre/+; tOtx2ov/+ mice, as detected in the open field test. Since conditional knockout mice lacking Otx2 in mesDA precursors ( En1Cre/+; Otx2floxv/flox mice) show a marked resistance to kainic acid (KA)-induced seizures, we investigated the behavioral response to KA in En1Cre/+; tOtx2ov/+ and control mice. No difference was observed between mutant and control mice, but En1Cre/+; tOtx2ov/+ 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 En1Cre/+; tOtx2ov/+ 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.

Original languageEnglish
Pages (from-to)173-183
Number of pages11
JournalNeuroscience
Volume261
DOIs
Publication statusPublished - Mar 7 2014

Keywords

  • Dopamine
  • Epilepsy
  • Hippocampus
  • Limbic system
  • Otx2
  • Prefrontal cortex

ASJC Scopus subject areas

  • Neuroscience(all)

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