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Vol. 281, Issue 2, 965-971, 1997
Department of Pharmacology, University of Colorado Health Sciences Center Denver, Colorado (T.J.G., P.C.B.) and Department of Veterans Affairs Medical Center, Research Service, Denver, Colorado (P.C.B.)
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Abstract |
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 Top
Abstract
Introduction
Methods
Results
Discussion
References
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Localization of age-related deficits in the cerebellar
beta adrenergic signal transduction cascade were
investigated electrophysiologically using forskolin (FORSK) and
adenosine-3
,5-cyclic monophosphothioate Sp-isomer (Sp-cAMPS) applied
via pressure ejection from extracellular multibarreled
glass electrodes to activate the transduction cascade. In young rats,
100 µM FORSK activated AC, and 100 µM Sp-cAMPS activated protein
kinase A; thus, both increased GABAergic inhibition of Purkinje cell
firing. In aged rats, however, 100 µM FORSK was unable to increase
GABAergic inhibition of Purkinje cell firing. In addition, 1 mM
7
-decacetyl-7-(
-N-methylpiperazino)butyryl-forskolin, an
analog of FORSK, was also unable to increase GABAergic inhibition in
aged rats. In contrast, Sp-cAMPS was able to increase GABAergic inhibition in aged rats, but higher doses were required than in young
rats. Isoproterenol (ISO), a beta adrenergic agonist,
was ineffective in increasing GABAergic inhibition of Purkinje firing in aged rats when tested alone, but ISO was effective in increasing Purkinje cell inhibition when ISO was tested with Sp-cAMPS. The results
of this experiment indicate that one age-related deficit in the
cerebellar beta adrenergic system occurs at the level of protein kinase A activation.
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Introduction |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Aging is
associated with decreased cerebellar noradrenergic function. NE has a
number of known actions in the cerebellum, including the ability to
increase GABAergic inhibition of Purkinje cell firing. This effect of
NE to increase GABAergic inhibition has been associated with the
beta-1 adrenergic receptor (Yeh and Woodward, 1983
), which
has been known to be selectively altered in aged rats (Parfitt and
Bickford-Wimer, 1990). It is well established that the beta
receptor is a Gs protein-linked receptor that activates AC
and increases intracellular cAMP levels (Sessler et al.,
1989). Next, cAMP activates PKA, which ultimately may result in
potentiated Cl
currents of the GABAA receptor
(Cheun and Yeh, 1992). Where in this signal transduction cascade aging
is producing its deleterious effects, however, is unknown.
A variety of age-related neural changes are seen in G protein-coupled
receptor second-messenger substrates; these changes include alterations
in AC, cAMP and PDE. Age-related changes in AC appear to be extremely
variable. Age-related decreases in FORSK binding were reported in
cerebellum and striatum (Araki et al., 1995; Hara et
al., 1992). Similarly, FORSK-stimulated AC activity in striatal
and nucleus accumbens tissue was lower in aged rats, but no difference
was seen in FORSK binding to the Gs
protein-coupled subunit of AC (Sugawa and May, 1993). However, no
age-related change in basal or NaF-stimulated AC was reported in rat
striatum (Puri and Volicer, 1977) and cerebral cortex (Zimmerman and
Berg, 1975) in other studies.
Age-related changes in cAMP and PDE show variability similar to AC. In
striatum and nucleus accumbens, cAMP-dependent phosphorylation decreased with age (Govoni et al., 1988). In addition, cAMP
levels and binding decreased in aged cerebral cortex (Hara et
al., 1992; Zimmerman and Berg, 1974), but binding did not change
in the cerebellum (Hara et al., 1992), and cAMP levels did
not change in the striatum (Puri and Volicer, 1977). PDE activity
decreased in aged cerebral cortex and striatum (Puri and Volicer, 1977;
Zimmerman and Berg, 1974) but did not change in superior cervical
ganglion (Giorgi et al., 1994). In addition, a significant
rise only in high-KM cAMP PDE activity occurred
in cerebral cortex, hypothalamus and hippocampus with age (Stancheva
and Alova, 1991). Thus, it remains uncertain whether age-related G
protein-coupled receptor dysfunction is region specific and whether
multiple sites of damage along the signal transduction cascade exist in
a given region.
It was the goal of the study to elucidate what steps in the cerebellar
beta adrenergic signal transduction cascade are particularly sensitive to the deleterious effects of aging. Commonly, we assess cerebellar beta adrenergic function by applying the
beta adrenergic agonist ISO during GABAergic inhibition of
Purkinje cell firing. In the present study, we used FORSK (to
presumably activate AC) and Sp-cAMPS (an analog of cAMP that presumably
activates PKA) (Mewes et al., 1993)) to attempt enhancement
of GABAergic inhibition in aged rats. By using these compounds, we
hoped to activate the signal transduction cascade downstream from where
the age-related deficits occur and thus clarify what sites of the
-adrenergic signal transduction cascade are damaged in aged F344 rat
cerebellum.
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Methods |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Subjects. Fifteen 3-month-old and 37 18- to 21-month-old male F344 rats were obtained from the NIA contract colonies at Harlan Sprague-Dawley. Rats were housed in an AAALAC-approved barrier facility. Rats were maintained on a 12-hr light/dark cycle and had free access to food and water.
Electrophysiology.
Rats were anesthetized with urethane
(0.75-1.25 g/kg), intubated and allowed to breath spontaneously. Aged
rats required lower doses of anesthetic to induce an equivalent level
of anesthesia. Corneal reflex and toe pinch were used to monitor
anesthetic level to ensure equivalent levels of anesthesia between
young and old rats. A heating pad was used to maintain body temperature
at 37°C. Animals were placed in a stereotaxic frame, and the skin and
muscle over the posterior cerebellum was removed. The cistern was
drained, and the skull and dura over the cerebellum were removed. A
solution of 2% agar in saline covered the brain. Recordings were made
in lobules VI and VII of cerebellar vermis from Purkinje cells as identified by anatomical location and the characteristic complex spiking of Purkinje cells (Eccles et al., 1967).
3 dB at 0.3 and 5 kHz)
and displayed on a storage oscilloscope. Action potentials were
isolated using a window discriminator, and the output was displayed
using a strip-chart recorder. Single units had to have a
signal-to-noise ratio of the action potential amplitude vs. background of 
2:1. Multibarrel glass micropipettes were used for
single cell recording, and drugs were applied locally via microiontophoresis and pressure ejection. The resistance of the recording electrodes was 1.5 to 3.3 M
. In the multibarrel glass micropipettes, two barrels were filled with 3 M NaCl; two barrels were
filled with GABA (0.25 M, pH 4.0-4.5) and with the beta
adrenergic agonist ISO (0.25 M, pH 4.0-4.5), respectively; and the
final barrel was filled with one of the test compounds: 1 mM, 100 µM and 10 µM Sp-cAMPS (pH 7.0-7.4 in saline, Calbiochem), 100 µM FORSK (pH 7.0-7.4 in 4% DMSO, Calbiochem, San Diego, CA), 100 µM
DIDEOXY (pH 7.0-7.4 in 4% DMSO, Calbiochem) or 1 mM 7-FORSK (pH
7.0-7.4 in saline, Calbiochem). All test compounds were delivered via pressure ejection except for GABA and ISO, which were
delivered by iontophoresis. A constant-current source provided ejection and retaining currents for the drug barrels and passed an equal current
of opposite polarity through the balance barrel to neutralize the tip
potential (Salmoiraghi and Weight, 1967). Uniform pulses of drug were
applied at regular intervals (Freedman et al., 1975).
Current was adjusted until GABA produced a 10% to 40% inhibition of
Purkinje cell firing. The dose of GABA was recorded, and at least four
applications were given before ISO was coadministered. The level of ISO
was adjusted until a change in GABA-induced Purkinje cell inhibition
was seen or until base-line Purkinje cell firing rate altered, thus
ensuring that drug was being ejected from the pipette. The ISO was then
administered continuously, and four samples of GABA with ISO were
taken. After the fourth sample, ISO was turned off, and GABA was
administered until recovery of the pre-ISO level of GABAergic
inhibition was observed. Once the pre-ISO level of GABAergic inhibition
returned, either FORSK or Sp-cAMPS was tested in an identical manner.
Only cells in which the post-test level of GABAergic inhibition matched
the pretest level of GABAergic inhibition were analyzed. To control for
order effects, sometimes the test compound was given before ISO. The order of presentation did not alter the response. The young rats (3 months old) served primarily as controls for the test compounds. We
were not concerned about the ISO response in the young rats because it
has been established in numerous experiments (in young rats, ISO
increases GABAergic inhibition in ~70-80% of Purkinje cells
recorded; Lin et al., 1993; Bickford, 1993; Parfitt et
al., 1990). The test compounds FORSK, 7-FORSK and Sp-cAMPS were
assessed in the young rats to establish the appropriate dose with which to increase GABAergic inhibition similar to that seen with ISO and to
provide control data for comparison with the aged rats. Administration
of the DIDEOXY compound (the inactive form of FORSK) was used as a
control for effects of FORSK unrelated to activation of AC and for the
effects of the vehicle.
For all data collected, drug-induced responses were quantified by
computer. The ratemeter data were digitized ,and the percent inhibition
of firing rate resulting from drug applications was calculated (Palmer
and Hoffer, 1980). The four responses to GABA before, during and after
ISO, FORSK or Sp-cAMPS were averaged and expressed as mean ± S.E.M. For analysis, cell responses were classified as either a
drug-induced increase in inhibition (15% increase), decrease in
inhibition (15% decrease) or no change in inhibition (<15%
increase and <15% decrease). Once the data were grouped,
2 analysis was used to detect differences between the
conditions.
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Results |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Young Rats
In young rats, Sp-cAMPS (21 cells), FORSK (22 cells) and
7-FORSK (12 cells) augmented GABAergic inhibition of Purkinje cell firing. As can be seen in figure 1, local application of
GABA onto Purkinje neurons elicits a decrease in spontaneous firing rate. The current was adjusted so that GABA application produced 40%
inhibition of cell firing rate; as shown in figure 1E, Sp-cAMPS is
concurrently applied by pressure microejection, and the GABAergic inhibition is augmented from 40% to 70% inhibition while spontaneous firing rate is unaltered. This is an effect similar to that observed with ISO as shown in figure 1, A and B. In young rats, this effect of
Sp-cAMPS to increase GABAergic inhibition was observed in 83% of the
cells tested. On average, the GABAergic inhibition was augmented by
26% (table 1). At a barrel concentration of 100 µM,
Sp-cAMPS was most efficient at increasing GABAergic inhibition of the
Purkinje cell. Barrel concentrations of 10 µM, 1 µM and 500 nM
Sp-cAMPS were ineffective in increasing GABAergic inhibition. A higher
barrel concentration of 1 mM Sp-cAMPS was also ineffective because in
76.9% of the cells recorded with this concentration, application of
Sp-cAMPS alone decreased spontaneous rates, so the effect on GABAergic
inhibitions could not be assessed.
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Application of FORSK augmented GABAergic inhibitions in 59.1% of the
cells tested. Applications of 7-FORSK produced an increase in
GABAergic responses in 75% of the cells tested. A summary of the
applications used is given in table 1. FORSK (100 µM barrel concentration) was found to be most effective in young
rats.2 In young rats, the percent change in
GABA inhibition when averaged over the entire population of cells
examined was only 12.2%. This was due to the fact that a number of
cells showed a decrease in GABA response as high as 47% during FORSK
application. Thus, when cells showing decreases in response are
averaged with cells showing increases, the percent change for the
population is lowered even though a majority of the cells showed an
increase in GABAergic inhibition. 7-FORSK (100 µM barrel
concentration) produced effects similar to those observed with FORSK
(100 µM) (table 1).
In 3 young rats, 20 cells were recorded using DIDEOXY. This form of FORSK does not activate AC and thus served as a control. Use of the DIDEOXY produced no increase in GABAergic inhibition of Purkinje cells; however, a change in base-line firing rate was observed, indicating that drug was being ejected from the barrel. The average inhibition with GABA (average application, 17.3 ± 3.1 nA) was 35.1 ± 2.4%, and the average inhibition of GABA with DIDEOXY (average application, 19.5 ± 2.0 psi) was 27.9 ± 3.2%.
Aged Rats
FORSK and 7-FORSK.
The effect of FORSK to augment GABAergic
inhibitions was next tested in 18- to 21-month-old F344 rats. FORSK
(100 µM barrel concentration) was ineffective at augmenting GABAergic
inhibitions as seen in table 1. Only 10.7% of the cells tested showed
a >15% increase in GABAergic inhibition during FORSK application. A
similar result was observed with ISO when it was tested on the same
neurons. Isoproterenol produced an increase in GABAergic inhibition in only 25% of the cells tested (28 cells). Using a 2 test
to examine differences in the ability of FORSK to increase GABAergic
inhibition between young and old rats, it was found that the
percentages of cells that increased, decreased or had no change in GABA
response during FORSK in the two groups were significantly different
[2(1) = 4.71, P < .05; fig. 2].
More cells from the young rats showed increased GABAergic inhibition in
the presence of FORSK than did cells from the old rats. Also, 35.7% of
the cells in the aged rats tested with 100 µM FORSK showed a 15%
decrease in GABAergic inhibition. This is similar to what is commonly
observed when testing with ISO in aged rats. Thus, 100 µM FORSK,
comparable to ISO, did not augment GABAergic inhibition in aged rats.
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-FORSK (1 mM barrel concentration). Applications of
7-FORSK elicited an augmentation of GABAergic inhibition in 29.6%
of 27 cells tested, and applications of ISO on the same cells increased
GABAergic inhibitions in 11.1% of the cells. Thus, 7-FORSK at 1 mM
barrel concentration did not increase GABAergic inhibition of Purkinje
neurons.
In addition to comparing the number of cells in each category of
response, the application pressures and currents can be compared between ages. There was no difference between groups with respect to
either the current used to elicit GABA responses or the percent change
in Purkinje cell firing elicited by the application of GABA. In the
aged rats, higher application pressures were used for 100 µM FORSK
[t(48) = 2.06, P < .05]. The application pressures were limited by the effects of FORSK on spontaneous firing rate, which
were observed at the maximal application pressures tested. Even at
these maximal pressures, no increase in GABAergic inhibition was
observed.
Sp-cAMPS.
Three barrel concentrations of Sp-cAMPS were
tested in the aged rats. As can be seen in figure 3, 10 µM Sp-cAMPS increased GABAergic inhibition in none of the cells
tested (12 cells; 5 rats). Of 40 cells recorded with the 100 µM
barrel concentration, Sp-cAMPS augmented GABAergic inhibition in 20%
of the cells. At the 1 mM barrel concentration, Sp-cAMPS increased
GABAergic inhibition in 52.5% of the 32 cells recorded. The aged 1 mM
Sp-cAMPS group was significantly different from the aged 100 µM group
[2(3) = 11.77, P < .01]. As a comparison, 100 µM Sp-cAMPS increased GABAergic inhibition in 83% of the cells
recorded from young rats (fig. 3). The application pressures used
between young and aged rats were similar, as can be seen in table 1.
The percent change in GABA inhibition, however, was different at the
100 µM barrel concentration between young and aged rats (P < .01, two-tailed t test). In addition, 25.0% of the cells
from aged rats tested with 100 µM Sp-cAMPS showed a decrease in
GABAergic inhibition. Again, this decrease is commonly seen when
testing with ISO in aged rats.
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2(1) = 7.22, P < .01].
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-FORSK at either 100 µM
or 1 mM barrel concentration was coapplied with Sp-cAMPS at barrel
concentrations of 10 to 100 µM, only 3% of cells showed an increase
in GABAergic inhibition; rather, a decrease in GABAergic inhibition was
observed in 71% of the cells (n = 38). This suggests
that the interaction of ISO and Sp-cAMPS may not be mediated
via an activation of adenylate cyclase.
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Discussion |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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In aged rats, ISO is unable to increase GABAergic inhibition of
Purkinje cell firing. This has been demonstrated in other studies
(Bickford, 1993; Gould et al., 1995; Gould and Bickford, 1994) and in the present study. The age-related deficits in cerebellar beta adrenergic function could occur at several points along
the beta adrenergic second-messenger cascade. To examine
where the age-related deficits occur, we used FORSK and Sp-cAMPS in
aged rats to attempt activation of the beta adrenergic
signal transduction cascade during GABAergic inhibition. The three
major findings of our study were as follows: (1) FORSK was ineffective
in activating the beta adrenergic cascade in aged rats, (2)
there was a decrease in Sp-cAMPS activation of the beta
adrenergic cascade in aged rats and (3) ISO and Sp-cAMPS appear to act
synergistically in activating the beta adrenergic cascade in
the aged rats. This was not observed with FORSK.
In the present study, FORSK was unable to increase GABAergic inhibition
of Purkinje cell firing in old rats, suggesting a problem at or beyond
the level of AC stimulation. This is in agreement with other literature
that has shown age-related decreases in FORSK binding in the cerebellum
(Araki et al., 1995) and striatum (Hara et al.,
1992; White et al., 1994). Hormone-stimulated cerebellar AC
activity is decreased in aged rats (Schmidt and Thornberry, 1978), and
decreases in FORSK stimulated AC have been reported in the striatum
(Puri and Volicer, 1977). However, no age-related change was observed
in basal or NaF-stimulated AC activity in striatum (Puri and Volicer,
1977) and cerebral cortex (Zimmerman and Berg, 1975). In this study,
Sp-cAMPS was effective in aged rats; thus, the question arises of why
increased concentrations of FORSK did not result in an increase in
GABAergic inhibition. One possible explanation is that there is a
decrease in FORSK binding sites, with no underlying change in enzyme
activity. Our data and those cited above cannot be used to determine
whether the observed effect is due to a decrease in the ability of
FORSK to bind to and thus activate AC or to a change in enzyme activity or enzyme levels. The data demonstrating no change in basal and NaF-stimulated AC activity might indicate that the deficit is in the
effect of FORSK to activate AC. This may also explain why ISO and
Sp-cAMPS could interact synergistically and FORSK and Sp-cAMPS could
not.
In contrast to the results with FORSK, Sp-cAMPS increased GABAergic
inhibition in both young and aged rats. The ability of Sp-cAMPS to
activate the beta adrenergic signal transduction cascade in
aged rats was dose dependent. In young rats, 100 µM was as effective
as ISO at increasing GABAergic inhibition, but in aged rats, 100 µM
was ineffective; 1 mM Sp-cAMPS was the more effective barrel
concentration. The results with Sp-cAMPS suggest that there is an
age-related deficit in PKA activation. This is in agreement with the
literature that has shown an age-related decrease in cAMP-stimulated
protein kinase activity in bovine cortex (Reichlmeier, 1976). No
age-related change in [3H]cAMP binding (presumed to be
reflective of PKA) was found in cerebellum, but decreased binding was
found in the cerebral cortex of aged gerbils (Hara et al.,
1992).
The data from Sp-cAMPS, however, did provide a surprising result in that when applied concurrently, Sp-cAMPS and ISO increased GABAergic inhibition in the aged rats. This was quite unexpected because ISO normally does not increase cerebellar GABAergic inhibition in aged rats. This effect was also in contrast with the age-related deficit in beta adrenergic function observed during testing with FORSK (i.e., ISO did not increase GABAergic inhibition when FORSK was present in the micropipette). In addition, when FORSK was concurrently applied with Sp-cAMPS, an augmentation of GABA was not observed. Although an explanation for this phenomenon has not been demonstrated in this report, it is possible that the interaction of ISO and Sp-cAMPS in the aged rats may not need activation of AC as an intermediate. In support of this, FORSK and Sp-cAMPS did not interact to produce similar results. However, an alternate explanation, as described above, is that FORSK is inactive in the aged rats due to a change in the ability of this compound to bind to AC; this does not, however, explain why ISO is less active in the aged rats.
In addition to the changes discussed above, the beta
adrenergic signal transduction cascade seems to have multiple sites
that are susceptible to age-related damage and shows regional
variability in the part of the cascade affected by aging. No changes in
cerebellar levels of NE were found in aged rats (Bickford et
al., 1992; McIntosh and Westfall, 1987). Changes in
beta adrenergic receptor binding, however, are seen with
aging. Decreased binding of the nonselective beta adrenergic
antagonist pindolol was seen with aging in the cerebellum, thalamus and
brainstem, but no changes were seen in cortex and hippocampus of F344
rats (Miller and Zahniser, 1988). When cerebellar beta-1 and
beta-2 adrenergic receptor subtypes were examined
individually, the beta-2 receptor density was decreased, but
beta-1 receptor density was increased with aging in
Sprague-Dawley rats (Pittman et al., 1980). We observed
subsensitivity to the beta-1 receptor subtype when examining
responses electrophysiologically (Parfitt and Bickford-Wimer, 1990);
thus, this increase in beta-1 adrenoceptors may be an
attempt to up-regulate in response to an apparent deafferentation due
to downstream deficits in signal transduction.
Results from studies of age-related changes in PDE levels have also
been mixed. In cerebral cortex and striatum, an age-related decrease in
PDE levels was reported (Puri and Volicer, 1977; Zimmerman and Berg,
1974), but another study reports increased levels of cerebral cortical,
hypothalamic and hippocampal PDE levels with age (Stancheva and Alova,
1991), and another study found no age-related change in superior
cervical ganglion PDE levels (Giorgi et al., 1994).
Likewise, age-related changes in levels of cAMP may be region specific.
No change in striatal levels of cAMP were found (Puri and Volicer,
1977), but numerous studies have reported age-related declines in cAMP.
Decreased basal and stimulated cAMP levels were found in cerebral
cortex (Berg and Zimmerman, 1975; Zimmerman and Berg, 1974).
Interestingly, it was demonstrated that the loss of beta
adrenergic binding does not correlate with decreased NE-stimulated cAMP
levels in aged rats (Maggi et al., 1979), which indicates that the deficit may not be at the receptor itself but rather at
another point along the cascade. Furthermore, it was shown that
compared with young rats, Purkinje cells from aged rats were less
sensitive to locally applied N6-cAMP (Marwaha et
al., 1981). The authors concluded that the age-related deficit in
adrenergic function was at or beyond cAMP generation. Our results
suggest that an age-related deficit occurs between AC and PKA
activation, which corresponds with findings of decreased cAMP levels
with aging. One additional locus for an age-related difference is at
the level of the GABA receptor. Subunit composition of the receptor may
influence the effect of phosphorylation because phosphorylation has
been demonstrated to either increase or decrease the function of the
receptor (Cheun and Yeh, 1991; Leidenheimer et al., 1991a,
1991b; Sweetnam et al., 1988) Thus, an age-related change in
the phosphorylation sites or subunit composition of the
GABAA receptor may be an additional mechanism for the
age-dependent decline in the ISO-induced increase in GABA-induced
inhibitions.
In conclusion, the present study demonstrated that FORSK stimulation of cerebellar AC in aged rats will not activate the beta adrenergic signal transduction cascade but that stimulation of PKA with Sp-cAMPS will activate the system, although higher doses of agonist are required in aged rats. These findings suggest that an age-related deficit in the cerebellar beta adrenergic system occurs at the level of PKA activation and that additional changes may also occur at the level of AC; these results do not rule out changes at other levels of the signal transduction cascade. Further experimental testing is required to resolve these issues.
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Footnotes |
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Accepted for publication January 23, 1997.
Received for publication June 10, 1996.
1 This work was supported by United States Public Health Service Grants AG04418 (P.C.B.) and AG05686 (T.J.G.) and the Department of Veterans Affairs; Medical Research Service (P.C.B.).
2 Dr. Ronald Freund, personal communication.
Send reprint requests to: Dr. Paula C. Bickford, Department of Pharmacology, C-236, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, CO 80262. E-mail: Paula.Bickford{at}UCHSC.EDU
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Abbreviations |
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NE, norepinephrine;
GABA, -aminobutyric
acid;
AC, adenylyl cyclase;
cAMP, cyclic adenosine-3,5-monophosphate;
ISO, isoproterenol;
FORSK, forskolin;
PDE, phosphodiesterase;
PKA, protein kinase A;
Sp-cAMPS, adenosine-3,5-cyclic monophosphothioate
sp-isomer;
DIDEOXY, 1,9-dideoxy-forskolin;
7-FORSK, 7-decacetyl-7-(-N-methylpiperazino)butyryl-forskolin;
DMSO, dimethylsulfoxide;
F344, Fischer 344.
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References |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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3: 33-36, 1974[Medline].This article has been cited by other articles:
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J. A. Joseph, B. Shukitt-Hale, N. A. Denisova, D. Bielinski, A. Martin, J. J. McEwen, and P. C. Bickford Reversals of Age-Related Declines in Neuronal Signal Transduction, Cognitive, and Motor Behavioral Deficits with Blueberry, Spinach, or Strawberry Dietary Supplementation J. Neurosci., September 15, 1999; 19(18): 8114 - 8121. [Abstract] [Full Text] [PDF]
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J. A. Joseph, B. Shukitt-Hale, N. A. Denisova, R. L. Prior, G. Cao, A. Martin, G. Taglialatela, and P. C. Bickford Long-Term Dietary Strawberry, Spinach, or Vitamin E Supplementation Retards the Onset of Age-Related Neuronal Signal-Transduction and Cognitive Behavioral Deficits J. Neurosci., October 1, 1998; 18(19): 8047 - 8055. [Abstract] [Full Text] [PDF]
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G. F. Reis, M. B. Lee, A. S. Huang, and K. D. Parfitt Adenylate Cyclase-Mediated Forms of Neuronal Plasticity in Hippocampal Area CA1 Are Reduced With Aging J Neurophysiol, June 1, 2005; 93(6): 3381 - 3389. [Abstract] [Full Text] [PDF]
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