Reduced dopamine signaling impacts pyramidal neuron excitability in mouse motor cortex

Abstract

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 regulation of M1 neurons by dopamine, we performed whole-cell recordings of excitatory neurons and measured excitability before and after local, acute dopamine receptor blockade. We then determined if 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 and D2 receptor (D1R, D2R) antagonism altered subthreshold 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 circuit with 6-hydroxydopamine (6OHDA) induced layer-specific synaptic transmission-dependent shifts in M1 neuron excitability 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 mechanisms engaged are distinct depending on the duration and origin of the manipulation. Our study highlights dopamine’s broad influence on M1 excitability by demonstrating the consequences of local and global dopamine depletion on neuronal input/output function.

Significance statement

Dopaminergic signaling is crucial for the control of voluntary movement, and loss of dopaminergic transmission in the motor circuit is thought to underlie motor symptoms in those with Parkinson’s disease (PD). Studies in animal models of PD highlight changes in M1 activity following dopamine depletion, however the mechanisms underlying this phenomenon remain poorly understood. Here we show that diminished dopamine signaling significantly alters the excitability and input/output function of M1 pyramidal neurons. The effects differed depending on the mode and location – local versus across the motor pathway - of the dopamine manipulation. Our results demonstrate how loss of dopamine can engage complex mechanisms to alter M1 neural activity.