Serotonin hyperinnervation abolishes seizure susceptibility in Otx2 conditional mutant mice

Prem Prakash Tripathi, Luca Giovanni Di Giovannantonio, Alessandro Viegi, Wolfgang Wurst, Antonio Simeone, Yuri Bozzi

Research output: Contribution to journalArticlepeer-review

Abstract

The homeobox-containing transcription factor Otx2 is crucially involved in fate determination of midbrain neurons. Mutant mice, in which Otx2 was conditionally inactivated by a Cre recombinase expressed under the transcriptional control of the Engrailed1 (En1) gene (En1cre/+; Otx2flox/flox), show a reduced number of dopaminergic neurons and an increased number of serotonergic neurons in the ventral midbrain. Despite these developmental anatomical alterations, En1cre/+; Otx2 flox/flox adult mice display normal motor function. Here, we further investigated the neurological consequences of Otx2 inactivation in adult En1cre/+; Otx2flox/flox mice. Adult En1cre/+; Otx2flox/flox mice showed increased serotonin (5-HT) levels in the pons, ventral midbrain, hippocampus (CA3 subfield), and cerebral cortex, as indicated by HPLC and immunohistochemistry. Conversely, SERT (5-HT transporter) levels were decreased in conditional mutant brains. As a consequence of this increased 5-HT hyperinnervation, En1cre/+; Otx2flox/flox mice were resistant to generalized seizures induced by the glutamate agonist kainic acid (KA). Indeed, prolonged pretreatment of En1cre/+; Otx2flox/flox mice with the 5-HT synthesis inhibitor para-chlorophenylalanine (pCPA) restored brain 5-HT content to control levels, fully reestablishing KA seizure susceptibility. Accordingly, c-fos mRNA induction after KA was restricted to the hippocampus in En1Cre/+; Otx2flox/flox mice, whereas a widespread c-fos mRNA labeling was observed throughout the brain of En1Cre/+; Otx2flox/flox mice pretreated with pCPA. These results clearly show that increased brain 5-HT levels are responsible for seizure resistance in En1cre/+; Otx2 flox/flox mice and confirm the important role of 5-HT in the control of seizure spread.

Original languageEnglish
Pages (from-to)9271-9276
Number of pages6
JournalJournal of Neuroscience
Volume28
Issue number37
DOIs
Publication statusPublished - Sep 10 2008

Keywords

  • Epilepsy
  • Hippocampus
  • Kainic acid
  • pCPA
  • Seizures
  • Serotonin transporter

ASJC Scopus subject areas

  • Neuroscience(all)
  • Medicine(all)

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