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.
Subscribe

Logo for

Science 319 (5867): 1260-1264

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

Transgenic Inhibition of Synaptic Transmission Reveals Role of CA3 Output in Hippocampal Learning

Toshiaki Nakashiba, Jennie Z. Young, Thomas J. McHugh, Derek L. Buhl, Susumu Tonegawa*

Abstract: The hippocampus is an area of the brain involved in learning and memory. It contains parallel excitatory pathways referred to as the trisynaptic pathway (which carries information as follows: entorhinal cortex -> dentate gyrus -> CA3 -> CA1 -> entorhinal cortex) and the monosynaptic pathway (entorhinal cortex -> CA1 -> entorhinal cortex). We developed a generally applicable tetanus toxin–based method for transgenic mice that permits inducible and reversible inhibition of synaptic transmission and applied it to the trisynaptic pathway while preserving transmission in the monosynaptic pathway. We found that synaptic output from CA3 in the trisynaptic pathway is dispensable and the short monosynaptic pathway is sufficient for incremental spatial learning. In contrast, the full trisynaptic pathway containing CA3 is required for rapid one-trial contextual learning, for pattern completion–based memory recall, and for spatial tuning of CA1 cells.

The Picower Institute for Learning and Memory, Howard Hughes Medical Institute, RIKEN-MIT Neuroscience Research Center, Department of Biology and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

* To whom correspondence should be addressed. E-mail: tonegawa{at}mit.edu

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Distinct Dendritic Arborization and In Vivo Firing Patterns of Parvalbumin-Expressing Basket Cells in the Hippocampal Area CA3.
J. J. Tukker, B. Lasztoczi, L. Katona, J. D. B. Roberts, E. K. Pissadaki, Y. Dalezios, L. Marton, L. Zhang, T. Klausberger, and P. Somogyi (2013)
J. Neurosci. 33, 6809-6825
   Abstract »    Full Text »    PDF »
Cell-type specific inactivation of hippocampal CA1 disrupts location-dependent object recognition in the mouse.
J. Haettig, Y. Sun, M. A. Wood, and X. Xu (2013)
Learn. Mem. 20, 139-146
   Abstract »    Full Text »    PDF »
FoxO6 regulates memory consolidation and synaptic function.
D. A. M. Salih, A. J. Rashid, D. Colas, L. de la Torre-Ubieta, R. P. Zhu, A. A. Morgan, E. E. Santo, D. Ucar, K. Devarajan, C. J. Cole, et al. (2012)
Genes & Dev. 26, 2780-2801
   Abstract »    Full Text »    PDF »
Hippocampal Phase Precession from Dual Input Components.
F. S. Chance (2012)
J. Neurosci. 32, 16693-16703
   Abstract »    Full Text »    PDF »
Hippocampal Place Fields Emerge upon Single-Cell Manipulation of Excitability During Behavior.
D. Lee, B.-J. Lin, and A. K. Lee (2012)
Science 337, 849-853
   Abstract »    Full Text »    PDF »
New insights into the regulation of synaptic plasticity from an unexpected place: Hippocampal area CA2.
D. A. Caruana, G. M. Alexander, and S. M. Dudek (2012)
Learn. Mem. 19, 391-400
   Abstract »    Full Text »    PDF »
Fluoxetine restores spatial learning but not accelerated forgetting in mesial temporal lobe epilepsy.
L. Barkas, E. Redhead, M. Taylor, A. Shtaya, D. A. Hamilton, and W. P. Gray (2012)
Brain 135, 2358-2374
   Abstract »    Full Text »    PDF »
The Effects of GluA1 Deletion on the Hippocampal Population Code for Position.
E. Resnik, J. M. McFarland, R. Sprengel, B. Sakmann, and M. R. Mehta (2012)
J. Neurosci. 32, 8952-8968
   Abstract »    Full Text »    PDF »
NMDA signaling in CA1 mediates selectively the spatial component of episodic memory.
R. Place, C. Lykken, Z. Beer, J. Suh, T. J. McHugh, S. Tonegawa, H. Eichenbaum, and M. M. Sauvage (2012)
Learn. Mem. 19, 164-169
   Abstract »    Full Text »    PDF »
Phosphatase and tensin homologue (PTEN) regulates synaptic plasticity independently of its effect on neuronal morphology and migration.
M. Sperow, R. B. Berry, I. T. Bayazitov, G. Zhu, S. J. Baker, and S. S. Zakharenko (2012)
J. Physiol. 590, 777-792
   Abstract »    Full Text »    PDF »
Npas4 Regulates a Transcriptional Program in CA3 Required for Contextual Memory Formation.
K. Ramamoorthi, R. Fropf, G. M. Belfort, H. L. Fitzmaurice, R. M. McKinney, R. L. Neve, T. Otto, and Y. Lin (2011)
Science 334, 1669-1675
   Abstract »    Full Text »    PDF »
Entorhinal Cortex Layer III Input to the Hippocampus Is Crucial for Temporal Association Memory.
J. Suh, A. J. Rivest, T. Nakashiba, T. Tominaga, and S. Tonegawa (2011)
Science 334, 1415-1420
   Abstract »    Full Text »    PDF »
Terminal Field and Firing Selectivity of Cholecystokinin-Expressing Interneurons in the Hippocampal CA3 Area.
B. Lasztoczi, J. J. Tukker, P. Somogyi, and T. Klausberger (2011)
J. Neurosci. 31, 18073-18093
   Abstract »    Full Text »    PDF »
Memory-Guided Learning: CA1 and CA3 Neuronal Ensembles Differentially Encode the Commonalities and Differences between Situations.
A. S. Bahar, P. R. Shirvalkar, and M. L. Shapiro (2011)
J. Neurosci. 31, 12270-12281
   Abstract »    Full Text »    PDF »
Contextual learning requires synaptic AMPA receptor delivery in the hippocampus.
D. Mitsushima, K. Ishihara, A. Sano, H. W. Kessels, and T. Takahashi (2011)
PNAS 108, 12503-12508
   Abstract »    Full Text »    PDF »
Remote Control of Neuronal Signaling.
S. C. Rogan and B. L. Roth (2011)
Pharmacol. Rev. 63, 291-315
   Abstract »    Full Text »    PDF »
Zinc transporter ZnT-3 regulates presynaptic Erk1/2 signaling and hippocampus-dependent memory.
C. Sindreu, R. D. Palmiter, and D. R. Storm (2011)
PNAS 108, 3366-3370
   Abstract »    Full Text »    PDF »
Tau-Induced Defects in Synaptic Plasticity, Learning, and Memory Are Reversible in Transgenic Mice after Switching Off the Toxic Tau Mutant.
A. Sydow, A. Van der Jeugd, F. Zheng, T. Ahmed, D. Balschun, O. Petrova, D. Drexler, L. Zhou, G. Rune, E. Mandelkow, et al. (2011)
J. Neurosci. 31, 2511-2525
   Abstract »    Full Text »    PDF »
Control of CA3 Output by Feedforward Inhibition Despite Developmental Changes in the Excitation-Inhibition Balance.
C. L. Torborg, T. Nakashiba, S. Tonegawa, and C. J. McBain (2010)
J. Neurosci. 30, 15628-15637
   Abstract »    Full Text »    PDF »
Low proliferation and differentiation capacities of adult hippocampal stem cells correlate with memory dysfunction in humans.
R. Coras, F. A. Siebzehnrubl, E. Pauli, H. B. Huttner, M. Njunting, K. Kobow, C. Villmann, E. Hahnen, W. Neuhuber, D. Weigel, et al. (2010)
Brain 133, 3359-3372
   Abstract »    Full Text »    PDF »
Gamma Oscillations in the Hippocampus.
L. L. Colgin and E. I. Moser (2010)
Physiology 25, 319-329
   Abstract »    Full Text »    PDF »
Granule Cells in the CA3 Area.
J. Szabadics, C. Varga, J. Brunner, K. Chen, and I. Soltesz (2010)
J. Neurosci. 30, 8296-8307
   Abstract »    Full Text »    PDF »
Computational Analysis of the Impact of Chronic Stress on Intrinsic and Synaptic Excitability in the Hippocampus.
R. Narayanan and S. Chattarji (2010)
J Neurophysiol 103, 3070-3083
   Abstract »    Full Text »    PDF »
Memory and Brain Systems: 1969-2009.
L. R. Squire (2009)
J. Neurosci. 29, 12711-12716
   Full Text »    PDF »
Transgenic Silencing of Neurons in the Mammalian Brain by Expression of the Allatostatin Receptor (AlstR).
M. Wehr, U. Hostick, M. Kyweriga, A. Tan, A. P. Weible, H. Wu, W. Wu, E. M. Callaway, and C. Kentros (2009)
J Neurophysiol 102, 2554-2562
   Abstract »    Full Text »    PDF »
Role of dentate gyrus in aligning internal spatial map to external landmark.
J. Won Lee, W. R. Kim, W. Sun, and M. W. Jung (2009)
Learn. Mem. 16, 530-536
   Abstract »    Full Text »    PDF »
A Functional Role for Adult Hippocampal Neurogenesis in Spatial Pattern Separation.
C. D. Clelland, M. Choi, C. Romberg, G. D. Clemenson Jr., A. Fragniere, P. Tyers, S. Jessberger, L. M. Saksida, R. A. Barker, F. H. Gage, et al. (2009)
Science 325, 210-213
   Abstract »    Full Text »    PDF »
Noradrenergic Depression of Neuronal Excitability in the Entorhinal Cortex via Activation of TREK-2 K+ Channels.
Z. Xiao, P.-Y. Deng, L. Rojanathammanee, C. Yang, L. Grisanti, K. Permpoonputtana, D. Weinshenker, V. A. Doze, J. E. Porter, and S. Lei (2009)
J. Biol. Chem. 284, 10980-10991
   Abstract »    Full Text »    PDF »
Kainate Receptors Act as Conditional Amplifiers of Spike Transmission at Hippocampal Mossy Fiber Synapses.
S. Sachidhanandam, C. Blanchet, Y. Jeantet, Y. H. Cho, and C. Mulle (2009)
J. Neurosci. 29, 5000-5008
   Abstract »    Full Text »    PDF »
Functional Specificity of Mossy Fiber Innervation of GABAergic Cells in the Hippocampus.
J. Szabadics and I. Soltesz (2009)
J. Neurosci. 29, 4239-4251
   Abstract »    Full Text »    PDF »
Dentate gyrus-specific knockdown of adult neurogenesis impairs spatial and object recognition memory in adult rats.
S. Jessberger, R. E. Clark, N. J. Broadbent, G. D. Clemenson Jr, A. Consiglio, D. C. Lie, L. R. Squire, and F. H. Gage (2009)
Learn. Mem. 16, 147-154
   Abstract »    Full Text »    PDF »
NMDA receptor-dependent switching between different gamma rhythm-generating microcircuits in entorhinal cortex.
S. Middleton, J. Jalics, T. Kispersky, F. E. N. LeBeau, A. K. Roopun, N. J. Kopell, M. A. Whittington, and M. O. Cunningham (2008)
PNAS 105, 18572-18577
   Abstract »    Full Text »    PDF »
Direct Cortical Inputs Erase Long-Term Potentiation at Schaffer Collateral Synapses.
Y. Izumi and C. F. Zorumski (2008)
J. Neurosci. 28, 9557-9563
   Abstract »    Full Text »    PDF »
Parallel memory processing by the CA1 region of the dorsal hippocampus and the basolateral amygdala.
M. Cammarota, L. R. Bevilaqua, J. I. Rossato, R. H. Lima, J. H. Medina, and I. Izquierdo (2008)
PNAS 105, 10279-10284
   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