Transcriptome profiling of hippocampal CA1 after early-life seizure-induced preconditioning may elucidate new genetic therapies for epilepsy

• Published in: The European journal of neuroscience 2013-07, Vol.38 (1), p.2139-2152
• Main Authors: Friedman, L. K., Mancuso, J., Patel, A., Kudur, V., Leheste, J. R., Iacobas, S., Botta, J., Iacobas, D. A., Spray, D. C.
• Format: Article
• Language: English
• Subjects: Age Factors; Animals; Biological and medical sciences; CA1 Region, Hippocampal - metabolism; calcium; conditioning; development; Fundamental and applied biological sciences. Psychology; Gene Expression Profiling; Genetic Therapy; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; hippocampus; Kainic Acid - toxicity; Medical sciences; microarray; Nervous system (semeiology, syndromes); Neurology; Rats; Rats, Sprague-Dawley; seizures; Seizures - chemically induced; Seizures - genetics; Seizures - metabolism; Seizures - therapy; Transcription, Genetic; Transcriptome; Vertebrates: nervous system and sense organs
• ISSN: 0953-816X; 1460-9568
• DOI: 10.1111/ejn.12168

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, Ca2+ 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 Ca2+ permeability of the hippocampus and redirecting inflammatory and apoptotic pathways. These changes could lead to new genetic therapies for epilepsy. Injury of the CA1 subregion induced by a single injection of kainic acid (1×KA) is attenuated when juvenile animals (P20) have a history of two 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.