Cortical efferents lacking mutant huntingtin improve striatal neuronal activity and behavior in a conditional mouse model of Huntington's disease

J Neurosci. 2015 Mar 11;35(10):4440-51. doi: 10.1523/JNEUROSCI.2812-14.2015.


Abnormal electrophysiological activity in the striatum, which receives dense innervation from the cerebral cortex, is believed to set the stage for the behavioral phenotype observed in Huntington's disease (HD), a neurodegenerative condition caused by mutation of the huntingtin (mhtt) protein. However, cortical involvement is far from clear. To determine whether abnormal striatal processing can be explained by mhtt alone (cell-autonomous model) or by mhtt in the corticostriatal projection cell-cell interaction model, we used BACHD/Emx1-Cre (BE) mice, a conditional HD model in which full-length mhtt is genetically reduced in cortical output neurons, including those that project to the striatum. Animals were assessed beginning at 20 weeks of age for at least the next 40 weeks, a range over which presymptomatic BACHD mice become symptomatic. Both open-field and nest-building behavior deteriorated progressively in BACHD mice relative to both BE and wild-type (WT) mice. Neuronal activity patterns in the dorsal striatum, which receives input from the primary motor cortex (M1), followed a similar age progression because BACHD activity changed more rapidly than either BE or WT mice. However, in the M1, BE neuronal activity differed significantly from both WT and BACHD. Although abnormal cortical activity in BE mice likely reflects input from mhtt-expressing afferents, including cortical interneurons, improvements in BE striatal activity and behavior suggest a critical role for mhtt in cortical output neurons in shaping the onset and progression of striatal dysfunction.

Keywords: BAC-Cre; BACHD mice; Huntington's disease; in vivo electrophysiology; motor cortex; striatum.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / genetics
  • Action Potentials / physiology
  • Animals
  • Brain Waves / genetics
  • Cerebral Cortex / pathology*
  • Conditioning, Psychological / physiology
  • Corpus Striatum / pathology*
  • Disease Models, Animal
  • Efferent Pathways / physiology
  • Exploratory Behavior / physiology
  • Female
  • Homeodomain Proteins / genetics
  • Huntingtin Protein
  • Huntington Disease* / complications
  • Huntington Disease* / genetics
  • Huntington Disease* / pathology
  • Learning Disabilities / etiology*
  • Male
  • Mice
  • Mice, Transgenic
  • Nerve Tissue Proteins / genetics*
  • Nesting Behavior / physiology
  • Neurons / physiology
  • Nuclear Proteins / genetics*
  • Transcription Factors / genetics
  • Trinucleotide Repeats / genetics*


  • Homeodomain Proteins
  • Htt protein, mouse
  • Huntingtin Protein
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Transcription Factors
  • empty spiracles homeobox proteins