Decoding the Neuronal Tower of Babel

Chris J. McBain
Science 338, 482 (2012);
DOI: 10.1126/science.1230338

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PERSPECTIVES

cesium and other radionuclides is needed to
predict long-term trends in fish and other sea-
food. Such knowledge would support smarter
and better targeted decision-making, reduce
public concern about seafood, and potentially
help to revive local fisheries safely, with con-
fidence, and in a timely manner.
References and Notes
1. N. Yoshida, J. Kanda, Science 336, 1115 (2012).
2. K. O. Buesseler et al., Proc. Natl. Acad. Sci. U.S.A. 109,
5984 (2012).
3. K. O. Buesseler, M. Aoyama, M. Fukasawa, Environ. Sci.
Technol. 45, 9931 (2011).
4. Japan Ministry of Agriculture, “Results of the inspection
on radioactivity materials in fisheries products” (press
release March 2011 to March 2012); www.jfa.maff.
go.jp/e/inspection/index.html.
5. Japan Ministry of Agriculture, “Results of the inspection
on radioactivity materials in fisheries products” (28
September 2012); www.jfa.maff.go.jp/e/inspection/index.
html.
6. Tokyo Electric Power Company, “Nuclide analysis results
of fish and shellfish” (August 2012); www.tepco.co.jp/en/
nu/fukushima-np/images/handouts_120821_01-e.pdf.
7. International Atomic Energy Agency, Sediment Distribu-
tion Coefficients and Concentration Factors for Biota in
the Marine Environment, Technical Report Series No. 422
(IAEA, Vienna, 2004).
8. H. Doi, T. Takahara, K. Tanaka, PLoS ONE 7, e29295
(2012).
9. D. J. Rowan, J. B. Rasmussen, Can. J. Fish. Aquat. Sci. 51,
2388 (1994).
10. D. J. Rowan, J. B. Rasmussen, J. Appl. Ecol. 32, 739 (1995).
11. Ministry of Education, Culture, Sports, Science and
Technology, Japan (2012), “Readings of marine soil
monitoring in sea area,” http://radioactivity.mext.go.jp/
en/list/260/list-1.html.
12. D. J. Madigan, Z. Baumann, N. S. Fisher, Proc. Natl.
Acad. Sci. U.S.A. 109, 9483 (2012).
Acknowledgments: Supported by the Gordon and Betty
Moore Foundation. I thank S. Clifford for compilation of MAFF
data and K. Kostel for assistance in writing.
Supplementary Materials
www.sciencemag.org/cgi/content/full/338/6106/480/DC1
Fig. S1
Reference
10.1126/science.1228250

Downloaded from www.sciencemag.org on October 29, 2012

NEUROSCIENCE

Decoding the Neuronal Tower Identification of a postsynaptic protein in the

hippocampus reveals how neurotransmitter
release from one neuron is tailored to different
of Babel target cells.

Chris J. McBain

I
ndividual neurons in the mammalian
central nervous system communicate
with their downstream targets by means
of subcellular specializations in their axon.
Arranged like pearls on a necklace, these pre-
synaptic terminals enable the rapid release
of neurotransmitter in response to an elec-
trical action-potential wave front that travels
from the cell body to the far reaches of the
axon. A single axon may contact hundreds
of downstream targets, including numerous
distinct cell types. Though separated by only
a few micrometers, each of these presynap-
tic release sites is often tuned to the partic-
ular cell type it innervates such that trans-
mission may be robust onto one particular
cell type yet weak at another, despite all ter-
minals sensing the same action-potential
waveform (1). This arrangement allows dif-
ferent terminals in the axon to behave inde-
pendently and “translate” presynaptic action
potentials into their own unique chemical
language to effect both short- and long-term
synaptic transmission and plasticity (2, 3).
Whether elements in the presynaptic termi-
nal, postsynaptic membrane, or transynap-
tic proteins dictate this differential synaptic
processing has been unclear. On page 536 in
this issue, Sylwestrak and Ghosh (4) show
that postsynaptic expression of the extra-
cellular leucine-rich repeat fibronectin-
Eunice Kennedy Shriver National Institute of Child Health
and Human Development, Porter Neuroscience Center,
Room 3C903, Lincoln Drive, Bethesda, MD 20892, USA.
E-mail: mcbainc@mail.nih.gov
CA1 axon
Low Pr High Pr
Neurotransmitters
Elfn1 ?
O-LM cell Basket cell
Tailoring one neuron to two synapses. In the hippocampus, somatostatin-containing O-LM and parvalbumin-
containing basket cells receive common afferent input from CA1 pyramidal neurons. The postsynaptic expres-
sion of the leucine-rich repeat protein Elfn1 in O-LM cells acts to set the presynaptic initial transmitter release
probability (Pr) low, ensuring short-term facilitation of synaptic transmission. In contrast, the absence of
Elfn1, of the presence of an as yet undiscovered trans-synaptic protein, endows CA1 pyramidal neuron syn-
apses onto basket cells with a high initial release probability, depressing synaptic transmission.
containing 1 (Elfn1) plays an important role are triggered early in the train, which then
in establishing such target-specific differen- rapidly wane as the train progresses (i.e.,
tial transmission. short-term depression). In contrast, synaptic
CA1 pyramidal neurons of the hippocam- events onto O-LM cells start small and grow
pus form synapses with many downstream as the train of action potentials progresses
inhibitory interneuron targets, including the (a process termed short-term facilitation,
parvalbumin-containing fast-spiking basket and indicative of synapses with a low initial
cell and the somatostatin-positive oriens- transmitter release probability). Sylwestrak
lacunosum moleculare (O-LM) neuron. and Ghosh demonstrate that Elfn1 is selec-
Under normal conditions, a train of presyn- tively expressed in O-LM inhibitory inter-
aptic action potentials in the CA1 pyrami- neurons and that its punctate expression on
dal neurons triggers robust synaptic trans- dendrites reveals a strong enrichment at syn-
mission onto basket cells (such synapses are apses where the neurotransmitter glutamate
referred to as having a high initial release but not the neurotransmitter γ-aminobutyric
probability), such that larger synaptic events acid is released. Targeted elimination of

482 26 OCTOBER 2012 VOL 338 SCIENCE www.sciencemag.org

Published by AAAS

Elfn1 from O-LM neurons with a lentivi-
rus construct containing short hairpin RNA
increased the evoked excitatory postsynaptic
current amplitude and strongly reduced the
degree of short-term facilitation observed
across a range of frequencies. Elimination
of Elfn1 in early postnatal neurons had the
greatest impact on transmission, suggest-
ing an instructive role in the development
and maturation of synaptic function. Elfn1
loss of function was not accompanied by
changes in postsynaptic properties, con-
sistent with a role for Elfn1 in establishing
low–presynaptic release probability syn-
apses onto O-LM cells (see the figure). Sur-
prisingly, despite this apparent Elfn1 con-
trol over release probability, the absence of
Elfn1 did not convert pyramidal neuron–
O-LM synaptic activity to match that of
pyramidal neuron–basket cell connections,
which have an extremely high initial release
probability. Rather, loss of Elfn1 normalized
transmission across the train of stimuli, with
only weak facilitation remaining. This sug-
gests that other factors must be involved in
establishing the high release probability at
pyramidal neuron–basket cell targets. Con-
sistent with a role for Elfn1 in establishing
low–release probability synapses, overex-
pression of Elfn1 in basket cells converted
their hallmark short-term synaptic depres-
MEDICINE
Can Intellectual Property Save
Drug Development?
Garret A. FitzGerald
T
he imbalance between the roughly
constant rate of new drug approvals
and the exploding cost estimates of
drug development—mostly the cost of fail-
ure—has raised concern about the declining
productivity of the pharmaceutical indus-
try. Efforts to address the situation have
included an investment in human capital—
particularly those individuals who can proj-
ect science across the translational divide
(bench to clinic)—and investment in infra-
structure, as exemplified by Clinical and
Translational Science Awards in the United
States and Biomedical Research Centers
in the United Kingdom, and an increase in
The Institute for Translational Medicine and Therapeutics,
Perelman School of Medicine Translational Research Center,
10th Floor, 3400 Civic Center Boulevard, Philadelphia, PA
19104–5158, USA. E-mail garret@upenn.edu
www.sciencemag.org SCIENCE VOL 338 26 OCTOBER 2012
sion into facilitation. The available data sug-
gest that the default setting for excitatory
synapses onto interneurons may occupy the
middle ground of release probability, such
that Elfn1 acts to lower release probability
at O-LM synapses and an as yet unidentified
element acts to elevate the release probabil-
ity of basket cell synapses.
Although structural roles for proteins
containing leucine-rich repeat (LRR)
motifs in axon guidance, synapse target
selection, maturation, and myelination are
well established (5), functional roles for
LRR proteins in regulating synaptic trans-
mission are also not without precedent. For
example, neurotrophins and their LRR-
containing Trk receptors have both struc-
tural and functional roles in cortical cir-
cuits. Similarly, leucine-rich glioma inacti-
vated 1 (LGI1) and ADAM22 interact with
postsynaptic density protein 95 (PSD95)
to regulate postsynaptic glutamate recep-
tor subunit availability. In addition, interac-
tion of LGI1 with the presynaptic voltage-
gated potassium channel Kv1.1 influences
presynaptic release probability in perforant
path–granule cell synapses. How Elfn1 acts
to influence release probability is currently
unknown. Sylwestrak and Ghosh indicate
that an interplay between Elfn1 and GluK2-
receptor mediated short-term plasticity, but
partnerships between academia and indus-
try (1). However, radical reform of the iron
rules of intellectual property (IP) worldwide
will be necessary if we are to harvest and
integrate the efforts of scientists and clini-
cians scattered across companies, universi-
ties, and countries, best qualified to generate
new therapies.
Traditionally, large pharmaceutical com-
panies embraced the entire process of drug
discovery, development, approval, and mar-
keting, but such large, “vertically” integrated
companies are disintegrating. A recent mar-
ket capital analysis of the 19 largest phar-
maceutical companies indicated that invest-
ment was $1 billion for sales that amounted
to only $75 million from 2005 to 2010—a
decline of more than 70% in yield compared
to the previous 8 years (2). This suggests
Published by AAAS
PERSPECTIVES
the underlying mechanism is unclear. The
available data suggest that Elfn1 must have
downstream diffusible or trans-synaptic
partners that can act to regulate the avail-
ability of synaptic glutamate for presynap-
tic kainate receptors.
The two Elfn genes have highly comple-
mentary expression patterns in mammalian
central neurons. Elfn2 is largely confined to
cortical and hippocampal principal gluta-
matergic neurons (6). Although Sylwestrak
and Ghosh show high enrichment of Elfn1 in
somatostatin-containing O-LM cells, a wider
pattern of expression among other unidenti-
fied inhibitory interneuron subtypes is sug-
gested (6, 7). Whether such expression coin-
cides with other excitatory inputs with low
Downloaded from www.sciencemag.org on October 29, 2012
release probabilities remains to be tested.
Thus, the first step to decode target-specific
synaptic transmission has been taken, with
undoubtedly many more to follow.
References
1. H. J. Koester, D. Johnston, Science 308, 863 (2005).
2. K. Tóth, C. J. McBain, J. Physiol. 525, 41 (2000).
3. K. A. Pelkey, C. J. McBain, J. Physiol. 586, 1495 (2008).
4. E. L. Sylwestrak, A. Ghosh, Science 338, 536 (2012).
5. J. de Wit, W. Hong, L. Luo, A. Ghosh, Annu. Rev. Cell Dev.
Biol. 27, 697 (2011).
6. J. Dolan et al., BMC Genet. 8, 320 (2007).
7. Allen Brain Atlas, www.brain-map.org.
10.1126/science.1230338
Continually refining the focus of intellectual
property during the drug development process
should encourage productive collaborations
and expedite the availability of new therapies.
that the current approach to drug develop-
ment is vulnerable to abrupt changes in mar-
ket forces, as has occurred in other markets
including news media, movies, music, and
transportation.
What might be a less costly and more
efficient path to develop drugs? An ideal
approach would be to engage talent, from
discovery through to approval, from the
experts most relevant to a particular chal-
lenge, irrespective of their geographic loca-
tion or professional setting. Such a modular
means has worked well in the nonprofit sec-
tor (such as the Medicines for Malaria Ven-
ture and One World Health), where altru-
ism, the provision of capital by governments,
charities, companies, the opportunity to
trade shares of IP, and so-called credit default
swaps (a type of insurance policy where the
483