title: Impaired Cholinergic Excitation of Prefrontal Attention Circuitry in the TgCRND8 Model of Alzheimer's Disease.
abstract: Attention deficits in Alzheimer's disease can exacerbate its other cognitive symptoms, yet relevant disruptions of key prefrontal circuitry are not well understood. Here, in the TgCRND8 mouse model of this neurological disorder, we demonstrate and characterize a disruption of cholinergic excitation in the major corticothalamic layer of the prefrontal cortex, in which modulation by acetylcholine is essential for optimal attentional function. Using electrophysiology with concurrent multiphoton imaging, we show that layer 6 pyramidal cells are unable to sustain cholinergic excitation to the same extent as their nontransgenic littermate controls, as a result of the excessive activation of calcium-activated hyperpolarizing conductances. We report that cholinergic excitation can be improved in TgCRND8 cortex by pharmacological blockade of SK channels, suggesting a novel target for the treatment of cognitive dysfunction in Alzheimer's disease.
  
  
  CONCLUSIONS
  Alzheimer's disease is accompanied by attention deficits that exacerbate its other cognitive symptoms. In brain slices of a mouse model of this neurological disorder, we demonstrate, characterize, and rescue impaired cholinergic excitation of neurons essential for optimal attentional performance. In particular, we show that the excessive activation of a calcium-activated potassium conductance disrupts the acetylcholine excitation of prefrontal layer 6 pyramidal neurons and that its blockade normalizes responses. These findings point to a novel potential target for the treatment of cognitive dysfunction in Alzheimer's disease.
authors.affiliation: Departments of Physiology.
authors.forename: Éliane
authors.initials: É
authors.lastname: Proulx
authors.affiliation: Medical Biophysics, Tanz Centre for Research in Neurodegenerative Diseases, and.
authors.forename: Paul
authors.initials: P
authors.lastname: Fraser
authors.affiliation: Laboratory Medicine and Pathobiology, Biological Sciences, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: JoAnne
authors.initials: J
authors.lastname: McLaurin
authors.affiliation: Departments of Physiology, Obstetrics and Gynaecology, Psychiatry, and evelyn.lambe@utoronto.ca.
authors.forename: Evelyn K
authors.identifier: http://orcid.org/0000-0002-5994-6090
authors.initials: EK
authors.lastname: Lambe
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology / Q000502:physiology; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000544:Alzheimer Disease / Q000235:genetics / Q000503:physiopathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001030:Apamin / Q000494:pharmacology; D001285:Atropine / Q000494:pharmacology; D001288:Attention / Q000187:drug effects / Q000502:physiology*; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D059329:Cholinergic Neurons / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D005838:Genotype; D015640:Ion Channel Gating / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D017397:Prefrontal Cortex / Q000503:physiopathology*; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology*; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000187:drug effects / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
chemical_list: D016564:Amyloid beta-Protein Precursor; D009419:Nerve Tissue Proteins; D051640:Small-Conductance Calcium-Activated Potassium Channels; D001030:Apamin; D001285:Atropine; D000109:Acetylcholine
keywords: Alzheimer's model; SK channels; acetylcholine receptors; afterhyperpolarization potential (AHP); corticothalamic; prefrontal cortex