amplitude of the Vm ramp induced by plateau-potential initiation compared to vehicle controls
(Vm ramp amplitude: vehicle, 6.2 ± 1.3 mV, n =
6; 5 mM nimodipine, 1.3 ± 0.4 mV, n = 5; P =
0.042) (Fig. 4, D and E). Plateau-potential duration was likewise unchanged by nimodipine
under these conditions (control: 264.7 ± 15.3 ms,
n = 6; nimodipine: 250.6 ± 16.7 ms, n = 5, P = 0.41)
(Fig. 4F). These experimental results directly link
BTSP with place-field formation in area CA1.
They also illuminate the potential mechanisms
generating the long-duration signals present
in the above realistic model (28–30). However,
extensive future studies are needed to determine
the specific signaling pathways involved.
A noteworthy type of synaptic plasticity underlies neuronal activity in hippocampal area CA1.
Although BTSP exhibits associativity and specificity, it nevertheless leads to the potentiation of
inputs that are neither causal nor even close in
time with complex spiking. Moreover, the magnitude of the induced plasticity is such that it can
abruptly form new place fields in just a single
trial. We speculate that complex spiking may be
enhanced by unfamiliar events, rewards, or
punishments. Hence, the BTSP induction mechanism may operate as an instructive-type signal,
promoting learning that is neither autonomous
BTSP can rapidly store the entire sequence of
events that occurred for several seconds before and
after plateau-potential initiation within the synap-
tic weights of area CA1. The potent, asymmetric
seconds-long plasticity produces, within a single
run, place-field firing that peaks before the lo-
cation where complex spiking occurred, providing
a predictive signal of behaviorally relevant events
(fig. S9). Such experience-dependent tailoring
of the CA1 representation by BTSP could create
network-level overrepresentations of particu-
larly important locations as well as the activation
of specific trajectories toward reward locations
observed during different phases of exploration
(31–34). In addition, various forms of hippocampal-
dependent learning such as that observed during
episodic memory and trace conditioning would
greatly benefit from a storage mechanism operating
on seconds-long time scales (35, 36). More gen-
erally, BTSP represents a plausible biophysical
implementation of plasticity rules proposed in
numerous theoretical studies in systems neuro-
science and machine learning (2, 3, 7, 11, 13–15). In
particular, the linking of past synaptic input and
neuronal activation by dendritic plateaus alle-
viates the need for prolonged internal stimulus
representations (13–15). Thus, BTSP may provide
a more straightforward physiological basis for
many types of learning than plasticity that explicitly
conforms to Hebb’s postulate.
REFERENCES AND NOTES
1. D. O. Hebb, The Organization of Behavior (Wiley, 1949).
2. R. S. Sutton, A. G. Barto, Psychol. Rev. 88, 135–170
3. P. Dayan, L. Abbott, Theoretical Neuroscience (MIT Press, 2001).
4. M. Mayford, S. A. Siegelbaum, E. R. Kandel, Cold Spring Harb.
Perspect. Biol. 4, a005751 (2012).
5. D. E. Feldman, Neuron 75, 556–571 (2012).
6. T. V. Bliss, T. Lomo, J. Physiol. 232, 331–356 (1973).
7. K. I. Blum, L. F. Abbott, Neural Comput. 8, 85–93 (1996).
8. J. C. Magee, D. Johnston, Science 275, 209–213 (1997).
9. H. Markram, J. Lübke, M. Frotscher, B. Sakmann, Science 275,
10. D. J. Foster, R. G. M. Morris, P. Dayan, Hippocampus 10, 1–16
11. E. M. Izhikevich, Cereb. Cortex 17, 2443–2452 (2007).
12. S. Cassenaer, G. Laurent, Nature 482, 47–52 (2012).
13. C. L. Hull, Principles of Behavior (Appleton-Century, New York,
14. P. R. Montague, P. Dayan, T. J. Sejnowski, J. Neurosci. 16,
15. P. J. Drew, L. F. Abbott, Proc. Natl. Acad. Sci. U.S.A. 103,
16. W. B. Scoville, B. Milner, J. Neurol. Neurosurg. Psychiatry 20,
17. L. R. Squire, Neurobiol. Learn. Mem. 82, 171–177 (2004).
18. D. Foster, J. Knierim, Curr. Opin. Neurobiol. 22, 294–300
19. K. C. Bittner et al., Nat. Neurosci. 18, 1133–1142 (2015).
20. C. Grienberger, A. D. Milstein, K. C. Bittner, S. Romani,
J. C. Magee, Nat. Neurosci. 20, 417–426 (2017).
21. C. D. Harvey, F. Collman, D. A. Dombeck, D. W. Tank, Nature
461, 941–946 (2009).
22. D. Lee, B.-J. Lin, A. K. Lee, Science 337, 849–853 (2012).
23. K. Mizuseki, S. Royer, K. Diba, G. Buzsáki, Hippocampus 22,
24. C. Geisler, D. Robbe, M. Zugaro, A. Sirota, G. Buzsáki,
Proc. Natl. Acad. Sci. U.S.A. 104, 8149–8154 (2007).
25. H. Takahashi, J. C. Magee, Neuron 62, 102–111 (2009).
26. C. Kentros et al., Science 280, 2121–2126 (1998).
27. S. Remy, N. Spruston, Proc. Natl. Acad. Sci. U.S.A. 104,
28. C. D. Harvey, R. Yasuda, H. Zhong, K. Svoboda, Science 321,
29. S. J. Lee, Y. Escobedo-Lozoya, E. M. Szatmari, R. Yasuda,
Nature 458, 299–304 (2009).
30. B. Li, M. R. Tadross, R. W. Tsien, Science 351, 863–867
31. S. A. Hollup, S. Molden, J. G. Donnett, M.-B. Moser, E. I. Moser,
J. Neurosci. 21, 1635–1644 (2001).
32. D. Dupret, J. O’Neill, B. Pleydell-Bouverie, J. Csicsvari,
Nat. Neurosci. 13, 995–1002 (2010).
33. B. E. Pfeiffer, D. J. Foster, Nature 497, 74–79 (2013).
34. A. Sarel, A. Finkelstein, L. Las, N. Ulanovsky, Science 355,
35. D. G. Lavond, J. J. Kim, R. F. Thompson, Annu. Rev. Psychol.
44, 317–342 (1993).
36. H. Eichenbaum, Nat. Rev. Neurosci. 15, 732–744 (2014).
We thank M. Tadross, G. Tervo, and I. Soltesz for discussions and
N. Brunel, J. Dudman, R. Gutig, G. Rubin, and M. Tadross for
comments on the manuscript. This work is supported by HHMI and
NIH BRAIN (Brain Research through Advancing Innovative
Neurotechnologies) grant NS090583. Data are archived on Janelia
Research Campus servers and are available upon request.
Materials and Methods
Figs. S1 to S9
References (37, 38)
5 April 2017; accepted 10 July 2017
1036 8 SEPTEMBER 2017 • VOL 357 ISSUE 6355 sciencemag.org SCIENCE
(15) (6) (6) D-APV (in vitro)
30 20 10 -10 0
nimodipine (in vitro)
30 20 10 -10 0
+80 plateau -80
nimodipine (in vivo) control (in vivo)
(cm) +80 (cm) plateau -80
(15) (6) (6)
time (min) time (min)
nim. con. nim.
Fig. 4. Pharmacology of BTSP and place-field formation. (A) Effect of
20 mM D-APV (left) and 10 mM nimodipine (right). Average EPSP amplitude
(normalized to baseline; ±SEM) for population of neurons that received
–750-ms interval induction protocol. Red line is mean for control [from (C)].
Gray lines are individual neurons. (B) Plot of EPSP amplitude (20 min
postpairing/baseline) for control (con.), nimodipine (nim.), and D-APV
conditions. *P = 0.0011; **P = 0.00033. Number of cells in each group shown
in parentheses. (C) Plot of average plateau-potential duration during the
induction protocol for control, nimodipine, and D-APV conditions. No statistical
differences were observed. (D) Vm ramp from individual neurons (gray traces)
and the population average for control (left; pressure application of external
solution containing vehicle) and for drug conditions (right; external solution
containing 5 mM nimodipine). (E) Plot of Vm ramp amplitude induced for control
and nimodipine conditions. *P = 0.042. (F) Plot of average plateau-potential
duration during the induction protocol for control and nimodipine conditions.
No statistical differences were observed.