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Mov Disord. 2019 Feb 6. doi: 10.1002/mds.27622. [Epub ahead of print]

Enhanced striatopallidal gamma-aminobutyric acid (GABA)A receptor transmission in mouse models of huntington's disease.

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Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
PsychoGenics Inc., Paramus, New Jersey, USA.
CHDI Management/CHDI Foundation, California, Los Angeles, USA.



Huntington's disease (HD) is caused by a CAG repeat expansion in the huntingtin gene. This mutation leads to progressive dysfunction that is largely attributable to dysfunction of the striatum. The earliest signs of striatal pathology in HD are found in indirect pathway gamma-Aminobutyric acid (GABA)-ergic spiny projection neurons that innervate the external segment of the globus pallidus (GPe). What is less clear is whether the synaptic coupling of spiny projection neurons with GPe neurons changes in HD.


The principal goal of this study was to determine whether striatopallidal synaptic transmission was altered in 2 mouse models of HD.


Striatopallidal synaptic transmission was studied using electrophysiological and optogenetic approaches in ex vivo brain slices from 2 HD models: Q175 heterozygous (het) and R6/2 mice.


Striatopallidal synaptic transmission increased in strength with the progression of behavioral deficits in Q175 and R6/2 mice. The alteration in synaptic transmission was evident in both prototypical and arkypallidal GPe neurons. This change did not appear attributable to an increase in the probability of GABA release but, rather, to an enhancement in the postsynaptic response to GABA released at synaptic sites. This alteration significantly increased the ability of striatopallidal axon terminals to pause ongoing GPe activity.


In 2 mouse models of HD, striatopallidal synaptic transmission increased in parallel with the progression of behavioral deficits. This adaptation could compensate in part for the concomitant deficit in the ability of corticostriatal signals to activate spiny projection neurons and pause GPe activity. © 2019 International Parkinson and Movement Disorder Society.


GABAergic; Globus pallidus; Huntington's disease; electrophysiology; mouse; optogenetics; patch clamp; release probability; striatopallidal; striatum; strontium


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