title: Transcriptome profiling of hippocampal CA1 after early-life seizure-induced preconditioning may elucidate new genetic therapies for epilepsy.
abstract: Injury of the CA1 subregion induced by a single injection of kainic acid (1 × KA) in juvenile animals (P20) is attenuated in animals with two prior sustained neonatal seizures on P6 and P9. To identify gene candidates involved in the spatially protective effects produced by early-life conditioning seizures we profiled and compared the transcriptomes of CA1 subregions from control, 1 × KA- and 3 × KA-treated animals. More genes were regulated following 3 × KA (9.6%) than after 1 × KA (7.1%). Following 1 × KA, genes supporting oxidative stress, growth, development, inflammation and neurotransmission were upregulated (e.g. Cacng1, Nadsyn1, Kcng1, Aven, S100a4, GFAP, Vim, Hrsp12 and Grik1). After 3 × KA, protective genes were differentially over-expressed [e.g. Cat, Gpx7, Gad1, Hspa12A, Foxn1, adenosine A1 receptor, Ca(2+) adaptor and homeostasis proteins, Cacnb4, Atp2b2, anti-apoptotic Bcl-2 gene members, intracellular trafficking protein, Grasp and suppressor of cytokine signaling (Socs3)]. Distinct anti-inflammatory interleukins (ILs) not observed in adult tissues [e.g. IL-6 transducer, IL-23 and IL-33 or their receptors (IL-F2 )] were also over-expressed. Several transcripts were validated by real-time polymerase chain reaction (QPCR) and immunohistochemistry. QPCR showed that casp 6 was increased after 1 × KA but reduced after 3 × KA; the pro-inflammatory gene Cox1 was either upregulated or unchanged after 1 × KA but reduced by ~70% after 3 × KA. Enhanced GFAP immunostaining following 1 × KA was selectively attenuated in the CA1 subregion after 3 × KA. The observed differential transcriptional responses may contribute to early-life seizure-induced pre-conditioning and neuroprotection by reducing glutamate receptor-mediated Ca(2+) permeability of the hippocampus and redirecting inflammatory and apoptotic pathways. These changes could lead to new genetic therapies for epilepsy.
authors.affiliation: Basic Sciences, Cell Biology & Anatomy, New York Medical College, 50 Dana Rd, Valhalla, NY 10595, USA. Linda_Friedman@nymc.edu
authors.forename: L K
authors.initials: LK
authors.lastname: Friedman
authors.forename: J
authors.initials: J
authors.lastname: Mancuso
authors.forename: A
authors.initials: A
authors.lastname: Patel
authors.forename: V
authors.initials: V
authors.lastname: Kudur
authors.forename: J R
authors.initials: JR
authors.lastname: Leheste
authors.forename: S
authors.initials: S
authors.lastname: Iacobas
authors.forename: J
authors.initials: J
authors.lastname: Botta
authors.forename: D A
authors.initials: DA
authors.lastname: Iacobas
authors.forename: D C
authors.initials: DC
authors.lastname: Spray
mesh_terms: D000367:Age Factors; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000378:metabolism*; D020869:Gene Expression Profiling; D015316:Genetic Therapy; D007608:Kainic Acid / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D014158:Transcription, Genetic; D059467:Transcriptome
chemical_list: D007608:Kainic Acid
keywords: calcium; conditioning; development; hippocampus; microarray; seizures
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