Medial septal dysfunction by Aβ-induced KCNQ channel-block in glutamatergic neurons

TY - JOUR

T1 - Medial septal dysfunction by Aβ-induced KCNQ channel-block in glutamatergic neurons

AU - Leão, Richardson N.

AU - Colom, Luis V.

AU - Borgius, Lotta

AU - Kiehn, Ole

AU - Fisahn, André

PY - 2012/9/1

Y1 - 2012/9/1

N2 - 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 Aβ25-35 and Aβ1-40 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 (IA and IM, respectively). While the IA block is similar in other MS neuron classes, the block of IM is specific to glutamatergic neurons. IM 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 IM decrease diminishes MS rhythmicity, which may negatively affect hippocampal rhythmogenesis and underlie the memory loss observed in Alzheimer's disease.

AB - 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 Aβ25-35 and Aβ1-40 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 (IA and IM, respectively). While the IA block is similar in other MS neuron classes, the block of IM is specific to glutamatergic neurons. IM 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 IM decrease diminishes MS rhythmicity, which may negatively affect hippocampal rhythmogenesis and underlie the memory loss observed in Alzheimer's disease.

KW - A-current

KW - Amyloid β peptide

KW - Cholinergic neurons

KW - GABAergic neurons

KW - Glutamatergic neurons

KW - M-current

KW - Medial septum

KW - Theta oscillations

UR - http://www.scopus.com/inward/record.url?scp=84863423626&partnerID=8YFLogxK

U2 - 10.1016/j.neurobiolaging.2011.07.013

DO - 10.1016/j.neurobiolaging.2011.07.013

M3 - Journal article

C2 - 21907458

AN - SCOPUS:84863423626

SN - 0197-4580

VL - 33

SP - 2046

EP - 2061

JO - Neurobiology of Aging

JF - Neurobiology of Aging

IS - 9

ER -