Abstract
Heightened juvenile cortical plasticity declines into adulthood, posing a challenge for functional recovery following brain injury or disease. A network of inhibition is critical for regulating plasticity in adulthood, yet contributions of specific interneurons other than parvalbumin (PV) interneurons have been underexplored. Here we show Lypd6, an endogenous positive modulator of nicotinic acetylcholine receptors (nAChRs), as a specific molecular target in somatostatin (SST) interneurons to reactivate cortical plasticity in adulthood. Selective overexpression of Lypd6 in adult SST interneurons reactivates plasticity through α2 subtype of nAChR by rapidly activating SST interneurons which in turn inhibit PV interneurons, a key early trigger of the juvenile form of plasticity. Chemogenetic activation of SST interneurons confirmed the causal role of SST interneuron activity in reactivating plasticity. Identification of Lypd6-nAChRα2 system and associated SST-PV disinhibitory circuits as the first SST interneuron-specific targets for reactivation of plasticity in adulthood provides potential therapeutic insights into treating disorders with limited recovery due to diminished plasticity such as amblyopia as well as psychiatric disorders characterized by deficits in SST interneurons.