Cortical inactivation of Darpp-32 impairs synaptic and structural plasticity associated with motor learning

Aim: Motor learning significantly impacts daily life, triggering notable changes in the primary motor cortex (M1) and basal ganglia (BG). Dopamine (DA) mediates these changes, with Darpp-32 playing a key role in DA transmission. Although extensively studied in the BG's striatum, Darpp-32's function in the motor cortex remains largely unexplored. This study aims to characterize Darpp-32 in motor cortices, examining cellular expression and its impact on motor behavior, synaptic and structural plasticity.Methods: Anatomical study: Using C57BL/6 mice, we examined Darpp-32 distribution across cortical layers, assessing colocalization with FoxP2 and CTIP2. Using CTB retrograde tracing, we studied Darpp32-positive neuron projections, targeting thalamic nuclei. We explored Darpp-32 colocalization with DA receptors using D1TdTomato and D2Cre mice. Knockout model: Employing a Darpp32 flox/flox mouse, we selectively depleted the protein in the motor cortex via a Cre virus. These mice underwent behavioral studies, assessing locomotion and motor learning (accelerod task), and electrophysiological experiments, investigating synaptic (LTP, mEPSCs, mIPSCs) and structural (dendritic spines) properties.Results: Darpp-32, highly expressed in deep motor cortex layers, shows limited colocalization with DA receptors but abundant association with FoxP2. Darpp32-deficient mice exhibit impaired motor learning but normal locomotion. Moreover, we found reduced long-term potentiation, lower dendritic spine count, and altered excitatory/inhibitory balance in motor cortex neurons.Conclusion: In the motor cortex, Darpp-32 functions autonomously of DA receptors and, unlike other brain regions like the striatum, is predominantly expressed in glutamatergic neurons. Cortical Darpp-32 plays a role in motor learning by mediating LTP and the formation of dendritic spines.