Clusters of Hyperactive Neurons Near Amyloid Plaques in a Mouse Model of Alzheimer's Disease
Marc Aurel Busche1,4,
Arthur Konnerth1,4*, and
1 Institut für Neurowissenschaften, Technische Universität München (TUM), 80802 München, Germany.
2 Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.
3 Adolf-Butenandt-Institute, Department of Biochemistry, Laboratory for Neurodegenerative Disease Research, Ludwig-Maximilians-Universität, 80336 München, Germany.
4 Center for Integrated Protein Science, 81377 München, Germany.
Fig. 1.. Altered activity of layer 2/3 neurons in APP23xPS45 mice. (A and B) Spontaneous Ca2+ transients (B) recorded in vivo in the corresponding neurons of the frontal cortex shown in (A) in a WT (top) and a APP23xPS45 (bottom) mouse. Traces in (B) bottom are color-coded to mark neurons that were either inactive during the recording period (blue) or showed an increased frequency of Ca2+ transients (red). (C and D) Histograms showing the frequency distribution of Ca2+ transients in WT and APP23xPS45 mice (in both cases n = 564 cells). There is a substantial increase in the amount of silent and hyperactive neurons in APP23xPS45 mice. (Insets) Pie charts showing the relative proportion of silent, normal, and hyperactive neurons in WT (n = 10) and APP23xPS45 (n = 20) mice.
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Fig. 2.. Spatial distribution of silent and hyperactive neurons in APP23xPS45 mice. (A) Maximal projection image (100- to 130-µm depth) of layer 2/3 in the frontal cortex of an APP23xPS45 mouse. To measure the distance from the plaque to the recorded cell, we fitted the plaque with a circle and measured the distance (arrow) between the plaque border and the middle of the cell. The cortical area located above and below the imaged plane (55- to 175-µm depth) was also scanned to assure that plaques shown were nearest to the recorded neurons. (B) Activity map of this region with neurons color-coded according to the frequency of their Ca2+ transients. The broken line circles are centered at the respective plaques and delineate the area located less than 60 µm from the plaque border. (C) Bar graph showing the abundance of silent, normal, and hyperactive neurons at different distances from the border of the nearest plaque (n = 422 cells).
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Fig. 3.. Synaptic mechanisms of hyperactivity. (A) Spontaneous Ca2+ transients in layer 2/3 neurons before, during, and after a local iontophoretic application of CNQX and APV. Here and below, the colored circles indicate the type of neuron (blue, silent; green, normal; and red, hyperactive). (B) Activity pattern in a region with many hyperactive neurons. Each Ca2+ transient in the cell is correlated with a transient in the neuropil. Each black square marks the beginning of a Ca2+ transient. (C and D) Cross-correlograms of digitized traces showing that Ca2+ transients in individual hyperactive neurons are correlated with each other and with Ca2+ transients in the neuropil. (E) Spontaneous Ca2+ transients before, during, and after a local pressure application of diazepam. (F) Summary graph illustrating the effect of diazepam on the frequency of Ca2+ transients (n = 21 normal and 13 hyperactive neurons). (G) Spontaneous Ca2+ transients before, during, and after a local iontophoretic application of gabazine (60 s, 500 µM in the application pipette). (H) Summary graph illustrating the effect of gabazine on the frequency of Ca2+ transients (n = 6 silent, 13 normal, and 9 hyperactive neurons). Error bars in each panel represent SEM.
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