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 journalArticle

4 Citations (Scopus)

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

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Seizures
Brain
Kainic Acid
Dopaminergic Neurons
Parvalbumins
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Dopamine Plasma Membrane Transport Proteins
Otx Transcription Factors
Parietal Lobe
Ventral Tegmental Area
Homeobox Genes
Neurotoxins
Frontal Lobe
Interneurons
Locomotion
Knockout Mice
Cerebral Cortex
Transgenic Mice
Hippocampus
Cell Count

Keywords

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

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Increased dopaminergic innervation in the brain of conditional mutant mice overexpressing Otx2 : Effects on locomotor behavior and seizure susceptibility. / Tripathi, P. P.; Di Giovannantonio, L. G.; Sanguinetti, E.; Acampora, D.; Allegra, M.; Caleo, M.; Wurst, W.; Simeone, A.; Bozzi, Y.

In: Neuroscience, Vol. 261, 07.03.2014, p. 173-183.

Research output: Contribution to journalArticle

Tripathi, PP, Di Giovannantonio, LG, Sanguinetti, E, Acampora, D, Allegra, M, Caleo, M, Wurst, W, Simeone, A & Bozzi, Y 2014, 'Increased dopaminergic innervation in the brain of conditional mutant mice overexpressing Otx2: Effects on locomotor behavior and seizure susceptibility', Neuroscience, vol. 261, pp. 173-183. https://doi.org/10.1016/j.neuroscience.2013.12.045
Tripathi, P. P. ; Di Giovannantonio, L. G. ; Sanguinetti, E. ; Acampora, D. ; Allegra, M. ; Caleo, M. ; Wurst, W. ; Simeone, A. ; Bozzi, Y. / Increased dopaminergic innervation in the brain of conditional mutant mice overexpressing Otx2 : Effects on locomotor behavior and seizure susceptibility. In: Neuroscience. 2014 ; Vol. 261. pp. 173-183.
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AU - Sanguinetti, E.

AU - Acampora, D.

AU - Allegra, M.

AU - Caleo, M.

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AU - Simeone, A.

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