Attenuated Single Neuron and Network Hyperexcitability Following MicroRNA-134 Inhibition in Mice with Drug-Resistant Temporal Lobe Epilepsy.

Abstract

The multifactorial pathophysiology of acquired epilepsies lends itself to a multitargeting therapeutic approach. MicroRNAs (miRNA) are short noncoding RNAs that individually can negatively regulate dozens of protein-coding transcripts. Previously, we reported that central injection of antisense oligonucleotides targeting microRNA-134 (Ant-134) shortly after status epilepticus potently suppressed the development of recurrent spontaneous seizures in rodent models of temporal lobe epilepsy. The mechanism(s) of these antiseizure effects remain, however, incompletely understood. Here we show that intracerebroventricular microinjection of Ant-134 in male mice with preexisting epilepsy caused by intra-amygdala kainic acid-induced status epilepticus potently reduces the occurrence of spontaneous seizures. Recordings from ex vivo brain slices collected 2-4 d after Ant-134 injection in epileptic mice detected a number of electrophysiological phenotypic changes consistent with reduced excitability. Specifically, Ant-134 reduced action potential bursts after current injection in CA1 neurons and reduced excitatory postsynaptic current frequencies in CA1 neurons. Ant-134 also reduced general network excitability, including attenuating proexcitatory CA1 responses to Schaffer collateral stimulation in hippocampal slices from epileptic mice. Together, the present study demonstrates inhibiting miR-134 reduces single neuron and network hyperexcitability in mice and extends support for this approach to treat drug-resistant epilepsies.