Early GABAergic transmission defects in the external globus pallidus and rest/activity rhythm alteration in a mouse model of Huntington's disease

Neuroscience. 2016 Aug 4;329:363-79. doi: 10.1016/j.neuroscience.2016.05.027. Epub 2016 May 20.

Abstract

Huntington's disease (HD) is characterized by progressive motor symptoms preceded by cognitive deficits and is regarded as a disorder that primarily affects the basal ganglia. The external globus pallidus (GPe) has a central role in the basal ganglia, projects directly to the cortex, and is majorly modulated by GABA. To gain a better understanding of the time course of HD progression and gain insight into the underlying mechanisms, we analyzed GABAergic neurotransmission in the GPe of the R6/1 mouse model at purportedly asymptomatic and symptomatic stages (i.e., 2 and 6months). Western blot and quantitative polymerase chain reaction (PCR) analyses revealed alterations in the GPe of male R6/1 mice compared with wild-type littermates. Expression of proteins involved in pre- and post-synaptic GABAergic compartments as well as synapse number were severely decreased at 2 and 6months. At both ages, patch-clamp electrophysiological recordings showed a decrease of spontaneous and miniature inhibitory post-synaptic currents (IPSCs) suggesting that HD mutation has an early effect on the GABA signaling in the brain. Therefore, we performed continuous locomotor activity recordings from 2 to 4months of age. Actigraphy analyses revealed rest/activity fragmentation alterations that parallel GABAergic system impairment at 2months, while the locomotor deficit is evident only at 3months in R6/1 mice. Our results reveal early deficits in HD and support growing evidence for a critical role played by the GPe in physiological and pathophysiological states. We suggest that actimetry may be used as a non-invasive tool to monitor early disease progression.

Keywords: basal ganglia; disease progression; inhibitory post-synaptic currents; locomotor activity; rest/activity fragmentation; synapse.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / metabolism
  • Animals
  • Disease Models, Animal
  • Disease Progression
  • Globus Pallidus / metabolism*
  • Globus Pallidus / pathology
  • Humans
  • Huntingtin Protein / genetics
  • Huntingtin Protein / metabolism
  • Huntington Disease / metabolism*
  • Huntington Disease / pathology
  • Inhibitory Postsynaptic Potentials / physiology
  • Male
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Miniature Postsynaptic Potentials / physiology
  • Motor Activity / physiology*
  • Sleep / physiology*
  • Synapses / metabolism*
  • Tissue Culture Techniques
  • Trinucleotide Repeat Expansion
  • gamma-Aminobutyric Acid / metabolism*

Substances

  • HTT protein, human
  • Huntingtin Protein
  • gamma-Aminobutyric Acid