Alterations of the gut microbiota with antibiotics protects dopamine neuron loss and improve motor deficits in a pharmacological rodent model of Parkinson's disease.

Parkinson's disease (PD) is a debilitating condition resulting in motor and non-motor symptoms affecting approximately 10 million people worldwide. Currently, there are no pharmacological treatments that can cure the condition or effectively halt its progression. The focus of PD research has been primarily on the neurobiological basis and consequences of dopamine (DA) neuron degeneration given that the loss of DA neurons projecting from the substantia nigra to the dorsal striatum results in the development of cardinal PD motor symptoms. Alternatively, gastrointestinal dysfunction is well recognized in PD patients, and often occurs prior to the development of motor symptoms. The gut microbiota, which contains thousands of bacterial species, play important roles in intestinal barrier integrity and function, metabolism, immunity and brain function. Pre-clinical and clinical studies suggest an important link between alterations in the composition of the gut microbiota and psychiatric and neurological conditions, including PD. Several reports have documented gut dysbiosis and alterations in the composition of the gut microbiota in PD patients. Therefore, the goal of this study was to explore the contribution of the gut microbiota to the behavioral and neurochemical alterations in a rodent toxin model of DA depletion that reproduces the motor symptoms associated with PD. We observed that chronic treatment of adult rats with non-absorbable antibiotics ameliorates the neurotoxicity of 6-hydroxydopamine (6-OHDA) in a unilateral lesion model. Specifically, immunohistochemistry against the dopaminergic neuron marker tyrosine hydroxylase (TH) showed an attenuation of the degree of 6-OHDA-induced dopaminergic neuron loss in antibiotic treated animals compared to control animals. In addition, we observed a reduction in the expression of pro-inflammatory markers in the striatum of antibiotic-treated animals. The degree of motor dysfunction after 6-OHDA was also attenuated in antibiotic-treated animals as measured by paw-rearing measurements in the cylinder test, forepaw stepping test, and ipsilateral rotations observed in the amphetamine-induced rotation test. These results implicate the gut microbiota as a potential contributor to pathology in the development of PD. Further studies are necessary to understand the specific mechanisms involved in transducing alterations in the gut microbiota to changes in dopaminergic neuron loss and motor dysfunction.

Clustered Kv2.1 decreases dopamine transporter activity and internalization.

The dopamine transporter (DAT) regulates dopamine neurotransmission via reuptake of dopamine released into the extracellular space. Interactions with partner proteins alter DAT function and thereby dynamically shape dopaminergic tone important for normal brain function. However, the extent and nature of these interactions are incompletely understood. Here, we describe a novel physical and functional interaction between DAT and the voltage-gated K+ channel Kv2.1 (potassium voltage-gated channel subfamily B member 1 or KCNB1). To examine the functional consequences of this interaction, we employed a combination of immunohistochemistry, immunofluorescence live-cell microscopy, co-immunoprecipitation, and electrophysiological approaches. Consistent with previous reports, we found Kv2.1 is trafficked to membrane-bound clusters observed both in vivo and in vitro in rodent dopamine neurons. Our data provide evidence that clustered Kv2.1 channels decrease DAT's lateral mobility and inhibit its internalization, while also decreasing canonical transporter activity by altering DAT's conformational equilibrium. These results suggest that Kv2.1 clusters exert a spatially discrete homeostatic braking mechanism on DAT by inducing a relative increase in inward-facing transporters. Given recent reports of Kv2.1 dysregulation in neurological disorders, it is possible that alterations in the functional interaction between DAT and Kv2.1 affect dopamine neuron activity.