Activation of Somatostatin Inhibitory Neurons by Lypd6-nAChRα2 System Restores Juvenile-like Plasticity in Adult Visual Cortex

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 interneuron types 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 for reactivating cortical plasticity in adulthood. Selective overexpression of Lypd6 in adult SST interneurons reactivates plasticity through the α2 subtype of nAChR by rapidly activating SST interneurons and in turn inhibiting sub-population of PV interneurons, a key early trigger of the juvenile form of plasticity. Chemogenetic activation of SST interneurons confirms the causal role of SST interneuron activity in reactivating plasticity. Collectively, we identify the Lypd6-nAChRα2 system and associated SST-PV disinhibitory microcircuit as the novel SST interneuron-specific targets for reactivating plasticity in adulthood. This provides potential insights into therapeutic strategies against disorders where recovery is limited due to diminished plasticity in adulthood, such as amblyopia and psychiatric disorders characterized by deficits in SST interneurons.