Spared CA1 pyramidal neuron function and hippocampal performance following antisense knockdown of microRNA‐134

• Published in: Epilepsia (Copenhagen) 2018-08, Vol.59 (8), p.1518-1526
• Main Authors: Morris, Gareth, Brennan, Gary P., Reschke, Cristina R., Henshall, David C., Schorge, Stephanie
• Format: Article
• Language: English
• Subjects: Action potential; Action Potentials - drug effects; Action Potentials - physiology; Animals; antagomir; Antisense oligonucleotides; Disease Models, Animal; Epilepsy; Excitatory Postsynaptic Potentials - drug effects; Exploratory Behavior - drug effects; Full‐length Original Research; Hippocampus; Hippocampus - cytology; Hippocampus - drug effects; In Vitro Techniques; Male; MicroRNAs; MicroRNAs - chemistry; MicroRNAs - genetics; MicroRNAs - metabolism; microRNA‐134; miRNA; Navigation behavior; Neurons - drug effects; Neurons - physiology; Oligodeoxyribonucleotides, Antisense - pharmacology; Potassium - pharmacology; Pyramidal cells; Rats; Rats, Sprague-Dawley; Seizures
• ISSN: 0013-9580; 1528-1167
• DOI: 10.1111/epi.14475

Summary Objective Inhibition of microRNA‐134 by an oligonucleotide antagomir (ant‐134) has been shown to produce powerful antiseizure effects in multiple models of epilepsy. However, to successfully translate the treatment to the clinic, it is important to assess what potential adverse effects it may have on naive brain tissue. Methods To investigate this, adult male Sprague‐Dawley rats were treated with either ant‐134 or a scrambled control sequence. Animals were later assessed for spatial navigation, before ex vivo slices were taken to assess the effects of microRNA‐134 knockdown on well‐defined measures of intrinsic and synaptic properties. Results Hippocampal field potential recordings determined that silencing of microRNA‐134 by ant‐134 injection was associated with a reduction in epileptiform activity following application of 9 mmol/L K+. Nevertheless, rats performed normally in the novel object location test. Action potential waveforms and miniature excitatory synaptic currents recorded in CA1 pyramidal neurons were unaffected by ant‐134. Significance These results demonstrate that ant‐134 confers a seizure‐protective effect without obvious interference with hippocampal neuronal properties or network function. These findings support further development of this novel approach to epilepsy treatment.