title: Medial septal dysfunction by Aβ-induced KCNQ channel-block in glutamatergic neurons.
abstract: Amyloid β (Aβ) peptides play a central role in the pathophysiology of Alzheimer's disease (AD). The cellular mechanisms underlying Aβ toxicity, however, are poorly understood. Here we show that Aβ(25-35) and Aβ(1-40) acutely and differentially affect the characteristics of 3 classes of medial septum (MS) neurons in mice. In glutamatergic neurons Aβ increases firing frequency and blocks the A- and the M-current (I(A) and I(M), respectively). While the I(A) block is similar in other MS neuron classes, the block of I(M) is specific to glutamatergic neurons. I(M) block and a simulated Aβ block mimic the Aβ-induced increase in spontaneous firing in glutamatergic neurons. Calcium imaging shows that under control conditions glutamatergic neurons rarely fire while nonglutamatergic neurons fire coherently at theta frequencies. Aβ increases the firing rate of glutamatergic neurons while nonglutamatergic neurons lose theta firing coherence. Our results demonstrate that Aβ-induced dysfunction of glutamatergic neurons via I(M) decrease diminishes MS rhythmicity, which may negatively affect hippocampal rhythmogenesis and underlie the memory loss observed in Alzheimer's disease.
authors: Neuronal Oscillations Laboratory, KI Alzheimer's Disease Research Center, NVS, Karolinska Institute, Stockholm, Sweden.
authors: Richardson N
authors: RN
authors: Leão
authors: Luis V
authors: LV
authors: Colom
authors: Lotta
authors: L
authors: Borgius
authors: Ole
authors: O
authors: Kiehn
authors: André
authors: A
authors: Fisahn
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D002118:Calcium; D002795:Choline O-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005968:Glutamate Decarboxylase / Q000235:genetics; D018698:Glutamic Acid / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics; D051656:KCNQ Potassium Channels / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger; D022661:RNA, Untranslated; D020665:Septum of Brain / Q000166:cytology*; D050599:Vesicular Glutamate Transport Protein 2 / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; C110853:Gt(ROSA)26Sor non-coding RNA, mouse; D051656:KCNQ Potassium Channels; D011506:Proteins; D012333:RNA, Messenger; D022661:RNA, Untranslated; D050599:Vesicular Glutamate Transport Protein 2; D049452:Green Fluorescent Proteins; D018698:Glutamic Acid; D002795:Choline O-Acetyltransferase; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2; D002118:Calcium