MicroRNA-128 Governs Neuronal Excitability and Motor Behavior in Mice

Abstract

The control of motor behavior in animals and humans requires constant adaptation of neuronal networks to signals of various types and strengths. We found that microRNA-128 (miR-128), which is expressed in adult neurons, regulates motor behavior by modulating neuronal signaling networks and excitability. miR-128 governs motor activity by suppressing the expression of various ion channels and signaling components of the extracellular signal-regulated kinase ERK2 network that regulate neuronal excitability. In mice, a reduction of miR-128 expression in postnatal neurons causes increased motor activity and fatal epilepsy. Overexpression of miR-128 attenuates neuronal responsiveness, suppresses motor activity and alleviates motor abnormalities associated with Parkinson’s–like disease and seizures in mice. These data suggest a therapeutic potential for miR-128 in the treatment of epilepsy and movement disorders.

Inhibition of microRNA 128 promotes excitability of cultured cortical neuronal networks

“…2). miR-128 targets several genes in upstream signaling events that activate MAPK3/1 by phosphorylation (Tan et al 2013). We confirmed via immunoblot that sponge-mediated miR-128 knockdown leads to modest but consistent MAPK3/1 activation on DIV12 and DIV19 (Supplemental Fig.…”

“…Recent literature indicates a clear link between miRNAs and epileptogenesis. One of the most striking examples demonstrated that mice lacking Mir128-2, one of the two genes that encode mature miR-128, in dopaminergic neurons developed fatal seizures within 3 mo of age (Tan et al 2013). …”

MicroRNAs in neural development: from master regulators to fine-tuners

“…Furthermore, although cell culture models have provided much insight into the role of miRNAs in neural development, animal models that examine miRNA function at the organismic level are still scarce. Nevertheless, first results from miRNA KO models are highly encouraging and suggest that the loss of specific miRNAs can have rather profound consequences for the development of neural circuits and animal behavior (Amin et al, 2015;Tan et al, 2013). Applying CRISPR-Cas technology to analyze miRNA function in the brain will no doubt accelerate efforts to investigate the physiological function of specific miRNA-target interactions.…”

Manipulating MicroRNAs in Murine Models: Targeting the Multi-Targeting in Epilepsy

“…Intracerebroventricular injection of oligonucleotides designed to bind the microRNA, termed antagomirs ( Figure 1B), resulted in suppression of evoked and spontaneous seizures in a mouse kainate model (26). Later, knockout of miR-128 in mice was shown to result in fatal epilepsy, whereas overexpression of miR-128 had acute seizure-suppressive effects (27). The hyperexcitability effect of reduced miR-128 was recently confirmed by an independent team using primary neurons transfected with a "sponge" construct to deplete miR-128 (28).…”