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Peripheral Delivery of a ROCK Inhibitor Improves Learning and Working Memory

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Previously, utilizing a series of genome-wide association, brain imaging, and gene expression studies we implicated the KIBRA gene and the RhoA/ROCK pathway in hippocampal-mediated human memory. Here we show that peripheral administration of the ROCK inhibitor hydroxyfasudil improves spatial learning and working memory in the rodent model. This study supports the action of ROCK on learning and memory, suggests the potential value of ROCK inhibition for the promotion of cognition in humans, and highlights the powerful potential of unbiased genome-wide association studies to inform potential novel uses for existing pharmaceuticals.
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Behavioral Neuroscience
© 2009 American Psychological Association
2009, Vol. 123, No. 1, 218 –223
0735-7044/09/$12.00
DOI: 10.1037/a0014260
Peripheral Delivery of a ROCK Inhibitor Improves Learning
and Working Memory
Matthew J. Huentelman and Dietrich A. Stephan
Joshua Talboom
Translational Genomics Research Institute, Phoenix, Arizona
Arizona State University
and Arizona Alzheimer’s Consortium
Jason J. Corneveaux, David M. Reiman,
Carol A. Barnes
and Jill D. Gerber
and Gene E. Alexander
Translational Genomics Research Institute, Phoenix, Arizona
Arizona Alzheimer’s Consortium and University of Arizona
Eric M. Reiman
Heather A. Bimonte-Nelson
Translational Genomics Research Institute, Phoenix, Arizona,
Arizona Alzheimer’s Consortium and Arizona State University
Arizona Alzheimer’s Consortium, The Banner Alzheimer’s
Institute, and University of Arizona
Previously, utilizing a series of genome-wide association, brain imaging, and gene expression
studies we implicated the KIBRA gene and the RhoA/ROCK pathway in hippocampal-mediated
human memory. Here we show that peripheral administration of the ROCK inhibitor hydroxyfasudil
improves spatial learning and working memory in the rodent model. This study supports the action
of ROCK on learning and memory, suggests the potential value of ROCK inhibition for the
promotion of cognition in humans, and highlights the powerful potential of unbiased genome-wide
association studies to inform potential novel uses for existing pharmaceuticals.
Keywords: learning, memory, ROCK, fasudil, aging
Supplemental materials: http://dx.doi.org/10.1037/a0014260.supp
The molecular processes involved in learning and memory
learning and memory declines associated with healthy aging as
provide promising targets for putative memory-enhancing (i.e.,
well as in the enhancement of normal learning and memory.
nootropic) pharmaceuticals, which might be helpful in the treat-
To date, nootropic drug discovery efforts have focused on the
ment of Alzheimer’s disease, other dementias, mild cognitive
enhancement of cholinergic, glutaminergic, and serotonergic
impairment, and other disorders associated with impairments in
neurotransmission and phosphodiesterase inhibition, and have
learning and memory. If safe and well tolerated, these medica-
had limited benefits (Sarter, 2006). Examples include the cho-
tions could even have roles in the treatment of the nondisabling
linesterase inhibitors and N-methyl-d-aspartate (NMDA) ago-
Matthew J. Huentelman and Dietrich A. Stephan, Neurogenomics
We acknowledge financial support from the Evelyn F. McKnight Brain
Division, The Translational Genomics Research Institute, Phoenix,
Research Foundation, the NIH National Institute on Aging (Grant
Arizona and Arizona Alzheimer’s Consortium; Joshua Talboom,
AG19610), the NIH National Institute of Neurological Disorders and
Department of Psychology, Arizona State University; Jason J. Corn-
Stroke (Grant NS059873), and the State of Arizona. Matthew J. Huentel-
man and Dietrich A. Stephan contributed equally to this work. We declare
eveaux, David M. Reiman, and Jill D. Gerber, Neurogenomics Division,
that we have no competing financial interests. We thank Cynthia Zay and
The Translational Genomics Research Institute, Phoenix, Arizona;
Britny Sundin for their excellent technical support.
Carol A. Barnes, Arizona Alzheimer’s Consortium, and Arizona Re-
Matthew Huentelman, Dietrich A. Stephan, David M. Reiman, and Eric
search Laboratories Division of Neural Systems, Memory, and Aging,
M. Reiman are stockholders in Sygnis Pharma AG, a German pharmaceu-
Evelyn F. McKnight Brain Institute, and Department of Psychology,
tical company, which previously purchased the rights to develop this drug
University of Arizona; Gene E. Alexander, Arizona Alzheimer’s
class as a potential memory-enhancing treatment. Sygnis was not directly
Consortium, and Evelyn F. McKnight Brain Institute and Department of
involved in this study and neither funded any part of the study, influenced
Psychology, University of Arizona; Eric M. Reiman, Neurogenomics
the decision to study the pharmaceuticals reported on, nor the conclusions
Division, The Translational Genomics Research Institute, Phoenix,
of this study.
Arizona, Arizona Alzheimer’s Consortium, The Banner Alzheimer’s
Correspondence concerning this article should be addressed to Matthew
Institute, Phoenix, Arizona, and Department of Psychiatry, University
J. Huentelman, Neurogenomics Division, The Translational Genomics
of Arizona; Heather A. Bimonte-Nelson, Arizona Alzheimer’s Consor-
Research Institute, 445 N Fifth Street, Phoenix, AZ, 85004. E-mail:
tium and Department of Psychology, Arizona State University.
mhuentelman@tgen.org
218

BRIEF COMMUNICATIONS
219
nists currently approved for the treatment of Alzheimer’s dis-
Method
ease,
-amino-3-hydroxy-5-methylisoxazole-4-propionic acid
(AMPA) receptor agonists, and nicotinic alpha 7 receptor ago-
Subjects and Treatment Procedures
nists.
Subjects were 27, 17-month-old Fischer-344 male rats (18-
Using a hypothesis-free 500K single nucleotide polymorphism
months old at the time of behavioral testing) born and raised at the
(SNP) genome-wide association study, followed by functional
aging colony of the National Institute on Aging at Harlan Labo-
brain imaging and gene expression studies, we recently associated
ratories (Indianapolis, IN). After arrival at Arizona State Univer-
the KIBRA gene with the variation in normal episodic memory
sity, animals were pair housed with a same-age cage mate, had
performance in both young (median age of 22; ranging from 18 to
exposure to food and water ad lib, and were maintained on a 12-hr
48 years) and late middle aged (median age of 55; ranging from 20
light– dark cycle. All procedures were approved by the local
to 81 years) adults (Papassotiropoulos et al., 2006). Our initial
IACUC committee and adhered to NIH standards. The experiment-
genetic findings have been replicated by a different research team
ers who performed the behavioral testing and brain dissections
in a unique cohort of older individuals (mean age of 67) thereby
were blind to treatment group.
further supporting KIBRA’s role in episodic memory as well as
One daily injection of the assigned substrate began 4 days prior
extending this relationship to the aged population (Schaper, Kol-
to behavioral testing and continued throughout testing. The half
sch, Popp, Wagner, & Jessen, 2007). In addition, two other groups
life of hydroxyfasudil in humans has been estimated at between 5
have published studies using independent cohorts that further
and 7 hr (Hinderling et al., 2007), therefore we administered the
support a genetic link between KIBRA and memory variation in
drug dose each morning prior to behavioral testing. The initial
healthy individuals (Almeida et al., 2008; Nacmias et al., 2008).
4-day period before testing was incorporated to habituate the
The genetic link between KIBRA and human memory disorders
animals to daily drug or vehicle delivery. Injections were given
has also been investigated. One group recently reported no effect
subcutaneously into the scruff of the neck. There were three
on risk for development of mild cognitive impairment (Almeida et
experimental groups: nine animals received saline vehicle (“aged
al., 2008), however, a manuscript published in 2007 as well as a
vehicle”), nine animals received hydroxyfasudil (Sigma-Aldrich,
recently published manuscript by members of our group support a
St. Louis, MO) at a dose of 0.1875 mg (“aged low dose”), and nine
link between KIBRA genetic variation and Alzheimer’s disease in
animals received hydroxyfasudil at a dose of 0.3750 mg (“aged
(Rodriguez-Rodriguez et al., in press) and (Corneveaux et al., in
high dose”).
press). There has also been a single recent report suggesting no
association between KIBRA and multiple-verbal memory tasks
Water Radial-Arm Maze
(Need et al., 2008).
A schematic of the water radial-arm maze is shown in Supple-
Based on these findings and a pathway analysis approach, we
mentary Figure 1A. This win-shift radial-arm maze tests working
hypothesized that KIBRA activity would be altered via the RhoA/
and reference memory and utilizes water escape onto hidden
ROCK/Rac pathway through the putative modulation of PKC-
platforms as the reinforcer (Bimonte & Denenberg, 1999, 2000;
(Van Kolen & Slegers, 2006). KIBRA is a demonstrated substrate
Bimonte, Granholm, Seo, & Isacson, 2002; Bimonte, Hyde, Hop-
for PKC- (Buther, Plaas, Barnekow, & Kremerskothen, 2004) and
light, & Denenberg, 2000; Hyde, Hoplight, & Denenberg, 1998;
has been shown to interact with Dendrin (Kremerskothen et al.,
Hyde, Sherman, & Denenberg, 2000). The eight-arm maze had
2003), a postsynaptic cytoskeleton modulatory molecule. Re-
submerged escape platforms placed in the ends of four of the arms.
cently, KIBRA also has been shown to colocalize with both a
Each subject had different platform locations that remained fixed
postsynaptic marker protein (ProSAP2/Shank3) and in close con-
throughout the experiment. A subject was released from the start
tact with a presynaptic marker (bassoon) in primary rat hippocam-
arm, which remained constant throughout testing and for all sub-
pal neurons (Johannsen, Duning, Pavenstadt, Kremerskothen, &
jects, and had 3 min to locate a platform. Once a platform was
Boeckers, 2008). In multiple-cell types the RhoA/ROCK/Rac
found, the animal remained on it for 15 s, and was then returned to
pathway has been demonstrated to be upstream of PKC-
its heated home cage for 30 s until its next trial. During the
(Kampfer et al., 2001; Scott, Arioka, & Jacobs, 2007; Uberall et
intertrial interval, the just-chosen platform was removed from the
al., 1999; Van Kolen & Slegers, 2006). In addition, because the
maze. The animal was placed again into the start alley and allowed
RhoA/ROCK/Rac pathway has been implicated in key neurobio-
to locate another platform. The same sequence of events was
logical processes that underlie cognitive function, such as neurite
repeated daily until all four platforms were located. Consequently,
outgrowth and growth cone modulation (Gopalakrishnan et al.,
for each animal a daily session consisted of four trials per session,
2008; Lingor et al., 2007; Loudon, Silver, Yee, & Gallo, 2006;
with the number of platformed arms reduced by one on each
Woo & Gomez, 2006), we postulated that an inhibitor of this
subsequent trial resulting in one more item of information needing
pathway might be useful as a treatment for the enhancement of
to be remembered after every trial. Hence, the working memory
learning and memory.
system was increasingly taxed as trials progressed. Animals per-
Several existing compounds have the capability to modulate the
formed for four trials each day for 12 days.
RhoA/ROCK pathway. Although a recently developed inhibitor of
Entry into an arm was counted when the tip of a rat’s snout
ROCK, fasudil has been investigated in patients as a potential
reached a mark delineated on the outside of the arm (11 cm into the
treatment for vasospasm and angina, fasudil or its active metabo-
arm). Errors were quantified for each daily session using the
lite hydroxyfasudil has not been evaluated in laboratory animals or
orthogonal measures of working and reference memory errors
human subjects for effects on learning and memory (Hirooka &
(Jarrard, Okaichi, Steward, & Goldschmidt, 1984), and blocked
Shimokawa, 2005).
into the initial and latter test phases based on previous studies

220
BRIEF COMMUNICATIONS
using the water escape radial-arm maze (Bimonte & Denenberg,
between-subjects factor and days and trials as the repeated mea-
1999, 2000; Bimonte et al., 2002, 2000; Bimonte, Nelson, &
sures. Each drug-treated group was compared to the saline group,
Granholm, 2003; Bimonte-Nelson, Francis, Umphlet, & Gran-
set a priori.
holm, 2006; Bimonte-Nelson, Hunter, Nelson, & Granholm, 2003;
Bimonte-Nelson, Singleton, Williams, & Granholm, 2004; Hyde et
Spatial Reference Memory Morris Maze
al., 1998, 2000). Day 1 was considered a training session be-
cause the animal had no previous experience in the maze. Days
A schematic of the Morris water maze is shown in Supplementary
2 through 12 were testing sessions. The 11 testing days were
Figure 1B. The Morris maze (Morris, 1984) consisted of a round tub
blocked into two phases: The initial phase consisting of testing
(188 cm in diameter) filled with room temperature (19 to 22 °C) water
Days 2 to 7, which is considered an acquisition measure as used
made opaque with black nontoxic paint. A black platform (10 cm)
in the learning index measure described below, and the latter
was submerged just below the water surface. The rat was placed in the
phase consisting of Days 8 to 12, which is considered a more
maze, facing the tub wall, from any of four locations (North, South,
steady-state measure of memory after the rules of the task have
East, or West) and had 60 s to locate the hidden platform that
been learned. Working memory correct errors were the number
remained in a fixed location throughout testing. After 15 s on the
of first and repeat entries into any arm from which a platform
platform, the rat was removed from the maze and placed into its
had been removed during that session. Reference memory er-
heated cage until the next trial. The intertrial interval was approxi-
rors were the number of first entries into any arm that never
mately 5 to 7 min. The rats were given five trials a day for 4 days, plus
contained a platform. Working memory incorrect errors were
a probe trial on Trial 6, Day 5 in which the platform was removed to
the number of repeat entries into an arm that never contained a
test platform spatial localization. A video camera suspended on the
platform in the past. A total error score was also obtained. The
ceiling above the maze tracked the rat’s path and a tracking system
ability to handle an increasing working memory load was tested
(Ethovision System, Noldus Instruments, Wageningen, The Nether-
by evaluating performance as trials increased during the latter
lands) was used to analyze each rat’s tracing. Performance was
testing phase for the working memory correct and incorrect
assessed by swim path distance to the platform. Distance scores were
variables. We showed that young rats can learn to handle a high
analyzed using repeated measures ANOVA with treatment as the
working memory load as testing days progress on this task,
between-subjects factor and days and trials as the repeated measures
whereas experimentally unaltered aged rats cannot (Bimonte et al.,
for the test trials.
2003). Thus, to evaluate learning of the water radial-arm maze task at
the highest memory load, we used a learning index. Total, working
Results and Discussion
memory correct, and working memory incorrect errors on Trial 4
were used to determine the learning index for each day of testing
Based on results from our prior whole-genome association
following the first day. This measure is based on similar indexes of
study, we evaluated the effects of two doses of the ROCK inhibitor
learning using a difference score, and corrects for potential differ-
hydroxyfasudil on spatial learning and memory in aged rats. For
ences in baseline variances across animals.
the water radial-arm maze, the aged high dose group showed
superior learning for all three measures evaluated (Figure 1a– c).
Learning index
For the measure of total errors (Figure 1a), the aged high dose
errors made in the initial phase
errors made in the latter phase
group showed the best learning, with a significantly higher learn-
.
ing index compared to the aged vehicle group, t(16)
2.42; p
errors made in the initial phase
.028. The aged high dose group also showed better learning of both
In addition to learning, we also measured memory competence by
orthogonal working memory measures at the most demanding
evaluating error scores on the latter testing phase via a repeated
memory load of the radial-arm maze, on Trial 4. Indeed, the aged
measures analysis of variance (ANOVA), with treatment as the
high dose group had a higher learning index than the aged vehicle
Figure 1.
Hydroxyfasudil treatment is associated with a dose-related increase in learning proficiency in aged
rats. Shown are the M
SE. Learning index scores for A) total errors, B) working memory correct (WMC)
errors, and C) working memory incorrect (WMI) errors for each group for the trial with the highest memory
demand. A higher learning index is indicative of better learning. Aged rats given high dose hydroxyfasudil
showed better learning on all three measures, and linear trends showed that drug dose was correlated with a
higher learning index for each of the three variables.
p
.05. # p
.09.

BRIEF COMMUNICATIONS
221
group for working memory correct, t(16)
2.70; p
.016
effects of ROCK inhibition on variables such as pain perception
(Figure 1b) and working memory incorrect, t(16)
2.19; p
.043
and anxiety, and one study evaluating memory retention after
(Figure 1c). The aged low dose group had only a marginally higher
hippocampal infusion of a ROCK inhibitor in the young rodent,
learning index for working memory incorrect errors compared to
aside from the current report there has been no study evaluating the
the aged vehicle group, t(16)
1.79; p
.09 (Figure 1c). This
effects of peripheral administration of a ROCK inhibitor on spatial
marginal finding may be due to a slight under powering in the aged
cognition (Buyukafsar et al., 2006; Dash, Orsi, Moody, & Moore,
low dose animals. However, for every learning index measure,
2004; Lamprecht, Farb, & LeDoux, 2002; Saitoh et al., 2006).
values for the aged low dose group were intermediate between the
Thus, the current study is the first to examine the effect of
aged vehicle and aged high dose groups, thereby suggesting a
peripheral delivery of hydroxyfasudil on spatial cognition as well
dose-dependent effect on learning the working memory task. Re-
as the first to test the mnemonic effects of ROCK inhibition in an
gression analyses confirmed this relationship between treatment
older population of animals.
dose and performance, with significant linear trends across groups
These findings underscore the potential of the promises of
for the learning index for total, ANOVA for linear trend: F(1,
genome-wide association studies. Our interest in ROCK as a
25)
7.24; p
.013; working memory correct, ANOVA for
potential target for cognitive enhancement arose from the elucida-
linear trend: F(1, 25)
6.10; p
.021; and working memory
tion of the genetic involvement of KIBRA in human episodic
incorrect, ANOVA for linear trend: F(1, 25)
6.24; p
.019
memory performance in our previously published association
errors.
study (Papassotiropoulos et al., 2006). The evidence detailed in
In addition to demonstrating better learning of the working
this manuscript illustrates that it is possible to move from a
memory task, the aged high dose group also outperformed the aged
validated human genetic association to an informed pharmaceuti-
vehicle group on working memory on the latter phase of testing,
cal decision. In our approach we first searched for targets with
with high dose hydroxyfasudil improving the ability to handle the
existing pharmaceutical agents that were at an advanced clinical
maximally increased memory load, Drug Treatment
Trial sig-
stage. The optimal study design might be envisioned to directly
nificant interaction for working memory incorrect: F(3, 48)
pharmaceutically target KIBRA, and the investigation of agents
2.84; p
.048 (Figure 2a); Drug Treatment
Trial marginal
that may be capable of disrupting key KIBRA interactions are
interaction for working memory correct: F(2, 32)
3.14; p
.057
currently ongoing. In lieu of directly altering the activity of the
(Figure 2b). Low-dose treatment did not significantly enhance
genetically associated gene product, the approach used in the
working memory performance for any variable. Finally, neither
present study was to influence the biomolecules that interact with
dose of hydroxyfasudil was associated with significantly altered
it, in turn, resulting in the functional consequences of cognitive
spatial reference memory performance on the water radial-arm
change. This approach may be widely applicable to many of the
maze or Morris water maze. Indeed, there were no drug treatment
associated genes currently being reported in the literature.
main effects or interactions for reference memory errors on the
Our current working hypothesis is that PKC- activity modula-
water radial-arm maze, nor for distance scores on the Morris maze.
tion alters learning and memory through KIBRA. It has been
The data presented here implicate ROCK activity in the pro-
shown in astrocytoma cells that ROCK inhibition leads to a sub-
cesses of both learning and the ability to handle a high working
sequent increase in Rac1 activity (Salhia et al., 2005). Rac1 acti-
memory load. In addition, there were no effects of hydroxyfasudil
vation has also been demonstrated to modulate the activity of PKC-
on reference memory. Thus, the effects of hydroxyfasudil were
(Liu et al., 2006; Scott et al., 2007; Uberall et al., 1999). In addition,
working memory specific, which may implicate effects in part, on
pioneering work has shown that a unique form of PKC- , termed
the frontal cortex. Indeed, the frontal cortex is intimately involved
PKM- , is essential for long term potentiation and plays a signif-
with working memory in both humans and rodents (Miotto, Bul-
icant role in the process of differing forms of memory as well
lock, Polkey, & Morris, 1996; Poucet, 1990; Poucet & Herrmann,
(Ling et al., 2002; Pastalkova et al., 2006; Shema, Sacktor, &
1990). Although there has been some research evaluating the
Dudai, 2007). Based on these reports, we hypothesized that inhi-
Figure 2.
Hydroxyfasudil treatment improves working memory in aged rats. Shown are the M
SE working
memory incorrect errors across trials for the latter testing phase of the water-escape radial arm maze. Aged
animals given high dose hydroxyfasudil treatment were better able to handle an increased memory load as
compared to aged animals given vehicle. Drug treatment by trial interactions were p
.048 and p
.057,
respectively.

222
BRIEF COMMUNICATIONS
bition of ROCK leading to activation of Rac1 and PKC- would in
Buyukafsar, K., Yalcin, I., Kurt, A. H., Tiftik, R. N., Sahan-Firat, S., &
turn phosphorylate KIBRA and alter its activity. However, as of
Aksu, F. (2006). Rho-kinase inhibitor, Y-27632, has an antinociceptive
yet the mechanism related to the nootropic benefits we observed
effect in mice. European Journal of Pharmacology, 541, 49 –52.
with hydroxyfasudil are unknown. Fasudil, the parent compound,
Corneveaux, J. J., Liang, W. S., Reiman, E. M., Webster, J. A., Myers,
has been shown to exhibit direct neuroprotective effects against
A. J., Zismann, V. L., et. al. (in press). Evidence for an association
between KIBRA and late-onset Alzheimer’s disease. Neurobiology of
ischemia (Satoh, Toshima, Ikegaki, Iwasaki, & Asano, 2007;
Aging.
Yamashita et al., 2007) as well as influence vasodilation, which
Dash, P. K., Orsi, S. A., Moody, M., & Moore, A. N. (2004). A role for
could then in turn influence cognitive function (Jiang et al., 2007;
hippocampal Rho-ROCK pathway in long-term spatial memory. Bio-
Nagata et al., 1993). Although further experiments are necessary to
chemical and Biophysical Research Communications, 322, 893– 898.
confirm the mechanism/s underlying hydroxyfasudil-induced
Gopalakrishnan, S. M., Teusch, N., Imhof, C., Bakker, M. H., Schurdak,
functional improvements on learning and memory, the present
M., Burns, D. J., et al. (2008). Role of Rho kinase pathway in chon-
results can be considered an initial step in that direction providing
droitin sulfate proteoglycan-mediated inhibition of neurite outgrowth in
support for the hypothesis that ROCK inhibition initiates a cascade
PC12 cells. Journal of Neuroscience Research, 86, 2214 –2226.
of events that can influence cognition.
Hinderling, P. H., Karara, A. H., Tao, B., Pawula, M., Wilding, I., & Lu,
Our findings suggest that peripheral administration of the
M. (2007). Systemic availability of the active metabolite hydroxy-
ROCK inhibitor hydroxyfasudil improves spatial learning and
fasudil after administration of fasudil to different sites of the human
memory, a finding that may have clinical relevance considering
gastrointestinal tract. Journal of Clinical Pharmacology, 47, 19 –25.
Hirooka, Y., & Shimokawa, H. (2005). Therapeutic potential of rho-kinase
that the parent drug (Fasudil) was found to be safe and extremely
inhibitors in cardiovascular diseases. American Journal of Cardiovas-
well tolerated when used in the human clinic in multiple-dosage
cular Drugs, 5, 31–39.
forms. The collected findings and the relative safety of fasudil
Hyde, L. A., Hoplight, B. J., & Denenberg, V. H. (1998). Water version of
support the potential of this ROCK inhibitor as a cognitive en-
the radial-arm maze: Learning in three inbred strains of mice. Brain
hancer in humans that have age- or neurodegenerative-related
Research, 785, 236 –244.
memory dysfunction.
Hyde, L. A., Sherman, G. F., & Denenberg, V. H. (2000). Non-spatial
water radial-arm maze learning in mice. Brain Research, 863, 151–159.
Jarrard, L. E., Okaichi, H., Steward, O., & Goldschmidt, R. B. (1984). On
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