Excessive firing of dyskinesia-associated striatal direct pathway neurons is gated by dopamine and excitatory synaptic input.

The striatum integrates dopaminergic and glutamatergic inputs to select preferred versus alternative actions. However, the precise mechanisms underlying this process remain unclear. One way to study action selection is to understand how it breaks down in pathological states. Here, we explored the cellular and synaptic mechanisms of levodopa-induced dyskinesia (LID), a complication of Parkinson's disease therapy characterized by involuntary movements. We used an activity-dependent tool (FosTRAP) in conjunction with a mouse model of LID to investigate functionally distinct subsets of striatal direct pathway medium spiny neurons (dMSNs). In vivo, levodopa differentially activates dyskinesia-associated (TRAPed) dMSNs compared to other dMSNs. We found this differential activation of TRAPed dMSNs is likely to be driven by higher dopamine receptor expression, dopamine-dependent excitability, and excitatory input from the motor cortex and thalamus. Together, these findings suggest how the intrinsic and synaptic properties of heterogeneous dMSN subpopulations integrate to support action selection.

Directly to the Point: Dopamine Persistently Enhances Excitability of Direct Pathway Striatal Neurons.

In this issue of Neuron, Lahiri and Bevan (2020) investigate the effects of dopamine release on striatal projection neurons. Using perforated patch recordings and optogenetics, they show that dopamine release persistently enhances the intrinsic excitability of direct pathway striatal neurons.

Circuit Mechanisms of Parkinson's Disease.

Parkinson's disease (PD) is a complex, multi-system neurodegenerative disorder. The second most common neurodegenerative disorder after Alzheimer's disease, it affects approximately 1% of adults over age 60. Diagnosis follows the development of one or more of the core motor features of the disease, including tremor, slowing of movement (bradykinesia), and rigidity. However, there are numerous other motor and nonmotor disease manifestations. Many PD symptoms result directly from neurodegeneration; others are driven by aberrant activity patterns in surviving neurons. This latter phenomenon, PD circuit dysfunction, is an area of intense study, as it likely underlies our ability to treat many disease symptoms in the face of (currently) irreversible neurodegeneration. This Review will discuss key clinical features of PD and their basis in neural circuit dysfunction. We will first review important disease symptoms and some of the responsible neuropathology. We will then describe the basal ganglia-thalamocortical circuit, the major locus of PD-related circuit dysfunction, and some of the models that have influenced its study. We will review PD-related changes in network activity, subdividing findings into those that touch on the rate, rhythm, or synchronization of neurons. Finally, we suggest some critical remaining questions for the field and areas for new developments.

Functionally Distinct Connectivity of Developmentally Targeted Striosome Neurons.

One long-standing model of striatal function divides the striatum into compartments called striosome and matrix. While some anatomical evidence suggests that these populations represent distinct striatal pathways with differing inputs and outputs, functional investigation has been limited by the methods for identifying and manipulating these populations. Here, we utilize hs599CreER mice as a new tool for targeting striosome projection neurons and testing their functional connectivity. Extending anatomical work, we demonstrate that striosome neurons receive greater synaptic input from prelimbic cortex, whereas matrix neurons receive greater input from primary motor cortex. We also identify functional differences in how striosome and matrix neurons process excitatory input, providing the first electrophysiological method for delineating striatal output neuron subtypes. Lastly, we provide the first functional demonstration that striosome neurons are the predominant striatal output to substantia nigra pars compacta dopamine neurons. These results identify striosome and matrix as functionally distinct striatal pathways.