Comment on ‘‘Role of NMDA Download full-text
Receptor Subtypes in Governing
the Direction of Hippocampal
Liu et al. (1) recently showed that block-
ade of N-methyl-D-aspartate (NMDA) sub-
type glutamate receptors containing either
NR2A or NR2B subunits leads to a selective
defect in either long-term potentiation
(LTP) or long-term depression (LTD),
respectively. Their report provides an ele-
gant demonstration of complementarity of
function of the receptor subtypes (2). We
would like to draw attention to a potentially
important implication of the results for
network behavior. NR2A-containing recep-
tors, unlike NR2B-containing receptors, are
located almost exclusively within synapses
(3–5). Therefore, the balance of LTP and
LTD in a cell could reflect the degree to
which synaptic, as opposed to extrasynaptic,
receptors are activated. Liu et al. modestly
omitted reference to a previous study from
the same group supporting precisely this
Taken together with recent evidence
that extrasynaptic spillover of glutamate is
detected exclusively by NR2B-containing
NMDA receptors (7–9), these findings pro-
vide a novel mechanism for homeostatic reg-
ulation of excitatory transmission (10) and
for sharpening pattern storage in the neu-
ronal network. An elevation in ambient glu-
tamate, released from multiple synapses and
sensed by extrasynaptic NR2B-containing
receptors, should trigger widespread LTD if
accompanied by neuronal depolarization
(Fig. 1). This does not preclude induction
of LTP at synapses where glutamate is re-
leased and opens synaptic NR2A-containing
receptors. The higher affinity of NR2B- than
NR2A-containing receptors for glutamate
(11) is well suited to their proposed role in
weakening transmission as a function of
Differential activation of NR2A- and
NR2B-containing receptors by synaptic and
extrasynaptic glutamate also has distinct con-
sequences for gene transcription (12). Finally,
because the relative density of synaptic and
extrasynaptic NR2A- and NR2B-containing
receptors changes with age (3, 13, 14), their
complementary roles in synaptic plasticity
may be developmentally regulated.
Dmitri A. Rusakov*
Matthew C. Walker
Dimitri M. Kullmann*
Institute of Neurology
University College London
London WC1N 2BG, UK
*To whom correspondence should
E-mail: firstname.lastname@example.org (D.M.K.);
1. L. Liu et al., Science 304, 1021 (2004).
2. T. V. P. Bliss, R. Schoepfer, Science 304, 973 (2004).
3. G. Stocca, S. Vicini, J. Physiol. 507, 13 (1998).
4. K. R. Tovar, G. L. Westbrook, J. Neurosci. 19, 4180
5. F. Steigerwald et al., J. Neurosci. 20, 4573 (2000).
6. H. C. Lu, E. Gonzalez, M. C. Crair, Neuron 32, 619
7. N. O. Dalby, I. Mody, J. Neurophysiol. 90, 786 (2003).
8. A. Scimemi, A. Fine, D. M. Kullmann, D. A. Rusakov,
J. Neurosci. 24, 4767 (2004).
9. N. A. Lozovaya et al., J. Physiol. 558, 451 (2004).
10. G. G. Turrigiano, S. B. Nelson, Nature Rev. Neurosci.
5, 97 (2004).
11. T. Kutsuwada et al., Nature 358, 36 (1992).
12. G. E. Hardingham, Y. Fukunaga, H. Bading, Nature
Neurosci. 5, 405 (2002).
13. E. D. Kirson, Y. Yaari, J. Physiol. 497, 437 (1996).
14. J. H. Li et al., Eur. J. Neurosci. 10, 1704 (1998).
4 June 2004; accepted 11 August 2004
Fig. 1. NR2B-containingreceptors(unlikeNR2A-
containing receptors) occur in the extrasynaptic
membrane. Glutamate escaping from synapses
selectively activates NR2B-containing receptors
(dotted arrows). The selective coupling of NR2A-
and NR2B-containing receptors to LTP and LTD,
respectively (1), provides a mechanism for ho-
meostatic plasticity if homosynaptic LTP is ac-
companied by heterosynaptic LTD. The model
also implies that LTP induction overrides or pre-
cludes LTD at the same synapse, indicated by the
www.sciencemag.org SCIENCE VOL 305 24 SEPTEMBER 2004