PT  - JOURNAL ARTICLE
AU  - Prem Prakash Tripathi
AU  - Luca Giovanni Di Giovannantonio
AU  - Alessandro Viegi
AU  - Wolfgang Wurst
AU  - Antonio Simeone
AU  - Yuri Bozzi
TI  - Serotonin Hyperinnervation Abolishes Seizure Susceptibility in <em>Otx2</em> Conditional Mutant Mice
AID  - 10.1523/JNEUROSCI.2208-08.2008
DP  - 2008 Sep 10
TA  - The Journal of Neuroscience
PG  - 9271--9276
VI  - 28
IP  - 37
4099  - http://www.jneurosci.org/content/28/37/9271.short
4100  - http://www.jneurosci.org/content/28/37/9271.full
SO  - J. Neurosci.2008 Sep 10; 28
AB  - 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/+; Otx2flox/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/+; Otx2flox/flox mice and confirm the important role of 5-HT in the control of seizure spread.