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Medial septal dysfunction by A beta-induced KCNQ channel-block in glutamatergic neurons
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
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2012 (English)In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 33, no 9, p. 2046-2061Article in journal (Refereed) Published
Abstract [en]

Amyloid beta (A beta) peptides play a central role in the pathophysiology of Alzheimer's disease (AD). The cellular mechanisms underlying A beta toxicity, however, are poorly understood. Here we show that A beta 25-35 and A beta 1-40 acutely and differentially affect the characteristics of 3 classes of medial septum (MS) neurons in mice. In glutamatergic neurons A beta 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 A beta block mimic the A beta-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. A beta increases the firing rate of glutamatergic neurons while nonglutamatergic neurons lose theta firing coherence. Our results demonstrate that A beta-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.

Place, publisher, year, edition, pages
2012. Vol. 33, no 9, p. 2046-2061
Keywords [en]
Amyloid beta peptide, Medial septum, Theta oscillations, Glutamatergic neurons, Cholinergic neurons, GABAergic neurons, M-current, A-current
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-181397DOI: 10.1016/j.neurobiolaging.2011.07.013ISI: 000306994600018OAI: oai:DiVA.org:uu-181397DiVA, id: diva2:557688
Available from: 2012-09-28 Created: 2012-09-24 Last updated: 2017-12-07Bibliographically approved

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Leão, Richardson N.

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