AbstractThe hypokinetic motor symptoms of Parkinson’s disease (PD) are closely linked with a decreased motor cortical output as a consequence of elevated basal ganglia inhibition. However, whether and how the loss of dopamine alters the cellular properties of motor cortical neurons in PD remains undefined. We induced experimental parkinsonism in adult C57BL6 mice of both sexes by injecting neurotoxin, 6-hydroxydopamine, into the medial forebrain bundle. By using ex vivo patch-clamp recording and retrograde tracing approach, we found that the intrinsic excitability of pyramidal tract neurons (PTNs) in the motor cortical layer 5b was greatly decreased following the degeneration of midbrain dopaminergic neurons; but the intratelencephalic neurons (ITNs) were not affected. The cell-type-specific intrinsic adaptations were associated with a significant broadening of the action potentials in PTNs but not in ITNs. Moreover, the loss of midbrain dopaminergic neurons impaired the capability of M1 PTNs to sustain high-frequency firing, which could underlie their abnormal pattern of activity in the parkinsonian state. We also showed that the decreased excitability and broadened action potentials were largely caused by a disrupted function of the large conductance, Ca2+-activated K+ channels. The restoration of dopaminergic neuromodulation failed to rescue the impaired intrinsic excitability of M1 PTNs in parkinsonian mice. Altogether, our data show cell-type-specific decreases of the excitability of M1 pyramidal neurons following the loss of midbrain dopaminergic neurons. Thus, intrinsic adaptations in the motor cortex, together with pathological basal ganglia inhibition, underlie the decreased motor cortical output in parkinsonian state and exacerbate parkinsonian motor deficits.Significance statementThe degeneration of midbrain dopaminergic neurons in Parkinson’s disease remodels the connectivity and function of cortico–basal ganglia–thalamocortical network. However, whether and how the loss of dopamine and aberrant basal ganglia activity alter motor cortical circuitry remain undefined. We found that pyramidal neurons in the layer 5b of the primary motor cortex (M1) exhibit distinct adaptations in response to the loss of midbrain dopaminergic neurons, depending on their long-range projections. Besides the decreased thalamocortical synaptic excitation as proposed by the classical model of Parkinson’s pathophysiology, these results, for the first time, show novel cellular and molecular mechanisms underlying the abnormal motor cortical output in parkinsonian state.
Cell-Type-Specific Decrease of the Intrinsic Excitability of Motor Cortical Pyramidal Neurons in Parkinsonism
