Credit: N. Smith/NPG

MicroRNA-128 (miR-128) is widely and abundantly expressed in the postnatal developing brain, but its function is not well understood. A new study by Tan et al. reveals that miR-128 plays a crucial part in the regulation of the excitability of dopamine D1 receptor-expressing neurons (D1 neurons) in the striatum.

Two genes encode miR-128, mir-128-1 and mir-128-2, but it is mir-128-2 that accounts for most miR-128 expression in the brain. Juvenile mice in which mir-128-2 is selectively silenced in forebrain neurons exhibit motor hyperactivity, seizures and death at 2–3 months of age. D1 neurons regulate motor behaviour in mice and humans, and when the authors generated mice lacking mir-128-2 selectively in D1 neurons, they found a similar fatal epilepsy phenotype to that observed in mice lacking mir-128-2 selectively in the forebrain. To identify the targets of mir-128-2 that mediate this seizure activity, Tan et al. used a combination of translating ribosome affinity purification (TRAP) and bioinformatic network and pathway analyses. They found that mir-128-2 regulates the expression of many ion channels and transporters, as well as other genes that contribute to neurotransmitter-driven neuronal excitability, motor activity and epilepsy in humans.

D1 neurons lacking mir-128-2 showed increased ERK2 activation and increased dendritic excitability

Among the targets of mir-128-2 were several components of the extracellular signal-regulated kinase 2 (ERK2; also known as MAPK1) signalling network, which has an important role in neuronal excitability. The authors found that D1 neurons lacking mir-128-2 showed increased ERK2 activation and increased dendritic excitability compared with controls. ERK2 overactivation is associated with increased motor activity and seizures in mice, suggesting that excessive activation of the ERK2 pathway might underlie the motor hyperactivity and fatal epilepsy that is observed in mice lacking mir-128-2.

Interestingly, increased ERK2 activation has also been detected in D1 neurons of mice with chemically induced Parkinson's-like disease. Hypersensitivity of D1 neurons to dopamine was found in both mice lacking mir-128-2 in D1 neurons and mice with Parkinson's-like disease. Importantly, the authors found that increased miR-128 expression in adult mouse forebrain neurons protects against abnormal motor activities associated with chemically induced Parkinson's disease. These findings suggest a role for mir-128-2 in motor disorders and epilepsy.