title: Impaired long-term potentiation in the prefrontal cortex of Huntington's disease mouse models: rescue by D1 dopamine receptor activation.
abstract: BACKGROUND
  The introduction of gene testing for Huntington's disease (HD) has enabled the neuropsychiatric and cognitive profiling of human gene carriers prior to the onset of overt motor and cognitive symptoms. Such studies reveal an early decline in working memory and executive function, altered EEG and a loss of striatal dopamine receptors. Working memory is processed in the prefrontal cortex and modulated by extrinsic dopaminergic inputs.
  
  
  OBJECTIVE
  We sought to study excitatory synaptic function and plasticity in the medial prefrontal cortex of mouse models of HD.
  
  
  METHODS
  We have used 2 mouse models of HD, carrying 89 and 116 CAG repeats (corresponding to a preclinical and symptomatic state, respectively) and performed electrophysiological field recording in coronal slices of the medial prefrontal cortex.
  
  
  RESULTS
  We report that short-term synaptic plasticity and long-term potentiation (LTP) are impaired and that the severity of impairment is correlated with the size of the CAG repeat. Remarkably, the deficits in LTP and short-term plasticity are reversed in the presence of a D(1) dopamine receptor agonist (SKF38393).
  
  
  CONCLUSIONS
  In a previous study, we demonstrated that a deficit in long-term depression (LTD) in the perirhinal cortex could also be reversed by a dopamine agonist. These and our current data indicate that inadequate dopaminergic modulation of cortical synaptic function is an early event in HD and may provide a route for the alleviation of cognitive dysfunction.
authors.affiliation: Huntington's Disease Research Forum, Department of Life Sciences, The Open University, Milton Keynes, UK.
authors.forename: G M
authors.initials: GM
authors.lastname: Dallérac
authors.forename: S C
authors.initials: SC
authors.lastname: Vatsavayai
authors.forename: D M
authors.initials: DM
authors.lastname: Cummings
authors.forename: A J
authors.initials: AJ
authors.lastname: Milnerwood
authors.forename: C J
authors.initials: CJ
authors.lastname: Peddie
authors.forename: K A
authors.initials: KA
authors.lastname: Evans
authors.forename: S W
authors.initials: SW
authors.lastname: Walters
authors.forename: P
authors.initials: P
authors.lastname: Rezaie
authors.forename: M C
authors.initials: MC
authors.lastname: Hirst
authors.forename: K P S J
authors.initials: KP
authors.lastname: Murphy
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000494:pharmacology; D004594:Electrophysiology; D005260:Female; D006816:Huntington Disease / Q000503:physiopathology*; D007150:Immunohistochemistry; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009924:Organ Culture Techniques; D017397:Prefrontal Cortex / Q000187:drug effects / Q000503:physiopathology*; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology
chemical_list: D018491:Dopamine Agonists; D017447:Receptors, Dopamine D1