Mapping synaptic glutamate transporter dysfunction in vivo to regions surrounding Aβ plaques by iGluSnFR two-photon imaging.
Amyloid-β (Aβ) plaques, a hallmark of Alzheimer's disease (AD), are surrounded by regions of neuronal and glial hyperactivity. We use in vivo two-photon and wide-field imaging of the glutamate sensor iGluSnFR to determine whether pathological changes in glutamate dynamics in the immediate vicinity of Aβ deposits in APPPS1 transgenic mice could alter neuronal activity in this microenvironment. In regions close to Aβ plaques chronic states of high spontaneous glutamate fluctuations are observed and the timing of glutamate responses evoked by sensory stimulation exhibit slower decay rates in two cortical brain areas. GLT-1 expression is reduced around Aβ plaques and upregulation of GLT-1 expression and activity by ceftriaxone partially restores glutamate dynamics to values in control regions. We conclude that the toxic microenvironment surrounding Aβ plaques results, at least partially, from enhanced glutamate levels and that pharmacologically increasing GLT-1 expression and activity may be a new target for early therapeutic intervention.
Djavad Mowafaghian Centre for Brain Health, Faculty of Medicine, University of British Columbia, 2211 Wesbrook Mall, Vancouver, British Columbia, Canada V6T 1Z3.
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JK
Hefendehl
Djavad Mowafaghian Centre for Brain Health, Faculty of Medicine, University of British Columbia, 2211 Wesbrook Mall, Vancouver, British Columbia, Canada V6T 1Z3.
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LeDue
Djavad Mowafaghian Centre for Brain Health, Faculty of Medicine, University of British Columbia, 2211 Wesbrook Mall, Vancouver, British Columbia, Canada V6T 1Z3.
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RW
Ko
Hertie-Institut für klinische Hirnforschung, Otfried-Müller-Strasse 27, 72076 Tübingen, Germany.
J
J
Mahler
Djavad Mowafaghian Centre for Brain Health, Faculty of Medicine, University of British Columbia, 2211 Wesbrook Mall, Vancouver, British Columbia, Canada V6T 1Z3.
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TH
Murphy
Djavad Mowafaghian Centre for Brain Health, Faculty of Medicine, University of British Columbia, 2211 Wesbrook Mall, Vancouver, British Columbia, Canada V6T 1Z3.
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BA
MacVicar
D027322:Amino Acid Transport System X-AG / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D002443:Ceftriaxone; D003952:Diagnostic Imaging / Q000379:methods*; D018698:Glutamic Acid; D051379:Mice; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000378:metabolism*
D027322:Amino Acid Transport System X-AG; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D018698:Glutamic Acid; D002443:Ceftriaxone