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The Journal of Neuroscience, September 10, 2008, 28(37):9271-9276; doi:10.1523/JNEUROSCI.2208-08.2008

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Brief Communications
Serotonin Hyperinnervation Abolishes Seizure Susceptibility in Otx2 Conditional Mutant Mice

Prem Prakash Tripathi,^1,2 Luca Giovanni Di Giovannantonio,^3,4 Alessandro Viegi,^1,2 Wolfgang Wurst,^5,6 Antonio Simeone,^3,4 and Yuri Bozzi¹

¹Istituto di Neuroscienze del Consiglio Nazionale delle Ricerche (CNR) and ²Laboratorio di Neurobiologia della Scuola Normale Superiore, 56100 Pisa, Italy, ³CEINGE-Biotecnologie Avanzate, 80145 Naples, Italy, ⁴Institute of Genetics and Biophysics "A. Buzzati-Traverso," CNR, 80131 Naples, Italy, ⁵Institute of Developmental Genetics, Helmholtz Zentrum München, 85764 Munich/Neuherberg, Germany, and ⁶Max Planck Institute of Psychiatry, Molecular Neurogenetics, 80804 Munich, Germany

Correspondence should be addressed to either of the following: Antonio Simeone, CEINGE-Biotecnologie Avanzate, via Comunale Margherita 482, 80145 Naples, Italy, Email: simeone{at}ceinge.unina.it; or Yuri Bozzi, Istituto di Neuroscienze del Consiglio Nazionale delle Ricerche, via G. Moruzzi 1, 56100 Pisa, Italy, Email: yuri{at}in.cnr.it

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.

Key words: serotonin transporter; pCPA; kainic acid; hippocampus; seizures; epilepsy

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Received May 8, 2008; revised July 25, 2008; accepted Aug. 6, 2008.

Correspondence should be addressed to either of the following: Antonio Simeone, CEINGE-Biotecnologie Avanzate, via Comunale Margherita 482, 80145 Naples, Italy, Email: simeone{at}ceinge.unina.it; or Yuri Bozzi, Istituto di Neuroscienze del Consiglio Nazionale delle Ricerche, via G. Moruzzi 1, 56100 Pisa, Italy, Email: yuri{at}in.cnr.it

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