Reduced Dopamine Signaling Impacts Pyramidal Neuron Excitability in Mouse Motor Cortex

Dopaminergic modulation is essential for the control of voluntary movement; however, the role of dopamine in regulating the neural excitability of the primary motor cortex (M1) is not well understood. Here, we investigated two modes by which dopamine influences the input/output function of M1 neurons. To test the direct regula-tion of M1 neurons by dopamine, we performed whole-cell recordings of excitatory neurons and measured ex-citability before and after local, acute dopamine receptor blockade. We then determined whether chronic depletion of dopaminergic input to the entire motor circuit, via a mouse model of Parkinson's disease, was sufficient to shift M1 neuron excitability. We show that D1 receptor (D1R) and D2R antagonism altered sub-threshold and suprathreshold properties of M1 pyramidal neurons in a layer-specific fashion. The effects of D1R antagonism were primarily driven by changes to intrinsic properties, while the excitability shifts following D2R antagonism relied on synaptic transmission. In contrast, chronic depletion of dopamine to the motor cir-cuit with 6-hydroxydopamine induced layer-specific synaptic transmission-dependent shifts in M1 neuron ex-citability that only partially overlapped with the effects of acute D1R antagonism. These results suggest that while acute and chronic changes in dopamine modulate the input/output function of M1 neurons, the mecha-nisms engaged are distinct depending on the duration and origin of the manipulation. Our study highlights the broad influence of dopamine on M1 excitability by demonstrating the consequences of local and global dopa -mine depletion on neuronal input/output function.