title: 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.affiliation: Istituto di Neuroscienze del Consiglio Nazionale delle Ricerche, Laboratorio di Neurobiologia della Scuola Normale Superiore, 56100 Pisa, Italy.
authors.forename: Prem Prakash
authors.initials: PP
authors.lastname: Tripathi
authors.forename: Luca Giovanni
authors.initials: LG
authors.lastname: Di Giovannantonio
authors.forename: Alessandro
authors.initials: A
authors.lastname: Viegi
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wurst
authors.forename: Antonio
authors.initials: A
authors.lastname: Simeone
authors.forename: Yuri
authors.initials: Y
authors.lastname: Bozzi
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D010134:Fenclonine / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics; D007608:Kainic Acid; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D051857:Otx Transcription Factors / Q000235:genetics*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000235:genetics*; D012701:Serotonin / Q000378:metabolism* / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D013997:Time Factors
chemical_list: C080330:En1 protein, mouse; D004791:Enzyme Inhibitors; D018398:Homeodomain Proteins; D051857:Otx Transcription Factors; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin; D010134:Fenclonine; D007608:Kainic Acid
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