Callahan, Joshua W.. Basal ganglia function in genetic mouse models of Huntington's disease: a circuit-level approach. Retrieved from https://doi.org/doi:10.7282/T3GT5K6B
DescriptionHuntington’s disease (HD) is an autosomal dominant neurodegenerative disorder that results in motor, cognitive and psychiatric abnormalities. Impairments in the processing of information between the cortex and basal ganglia are fundamental to the onset and progression of the HD phenotype. The corticosubthalamic hyperdirect pathway plays a crucial role in motor selection and blockade of neuronal activity in the STN results in a hyperkinetic movement syndrome, similar to the HD phenotype. The aim of the present study was to examine whether changes in the fidelity of information transmission between the cortex and STN emerge as a function of phenotype severity in R6/2 and YAC128 transgenic mouse models of HD. We performed in vivo extracellular recordings in the STN of anesthetized mice and measured concomitant cortical activity with electrocorticogram (ECoG) recordings during brain states that represented global cortical network synchronization or desynchronization. Dopamine (DA) can have profound effects on network synchronization between the cortex and basal ganglia and disturbances in DA transmission have been reported in HD. To monitor whether differences existed in DAergic tone in the basal ganglia we used in vivo microdialysis to measure extracellular striatal DA levels. We found in symptomatic HD transgenic mice that cortically patterned STN neuronal discharge was progressively disrupted as a function of phenotypic severity. In addition, the spontaneous activity of STN neurons was reduced in symptomatic HD transgenic mice. Stimulation of the ipsilateral cortex leads to a short latency monosynaptic excitatory response in STN neurons. Concomitant to the dissipation of STN entrainment, there was a reduction in the proportion of responsive STN neurons to cortical stimulation as a function of age. These results indicate dysfunction in the flow of information within the corticosubthalamic circuit and demonstrate progressive disconnection of the hyperdirect pathway in transgenic HD mice. Glutamatergic STN neurons provide the major excitatory drive to the output nuclei of the basal ganglia and altered discharge patterns could lead to aberrant basal ganglia output and disordered motor control.