Dynamic changes in murine forebrain miR-211 expression associate with cholinergic imbalances and epileptiform activity

• DOI: 10.1073/pnas.1701201114
• Publication Date: 2017-06-06T00:50:17Z
• Authors: Uriya Bekenstein; Nibha Mishra; Dan Z. Milikovsky; Geula Hanin; Daniel Zelig; Liron Sheintuch; Amit Berson; David S. Greenberg; Alon Friedman; Hermona Soreq
• Keywords: 0303 health sciences; Epilepsy; Cholinergic Agents; Pilocarpine; Brain; Mice, Transgenic; Receptors, Nicotinic; Acetylcholine; Mice; MicroRNAs; 03 medical and health sciences; Seizures; Acetylcholinesterase; Animals; Humans; Receptors, Transforming Growth Factor beta

Significance Acute traumatic stress increases the sensitivity to develop epileptic seizures in certain people. It is therefore important to discover physiological mechanisms that avoid epilepsy. To test if rapidly inducible microRNAs (miRs) could mediate such protection, we combined mouse engineering, RNA sequencing, electric recording of brain activity, and learning tests. We discovered that miR-211, originating from an epilepsy-related genomic locus, may be involved, and therefore engineered mice produce a drug-suppressible excess of brain miR-211. In these mice, suppressing miR-211 excess to the original expression levels in normal brains led to electrically recorded epilepsy and hypersensitivity to epilepsy-inducing compounds; it also modified acetylcholine receptor composition. The functional impact of miR-211 dynamics on seizure threshold may enable future development of miR-211–directed therapeutics.