Mesial
temporal lobe epilepsy (mTLE) is a chronic neurological disease characterized by recurrent
seizures. The
antiepileptic drugs currently available to treat mTLE are ineffective in one-third of patients and lack disease-modifying effects.
miRNAs, a class of small noncoding RNAs which control gene expression at the post-transcriptional level, play a key role in the pathogenesis of mTLE and other
epilepsies. Although manipulation of
miRNAs at acute stages has been reported to reduce subsequent spontaneous
seizures, it is uncertain whether targeting
miRNAs at chronic stages of mTLE can also reduce
seizures. Furthermore, the functional role and downstream targets of most
epilepsy-associated
miRNAs remain poorly understood. Here, we show that miR-135a is selectively upregulated within neurons in epileptic brain and report that targeting miR-135a in vivo using
antagomirs after onset of spontaneous recurrent
seizures can reduce seizure activity at the chronic stage of experimental mTLE in male mice. Further, by using an unbiased approach combining immunoprecipitation and
RNA sequencing, we identify several novel neuronal targets of miR-135a, including Mef2a
Mef2 proteins are key regulators of excitatory synapse density. Mef2a and miR-135a show reciprocal expression regulation in human (of both sexes) and experimental TLE, and miR-135a regulates dendritic spine number and type through Mef2. Together, our data show that miR-135a is target for reducing seizure activity in chronic
epilepsy, and that deregulation of miR-135a in
epilepsy may alter Mef2a expression and thereby affect synaptic function and plasticity.SIGNIFICANCE STATEMENT
miRNAs are post-transcriptional regulators of gene expression with roles in the pathogenesis of
epilepsy. However, the precise mechanism of action and therapeutic potential of most
epilepsy-associated
miRNAs remain poorly understood. Our study reveals dramatic upregulation of the key neuronal
miRNA miR-135a in both experimental and human mesial
temporal lobe epilepsy. Silencing miR-135a in experimental
temporal lobe epilepsy reduces seizure activity at the spontaneous recurrent seizure stage. These data support the exciting possibility that
miRNAs can be targeted to combat
seizures after spontaneous seizure activity has been established. Further, by using unbiased approaches novel neuronal targets of miR-135a, including members of the Mef2
protein family, are identified that begin to explain how deregulation of miR-135a may contribute to
epilepsy.