DARPP-32 in motor cortex regulates structural and synaptic plasticity in corticothalamic neurons and enables motor learning.

The dopamine and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), a key mediator of monoaminergic signaling, is expressed in the cortex; however, its cellular distribution and role in cortically dependent behaviors remain elusive. Here, we determined the functional integration of DARPP-32 in motor cortex circuitry using molecular profiling, circuit tracing, patch-clamp electrophysiology, virus-assisted gene targeting and motor behavior analyses. Unlike the significant overlap between DARPP-32 and dopamine receptors in striatal GABAergic medium spiny projection neurons, we found that the majority of DARPP-32-positive cortical neurons express the corticothalamic marker FoxP2 but not dopamine D1 or D2 receptors. Notably, in cortical slices, adenylyl cyclase activation induced a more robust increase in DARPP-32 phosphorylation at threonine 34, a protein kinase A target site, compared to dopamine D1 receptor stimulation. Conditional ablation of DARPP-32 in the motor cortex did not affect basal or psychostimulant-induced motor activity but reduced motor aptitude and compromised overnight retention of motor skill. Concomitantly, the absence of DARPP-32 reduced dendritic spines density and prevented the induction of glutamatergic long-term potentiation in layer 6 motor cortical neurons. Altogether, our study demonstrates a critical role for DARPP-32 in cortical synaptic plasticity, emphasizing its importance in corticothalamic regulation of motor skill learning.