MicroRNA-138 controls hippocampal interneuron function and short-term memory in mice.

Abstract

The proper development and function of neuronal circuits rely on a tightly regulated balance between excitatory and inhibitory (E/I) synaptic transmission, and disrupting this balance can cause neurodevelopmental disorders, for example, schizophrenia. MicroRNA-dependent gene regulation in pyramidal neurons is important for excitatory synaptic function and cognition, but its role in inhibitory interneurons is poorly understood. Here, we identify <i>miR138-5p</i> as a regulator of short-term memory and inhibitory synaptic transmission in the mouse hippocampus. Sponge-mediated <i>miR138-5p</i> inactivation specifically in mouse parvalbumin (PV)-expressing interneurons impairs spatial recognition memory and enhances GABAergic synaptic input onto pyramidal neurons. Cellular and behavioral phenotypes associated with <i>miR138-5p</i> inactivation are paralleled by an upregulation of the schizophrenia (SCZ)-associated <i>Erbb4</i>, which we validated as a direct <i>miR138-5p</i> target gene. Our findings suggest that <i>miR138-5p</i> is a critical regulator of PV interneuron function in mice, with implications for cognition and SCZ. More generally, they provide evidence that microRNAs orchestrate neural circuit development by fine-tuning both excitatory and inhibitory synaptic transmission.