Serotonin hyperinnervation abolishes seizure susceptibility in Otx2 conditional mutant mice.

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 (En1(cre/+); Otx2(flox/flox)), show a reduced number of dopaminergic neurons and an increased number of serotonergic neurons in the ventral midbrain. Despite these developmental anatomical alterations, En1(cre/+); Otx2(flox/flox) adult mice display normal motor function. Here, we further investigated the neurological consequences of Otx2 inactivation in adult En1(cre/+); Otx2(flox/flox) mice. Adult En1(cre/+); Otx2(flox/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, En1(cre/+); Otx2(flox/flox) mice were resistant to generalized seizures induced by the glutamate agonist kainic acid (KA). Indeed, prolonged pretreatment of En1(cre/+); Otx2(flox/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 En1(cre/+); Otx2(flox/flox) mice, whereas a widespread c-fos mRNA labeling was observed throughout the brain of En1(cre/+); Otx2(flox/flox) mice pretreated with pCPA. These results clearly show that increased brain 5-HT levels are responsible for seizure resistance in En1(cre/+); Otx2(flox/flox) mice and confirm the important role of 5-HT in the control of seizure spread.

• Authors: Prem Prakash Tripathi, Luca Giovanni Di Giovannantonio, Alessandro Viegi, Wolfgang Wurst, Antonio Simeone, Yuri Bozzi
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 28 Issue 37 Pg. 9271-6 (Sep 10 2008) ISSN: 1529-2401 [Electronic] United States
• PMID: 18784307 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• En1 protein, mouse
• Enzyme Inhibitors
• Homeodomain Proteins
• Otx Transcription Factors
• Proto-Oncogene Proteins c-fos
• RNA, Messenger
• Serotonin Plasma Membrane Transport Proteins
• Serotonin
• Fenclonine
• Kainic Acid

Topics

• Analysis of Variance
• Animals
• Enzyme Inhibitors (pharmacology)
• Fenclonine (pharmacology)
• Gene Expression Regulation (drug effects, genetics)
• Hippocampus (drug effects, metabolism)
• Homeodomain Proteins (genetics)
• Kainic Acid
• Mesencephalon (drug effects, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Mutation
• Otx Transcription Factors (genetics)
• Proto-Oncogene Proteins c-fos (genetics)
• RNA, Messenger (metabolism)
• Seizures (chemically induced, genetics)
• Serotonin (metabolism, pharmacology)
• Serotonin Plasma Membrane Transport Proteins (metabolism)
• Time Factors