news and views
ment of the photo-switchable ligand and theempirical demonstration that the modification
leads to biologically relevant readout ex vivo
and in vivo. Levitz et al.1 confirmed the powerof using tethered photo-switchable ligands tocontrol cell surface protein activity and control
neuronal excitability without directly modifying ion channels themselves. Because theauthors exploited native proteins that were
only slightly modified, these tools are optimized to perfectly mimic the proteins’ naturalcoupling to the intracellular signal transduction pathways, as the modified GPCR should
behave similarly to the endogenous GPCR interms of its binding and signaling partners

and intracellular trafficking. This concept
is well illustrated by the success of the lightantagonized LimGluR2block in interferingwith the function of the endogenous intracellular signaling pathway downstream ofmGluR2. There is no doubt that such tools will
help link precise molecular events to behavior
and help propose better strategies for disease
treatments given the diversity of GPCRs in themammalian genome.
COMPETING FINANCIAL INTERESTS
The author declares no competing financial interests.
1. Levitz, J. et al. Nat. Neurosci. 16, 507–516 (2013).
2. Coward, P. et al. Proc. Natl. Acad. Sci. USA 95,352–357 (1998).

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npg© 2013 Nature America, Inc. All rights reserved.

mTORC2: actin on your memory
Sheena A Josselyn & Paul W Frankland
To be become long-lasting, short-term memories must be transformed into more permanent forms. mTORC2 has now
been found to be crucial for the molecular reorganization of the cytoskeleton needed for memory consolidation.
How do you make a memory? The formationof a long-term memory is thought to involveat least two ingredients. First, it requires
the strengthening of synaptic connections
between neurons, a process that depends onprotein synthesis. Second, it also requires
changes in the physical structure of the synaptic connections, a process that depends
on actin cytoskeleton rearrangement. Most
studies have focused on the role of protein synthesis in memory formation; muchless is known about actin poly­merizationand memory. Although protein synthesis and actin cytoskeleton rearrangement
must be intimately intertwined, even less isknown about how these necessary memory
processes interact at the molecular level.
A study by Huang et al.1 in this issue of Nature
Neuroscience reveals that mTORC2 (mammalian target of rapamycin complex 2) positively
regulates the actin dynamics required for theformation of long-term memories (Fig. 1)
and also suggests that actin polymerization is
upstream of protein synthesis.
mTOR (mammalian target of rapamycin) is
a serine-threonine protein kinase integral tosignal transduction pathways that control cell
growth and survival, translation, autophagy
Sheena A. Josselyn and Paul W. Frankland are in
the Program in Neurosciences & Mental Healthat The Hospital for Sick Children, and in theDepartments of Psychology and Physiology and theInstitute of Medical Science, University of Toronto,Toronto, Ontario, Canada.
e-mail: sheena.josselyn@sickkids.caand cytoskeleton organization2. It serves as
an intracellular sensor for energy metabolism,
nutrient availability and stresses, regulating
cellular and organism growth and metabolism
to adapt to environmental changes. The beststudied and understood function of mTOR is
the regulation of protein translation. mTOR
forms two distinct multiprotein complexes,
which are distinguished by their accessory
proteins. The mTOR complex 1 (mTORC1)
contains the accessory protein raptor(regulatory-associated protein of mTOR) andis sensitive to the drug rapamycin. By contrast, mTORC2 contains rictor (rapamycininsensitive companion of mTOR) and is resistant to acute rapamycin treatment3–5. Not
only do these mTOR complexes differ in their
sensitivity to rapamycin, but they also show
functional differences. mTORC1 is well characterized and is known to positively regulate
protein translation necessary for long-term
synaptic plasticity and memory formation6,7.
In contrast, relatively little is known about
the overall function of mTORC2, let alone itsrole in synaptic plasticity and memory. Hints
from other species and tissues suggest thatmTORC2, through its defining component
rictor, controls the actin cytoskeleton5,8 andtherefore might regulate some aspects of thestructural plasticity required for memory formation. By targeting rictor, Huang et al.1 identified an important function of this complex inregulating both long-term synaptic plasticity
and long-term memory formation.
Because rictor is important during brain
development, Huang et al.1 developed anature neuroscience volume 16 | number 4 | april 2013

conditional knockout mouse in which rictor
was deleted only from postnatal forebrain
excitatory neurons. These rictor-deficient
mice showed disrupted mTORC2, but intact
mTORC1, activity. The authors first used
these mice to examine the effects on synaptic plasticity of deleting mTORC2. Long-term
potentiation (LTP) of excitatory synaptic
responses is a commonly used electrophysiological correlate of memory formation. In
the CA1 region of the hippocampus, weaktetanization (for example, one train at 100 Hz)
induces early phase-LTP (E-LTP), which, as its
name implies, decays over time. In contrast,stronger tetanization (for example, four trains
at 100 Hz) induces late phase-LTP (L-LTP),
a form of LTP that lasts for several hours.
The conversion of E-LTP into L-LTP requires
both protein synthesis and actin cytoskeletal
rearrangement9,10. Actin is the main structuralcomponent of dendritic spines, and its rearrangement via polymerization is critical for
L-LTP (but not E-LTP). Mice with a forebrain
deletion of rictor showed normal basal synaptic transmission and E-LTP. However, thisE-LTP could not be converted to L-LTP.
Of course, studies of LTP and synapticphysiology greatly inform our understandingof the mechanistic recipe for memory formation, but the real proof is in the pudding. Inshort, do these mTORC2-deficient mice show
impaired long-term memory? Previous studies have shown that actin polymerization isrequired for the conversion of a weak shortterm memory into long-term memory10. To
examine mTORC2 in memory, the authors379

news and views

NMDAR

TrkBmTORmTORC2

RictorRacnpg© 2013 Nature America, Inc. All rights reserved.

PAKCofilin

G-actinF-actin

E-LTP, STM

L-LTP, LTMFigure 1 mTORC2 regulates actin dynamics toform long-term memories. The mTOR complex 2(mTORC2) is composed of mTOR and rictor(rapamycin-insensitive companion of mTOR),
among other accessory proteins. Several signaling
pathways (for example, Ca2+ acting through
NMDA-type glutamate receptors (NMDAR), orbrain-derived neurotrophic factor (BDNF) acting
through TrkB receptors) activate mTORC2, which
in turn acts through Rac, PAK and cofilin topromote the actin polymerization required forthe conversion of early LTP (E-LTP) into late LTP(L-LTP) and short-term memory (STM) into longterm memory (LTM).

tested rictor-deficient mice in several different tasks that differ in their training scheduleand performance demands. Classical fear conditioning is a memory model in which a tone
is paired with a shock in a specific context.
Rictor-deficient mice showed normal memory
for both the context and tone when tested 2 hafter training, indicating that their short-termmemory was intact. However, when tested 24 hafter training, they showed impaired memory
for both the context and tone. These behavioral results parallel the synaptic physiology
data: similarly to the failure to convert E-LTP
to L-LTP, these mice seemed unable to convert
a short-term memory into a long-term memory. Consistent with this conclusion, Huang
et al.1 went on to examine spatial memory
formation in rictor-deficient mice using theMorris water maze. In this model, mice learn
to find a hidden platform submerged under
the surface of an opaque liquid by using
380

spatial cues around the room. Training takes
place over several days, and therefore miceneed to remember from one day to the next.
Again, rictor-deficient mice were unable toform a stable spatial memory.
Many foundational studies of the molecular basis of long-term memory were conducted in invertebrates, including Drosophilamelanogaster11,12. Although the results of fly
studies have certainly informed rodent studies(and vice versa), these research streams haveoften existed in parallel universes. Notably,Huang et al.1 unite these research traditions bycomparing memory in both rodents and flies
with genetically disrupted mTORC2 function.
Seymour Benzer and his students pioneered
the use of classical fear conditioning, in which
an odor is paired with shock, to examine memory in flies10. In this model, massed training(training trials with no inter-trial rest periods)
produces a short-term memory that is independent of protein synthesis, whereas spaced
training (training trials with intervening restperiods) produces protein synthesis–dependent
long-term memory10. In a striking parallel tothe findings with mice, rictor-deficient flies
showed intact short-term but impaired longterm memory, indicating that the function ofrictor in memory is conserved.
To better understand the mechanism
behind mTORC2’s effect on memory, theauthors turned to its downstream targets.
Consistent with mTORC2 and rictor’s role inactin polymerization, the authors found thatrictor-deficient mice showed disrupted actin
dynamics. The polymerization of free globular actin (G-actin) to form filamentous actin(F-actin) is thought to underlie the growthof dendritic spines necessary for memory
formation10. Rictor-deficient mice showed areduction in the ratio of F-actin to G-actin, as
well as a reduction in expression of a numberof upstream positive regulators of actin poly­merization. These correlational data suggested
that rictor is required for long-term memory
formation by increasing the F-actin importantfor dendritic spine growth and remodeling.
To directly test this hypothesis, the authors
manipulated actin itself. First they mimicked
the effect of disrupting actin polymerization inotherwise normal wild-type mice using cyto­chalasin D, a drug that specifically disrupts
actin polymerization. Like rictor-deficientslices, wild-type slices treated with cytochalasin
D showed intact E-LTP but disrupted L-LTP. Is
normalizing actin dynamics sufficient to rescue the L-LTP and long-term memory deficits
in rictor-deficient mice? Jasplakinolide (JPK),
a compound that promotes actin polymerization, restored both the F-actin to G-actin
ratio and the ability to produce L-LTP inslices in rictor-deficient mice, without affecting these processes in slices from wild-type
mice. Remarkably, infusion of JPK directly
into the hippocampus similarly reversed thelong-term memory deficits in rictor-deficientmice. Might increasing actin polymerization
enhance synaptic plasticity and memory formation in wild-type mice? To examine this, theauthors used weak training conditions that arenormally sufficient to induce only E-LTP andshort-lasting memory in wild-type miceand found that this drug enabled both
L-LTP and long-term memory formation.
Intriguingly, the L-LTP induced by weaktraining in the presence of JPK was blocked
by application of anisomycin, a protein synthesis inhibitor, suggesting that actin polymerization is upstream of protein synthesis.
Finally, systemic injection of a small moleculethat increases mTORC2 activity (A-443654)
not only facilitated L-LTP in the slice but alsoenhanced long-term memory formation inwild-type mice.
By both increasing and decreasing mTORC2
function, Huang et al.1 provide compelling
evidence that mTORC2, acting through actin
polymerization, is important in formationof stable memories. They showed that thismechanism was conserved in both flies andmice. Taken together, these findings raise thequestion of whether targeting mTORC2 might
similarly enhance memory and other cognitive
functions in humans. Given that mTORC2 disruption is implicated in many human diseases
associated with cognitive dysfunction13–15, thepresent study offers a tantalizing prospect forfuture therapeutic avenues.
COMPETING FINANCIAL INTERESTS
The authors declare no competing financial interests.
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volume 16 | number 4 | april 2013 nature neuroscience