Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Science 321 (5896): 1686-1689

Copyright © 2008 by the American Association for the Advancement of Science

Clusters of Hyperactive Neurons Near Amyloid Plaques in a Mouse Model of Alzheimer's Disease

Marc Aurel Busche,1,4 Gerhard Eichhoff,1,4 Helmuth Adelsberger,1,4 Dorothee Abramowski,2 Karl-Heinz Wiederhold,2 Christian Haass,3,4 Matthias Staufenbiel,2 Arthur Konnerth,1,4* Olga Garaschuk1,4{dagger}

Abstract: The neurodegeneration observed in Alzheimer's disease has been associated with synaptic dismantling and progressive decrease in neuronal activity. We tested this hypothesis in vivo by using two-photon Ca2+ imaging in a mouse model of Alzheimer's disease. Although a decrease in neuronal activity was seen in 29% of layer 2/3 cortical neurons, 21% of neurons displayed an unexpected increase in the frequency of spontaneous Ca2+ transients. These "hyperactive" neurons were found exclusively near the plaques of amyloid β–depositing mice. The hyperactivity appeared to be due to a relative decrease in synaptic inhibition. Thus, we suggest that a redistribution of synaptic drive between silent and hyperactive neurons, rather than an overall decrease in synaptic activity, provides a mechanism for the disturbed cortical function in Alzheimer's disease.

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.

{dagger} Present address: Institute of Physiology II, Wilhelmstraße 27, 72074 Tübingen, Germany.

* To whom correspondence should be addressed. E-mail: arthur.konnerth{at}

The central molecular clock is robust in the face of behavioural arrhythmia in a Drosophila model of Alzheimer's disease.
K.-F. Chen, B. Possidente, D. A. Lomas, and D. C. Crowther (2014)
Dis. Model. Mech. 7, 445-458
   Abstract »    Full Text »    PDF »
Apathy correlates with prefrontal amyloid {beta} deposition in Alzheimer's disease.
T. Mori, H. Shimada, H. Shinotoh, S. Hirano, Y. Eguchi, M. Yamada, R. Fukuhara, S. Tanimukai, M.-R. Zhang, S. Kuwabara, et al. (2014)
J. Neurol. Neurosurg. Psychiatry 85, 449-455
   Abstract »    Full Text »    PDF »
Genetic Suppression of Transgenic APP Rescues Hypersynchronous Network Activity in a Mouse Model of Alzeimer's Disease.
H. A. Born, J.-Y. Kim, R. R. Savjani, P. Das, Y. A. Dabaghian, Q. Guo, J. W. Yoo, D. R. Schuler, J. R. Cirrito, H. Zheng, et al. (2014)
J. Neurosci. 34, 3826-3840
   Abstract »    Full Text »    PDF »
Calcium regulation of neural rhythms, memory and Alzheimer's disease.
M. J. Berridge (2014)
J. Physiol. 592, 281-293
   Abstract »    Full Text »    PDF »
Bidirectional homeostatic plasticity induced by interneuron cell death and transplantation in vivo.
M. A. Howard, J. L. R. Rubenstein, and S. C. Baraban (2014)
PNAS 111, 492-497
   Abstract »    Full Text »    PDF »
Frontotemporal Network Connectivity during Memory Encoding Is Increased with Aging and Disrupted by Beta-Amyloid.
H. Oh and W. J. Jagust (2013)
J. Neurosci. 33, 18425-18437
   Abstract »    Full Text »    PDF »
A biased competition account of attention and memory in Alzheimer's disease.
K. Finke, N. Myers, P. Bublak, and C. Sorg (2013)
Phil Trans R Soc B 368, 20130062
   Abstract »    Full Text »    PDF »
A Novel Nicotinic Mechanism Underlies {beta}-Amyloid-Induced Neuronal Hyperexcitation.
Q. Liu, X. Xie, R. J. Lukas, P. A. St. John, and J. Wu (2013)
J. Neurosci. 33, 7253-7263
   Abstract »    Full Text »    PDF »
Sodium Channel Cleavage Is Associated with Aberrant Neuronal Activity and Cognitive Deficits in a Mouse Model of Alzheimer's Disease.
B. F. Corbett, S. C. Leiser, H.-P. Ling, R. Nagy, N. Breysse, X. Zhang, A. Hazra, J. T. Brown, A. D. Randall, A. Wood, et al. (2013)
J. Neurosci. 33, 7020-7026
   Abstract »    Full Text »    PDF »
Physiological release of endogenous tau is stimulated by neuronal activity.
A. M. Pooler, E. C. Phillips, D. H. W. Lau, W. Noble, and D. P. Hanger (2013)
EMBO Rep. 14, 389-394
   Abstract »    Full Text »    PDF »
Disruption of the Sleep-Wake Cycle and Diurnal Fluctuation of {beta}-Amyloid in Mice with Alzheimer's Disease Pathology.
J. H. Roh, Y. Huang, A. W. Bero, T. Kasten, F. R. Stewart, R. J. Bateman, and D. M. Holtzman (2012)
Science Translational Medicine 4, 150ra122
   Abstract »    Full Text »    PDF »
Interaction between Amyloid-{beta} Pathology and Cortical Functional Columnar Organization.
S. Beker, V. Kellner, L. Kerti, and E. A. Stern (2012)
J. Neurosci. 32, 11241-11249
   Abstract »    Full Text »    PDF »
In Vivo Alterations in Calcium Buffering Capacity in Transgenic Mouse Model of Synucleinopathy.
L. Reznichenko, Q. Cheng, K. Nizar, S. L. Gratiy, P. A. Saisan, E. M. Rockenstein, T. Gonzalez, C. Patrick, B. Spencer, P. Desplats, et al. (2012)
J. Neurosci. 32, 9992-9998
   Abstract »    Full Text »    PDF »
Neurotoxicity of Amyloid {beta}-Protein: Synaptic and Network Dysfunction.
L. Mucke and D. J. Selkoe (2012)
Cold Spring Harb Perspect Med 2, a006338
   Abstract »    Full Text »    PDF »
Critical role of soluble amyloid-{beta} for early hippocampal hyperactivity in a mouse model of Alzheimer's disease.
M. A. Busche, X. Chen, H. A. Henning, J. Reichwald, M. Staufenbiel, B. Sakmann, and A. Konnerth (2012)
PNAS 109, 8740-8745
   Abstract »    Full Text »    PDF »
Synapses and Alzheimer's Disease.
M. Sheng, B. L. Sabatini, and T. C. Sudhof (2012)
Cold Spring Harb Perspect Biol 4, a005777
   Abstract »    Full Text »    PDF »
Brain Imaging in Alzheimer Disease.
K. A. Johnson, N. C. Fox, R. A. Sperling, and W. E. Klunk (2012)
Cold Spring Harb Perspect Med 2, a006213
   Abstract »    Full Text »    PDF »
Microvesicles released from microglia stimulate synaptic activity via enhanced sphingolipid metabolism.
F. Antonucci, E. Turola, L. Riganti, M. Caleo, M. Gabrielli, C. Perrotta, L. Novellino, E. Clementi, P. Giussani, P. Viani, et al. (2012)
EMBO J. 31, 1231-1240
   Abstract »    Full Text »    PDF »
Mechanistic involvement of the calpain-calpastatin system in Alzheimer neuropathology.
M. Higuchi, N. Iwata, Y. Matsuba, J. Takano, T. Suemoto, J. Maeda, B. Ji, M. Ono, M. Staufenbiel, T. Suhara, et al. (2012)
FASEB J 26, 1204-1217
   Abstract »    Full Text »    PDF »
Inhibition of the NFAT Pathway Alleviates Amyloid Beta Neurotoxicity in a Mouse Model of Alzheimer's Disease.
E. Hudry, H.-Y. Wu, M. Arbel-Ornath, T. Hashimoto, R. Matsouaka, Z. Fan, T. L. Spires-Jones, R. A. Betensky, B. J. Bacskai, and B. T. Hyman (2012)
J. Neurosci. 32, 3176-3192
   Abstract »    Full Text »    PDF »
A{beta} neurotoxicity depends on interactions between copper ions, prion protein, and N-methyl-D-aspartate receptors.
H. You, S. Tsutsui, S. Hameed, T. J. Kannanayakal, L. Chen, P. Xia, J. D. T. Engbers, S. A. Lipton, P. K. Stys, and G. W. Zamponi (2012)
PNAS 109, 1737-1742
   Abstract »    Full Text »    PDF »
Hippocampal Hyperactivation Associated with Cortical Thinning in Alzheimer's Disease Signature Regions in Non-Demented Elderly Adults.
D. Putcha, M. Brickhouse, K. O'Keefe, C. Sullivan, D. Rentz, G. Marshall, B. Dickerson, and R. Sperling (2011)
J. Neurosci. 31, 17680-17688
   Abstract »    Full Text »    PDF »
Sensory Network Dysfunction, Behavioral Impairments, and Their Reversibility in an Alzheimer's {beta}-Amyloidosis Mouse Model.
D. W. Wesson, A. H. Borkowski, G. E. Landreth, R. A. Nixon, E. Levy, and D. A. Wilson (2011)
J. Neurosci. 31, 15962-15971
   Abstract »    Full Text »    PDF »
Two-Photon Imaging of Neural Networks in a Mouse Model of Alzheimer's Disease.
G. Eichhoff and O. Garaschuk (2011)
Cold Spring Harb Protoc 2011, pdb.prot065789
   Abstract »    Full Text »    PDF »
Amyloid {beta} Peptide-(1-42) Induces Internalization and Degradation of {beta}2 Adrenergic Receptors in Prefrontal Cortical Neurons.
D. Wang, E. Y. Yuen, Y. Zhou, Z. Yan, and Y. K. Xiang (2011)
J. Biol. Chem. 286, 31852-31863
   Abstract »    Full Text »    PDF »
Attenuated A{beta}42 Responses to Low Potency {gamma}-Secretase Modulators Can Be Overcome for Many Pathogenic Presenilin Mutants by Second-generation Compounds.
B. Kretner, A. Fukumori, A. Gutsmiedl, R. M. Page, T. Luebbers, G. Galley, K. Baumann, C. Haass, and H. Steiner (2011)
J. Biol. Chem. 286, 15240-15251
   Abstract »    Full Text »    PDF »
Alzheimer's Disease: The Challenge of the Second Century.
D. M. Holtzman, J. C. Morris, and A. M. Goate (2011)
Science Translational Medicine 3, 77sr1
   Full Text »    PDF »
Molecular reorganization of endocannabinoid signalling in Alzheimer's disease.
J. Mulder, M. Zilberter, S. J. Pasquare, A. Alpar, G. Schulte, S. G. Ferreira, A. Kofalvi, A. M. Martin-Moreno, E. Keimpema, H. Tanila, et al. (2011)
Brain 134, 1041-1060
   Abstract »    Full Text »    PDF »
Robust Amyloid Clearance in a Mouse Model of Alzheimer's Disease Provides Novel Insights into the Mechanism of Amyloid-{beta} Immunotherapy.
A. Wang, P. Das, R. C. Switzer III, T. E. Golde, and J. L. Jankowsky (2011)
J. Neurosci. 31, 4124-4136
   Abstract »    Full Text »    PDF »
Noninvasive Magnetic Resonance Imaging Detection of Cerebral Amyloid Angiopathy-Related Microvascular Alterations Using Superparamagnetic Iron Oxide Particles in APP Transgenic Mouse Models of Alzheimer's Disease: Application to Passive A{beta} Immunotherapy.
N. Beckmann, C. Gerard, D. Abramowski, C. Cannet, and M. Staufenbiel (2011)
J. Neurosci. 31, 1023-1031
   Abstract »    Full Text »    PDF »
Amyloid-{beta}/Fyn-Induced Synaptic, Network, and Cognitive Impairments Depend on Tau Levels in Multiple Mouse Models of Alzheimer's Disease.
E. D. Roberson, B. Halabisky, J. W. Yoo, J. Yao, J. Chin, F. Yan, T. Wu, P. Hamto, N. Devidze, G.-Q. Yu, et al. (2011)
J. Neurosci. 31, 700-711
   Abstract »    Full Text »    PDF »
Calpain Activation Promotes BACE1 Expression, Amyloid Precursor Protein Processing, and Amyloid Plaque Formation in a Transgenic Mouse Model of Alzheimer Disease.
B. Liang, B.-Y. Duan, X.-P. Zhou, J.-X. Gong, and Z.-G. Luo (2010)
J. Biol. Chem. 285, 27737-27744
   Abstract »    Full Text »    PDF »
Binding of amyloid {beta} peptide to {beta}2 adrenergic receptor induces PKA-dependent AMPA receptor hyperactivity.
D. Wang, G. Govindaiah, R. Liu, V. De Arcangelis, C. L. Cox, and Y. K. Xiang (2010)
FASEB J 24, 3511-3521
   Abstract »    Full Text »    PDF »
Decreased Rhythmic GABAergic Septal Activity and Memory-Associated {theta} Oscillations after Hippocampal Amyloid-{beta} Pathology in the Rat.
V. Villette, F. Poindessous-Jazat, A. Simon, C. Lena, E. Roullot, B. Bellessort, J. Epelbaum, P. Dutar, and A. Stephan (2010)
J. Neurosci. 30, 10991-11003
   Abstract »    Full Text »    PDF »
{beta}-Amyloid Disrupts Activity-Dependent Gene Transcription Required for Memory through the CREB Coactivator CRTC1.
J. Espana, J. Valero, A. J. Minano-Molina, R. Masgrau, E. Martin, C. Guardia-Laguarta, A. Lleo, L. Gimenez-Llort, J. Rodriguez-Alvarez, and C. A. Saura (2010)
J. Neurosci. 30, 9402-9410
   Abstract »    Full Text »    PDF »
Role of Presenilins in Neuronal Calcium Homeostasis.
H. Zhang, S. Sun, A. Herreman, B. De Strooper, and I. Bezprozvanny (2010)
J. Neurosci. 30, 8566-8580
   Abstract »    Full Text »    PDF »
Calcium Signaling and Amyloid Toxicity in Alzheimer Disease.
A. Demuro, I. Parker, and G. E. Stutzmann (2010)
J. Biol. Chem. 285, 12463-12468
   Abstract »    Full Text »    PDF »
Amyloid {beta} Induces the Morphological Neurodegenerative Triad of Spine Loss, Dendritic Simplification, and Neuritic Dystrophies through Calcineurin Activation.
H.-Y. Wu, E. Hudry, T. Hashimoto, K. Kuchibhotla, A. Rozkalne, Z. Fan, T. Spires-Jones, H. Xie, M. Arbel-Ornath, C. L. Grosskreutz, et al. (2010)
J. Neurosci. 30, 2636-2649
   Abstract »    Full Text »    PDF »
A Reporter of Local Dendritic Translocation Shows Plaque- Related Loss of Neural System Function in APP-Transgenic Mice.
M. Meyer-Luehmann, M. Mielke, T. L. Spires-Jones, W. Stoothoff, P. Jones, B. J. Bacskai, and B. T. Hyman (2009)
J. Neurosci. 29, 12636-12640
   Abstract »    Full Text »    PDF »
Sparsification of neuronal activity in the visual cortex at eye-opening.
N. L. Rochefort, O. Garaschuk, R.-I. Milos, M. Narushima, N. Marandi, B. Pichler, Y. Kovalchuk, and A. Konnerth (2009)
PNAS 106, 15049-15054
   Abstract »    Full Text »    PDF »
Characterizing the Appearance and Growth of Amyloid Plaques in APP/PS1 Mice.
P. Yan, A. W. Bero, J. R. Cirrito, Q. Xiao, X. Hu, Y. Wang, E. Gonzales, D. M. Holtzman, and J.-M. Lee (2009)
J. Neurosci. 29, 10706-10714
   Abstract »    Full Text »    PDF »
Treatment with a C5aR Antagonist Decreases Pathology and Enhances Behavioral Performance in Murine Models of Alzheimer's Disease.
M. I. Fonseca, R. R. Ager, S.-H. Chu, O. Yazan, S. D. Sanderson, F. M. LaFerla, S. M. Taylor, T. M. Woodruff, and A. J. Tenner (2009)
J. Immunol. 183, 1375-1383
   Abstract »    Full Text »    PDF »
Amyloid Goes Global.
I. Bezprozvanny (2009)
Science Signaling 2, pe16
   Abstract »    Full Text »    PDF »
Amyloid {beta}-Induced Neuronal Hyperexcitability Triggers Progressive Epilepsy.
R. Minkeviciene, S. Rheims, M. B. Dobszay, M. Zilberter, J. Hartikainen, L. Fulop, B. Penke, Y. Zilberter, T. Harkany, A. Pitkanen, et al. (2009)
J. Neurosci. 29, 3453-3462
   Abstract »    Full Text »    PDF »
Synchronous Hyperactivity and Intercellular Calcium Waves in Astrocytes in Alzheimer Mice.
K. V. Kuchibhotla, C. R. Lattarulo, B. T. Hyman, and B. J. Bacskai (2009)
Science 323, 1211-1215
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882