This study shows that in two mouse PD models, tremor-dominant alpha-synucleinopathy (3K) produces selective dysfunction in cerebellar-recipient motor thalamus (CBMT) whereas dopamine-depletion (6-OHDA) produces broader thalamic abnormalities (CBMT and BGMT) with reduced firing and movement-related…

By pinpointing cerebellar-thalamic circuit dysfunction in an alpha-synuclein model that manifests tremor, the work highlights a non-dopaminergic circuit-level target that could guide development of therapies or circuit-based interventions for PD symptoms refractory to dopamine replacement.

The motor thalamus functions as a gateway between subcortical and cortical motor circuits, relaying information critical to movement initiation and execution. Inputs to motor thalamus from the basal ganglia and cerebellum form functionally distinct circuits responsible for different aspects of healthy and dysfunctional motor control. Here, we use mouse models that capture different features of Parkinson's disease pathophysiology - alpha-synuclein (α-syn) aggregation and dopamine loss - to study how thalamic sub-circuits are altered under different pathophysiological conditions. Using a trans-synaptic viral approach to delineate cerebellar-recipient (CBMT) and basal ganglia-recipient (BGMT) territories of motor thalamus in mice of both sexes, we found that in the 3K α-syn model where tremor is the dominant phenotype, thalamic pathophysiology was restricted to the CBMT, whereas in the 6-OHDA depletion model where the dominant phenotype is bradykinesia, thalamic pathophysiology was present in both the CBMT and BGMT. In the CBMT of both disease models, neuronal activity was irregular and showed dampened responses to movement compared to healthy control mice. Additionally, in the 6-OHDA model, the baseline firing rates of CBMT neurons were reduced. In the BGMT, firing rates and patterns of neurons in the 3K model were indistinguishable from those of controls, but in the 6-OHDA model, firing rates and movement-related activity of BGMT neurons were reduced relative to healthy controls. These results suggest selective CBMT involvement in the 3K α-syn model whereas the 6-OHDA model involves more global thalamic pathophysiology encompassing both the CBMT and BGMT.Significance Statement Parkinson disease pathology includes both the loss of dopamine neurons and accumulation of phosphorylated α-syn aggregates throughout the brain. While there is strong evidence linking dopamine loss to bradykinesia, other symptoms of PD are not responsive to dopamine replacement therapy, suggesting mechanisms outside of the dopamine system. A recently developed '3K' mouse model of α-synucleinopathy exhibits only modest dopamine loss yet develops a progressive motor syndrome with tremor as a dominant symptom. Using trans-synaptic viral tools and in vivo electrophysiology, we identify features of neuronal pathophysiology in the motor thalamus of 3K mice indicative of cerebellar dysfunction but not basal ganglia. Our results merit a deeper investigation of the role of the cerebellum in motor symptoms of synucleinopathies.