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1Departments of Physiology and Pharmacology, 2Roena Kulynych Center for Memory and Cognition Research, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, North Carolina
Submitted 28 July 2004; accepted in final form 2 March 2005
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate (AMPA) but not N-methyl-D-aspartate receptors. Furthermore, the enhancement was completely blocked by the broad-spectrum tyrosine kinase inhibitor, genistein (220 µM), and significantly reduced by the PI3K blockers wortmannin (1 µM) and 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (10 µM), suggesting that the effect was predominantly dependent on PI3K activation. This characterization of the acute actions of des-IGF-1 at hippocampal excitatory synapses may provide insight into the mechanism by which long-term increases in plasma IGF-1 impart cognitive benefits in aged rats. Increases in AMPA receptor-mediated synaptic transmission may contribute directly to cognitive improvement or initiate long-term changes in synthesis of proteins such as brain-derived neurotrophic factor that are important to learning and memory. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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; Baserga et al. 2003; Giovannucci 2003; Greenlund and Nair 2003; Yakar et al. 2002). However, >20 yr ago, it was revealed that elderly individuals experience a decline in the ability to secrete growth hormone in response to several stimuli, including insulin-induced hypoglycemia and arginine administration (Laron and Rosenberg 1970). Subsequent studies revealed a loss of the nocturnal surges of growth hormone (Carlson et al. 1972; Finkelstein et al. 1972) and a decrease in plasma IGF-1 concentrations that paralleled the decline in growth hormone pulses (Johanson and Blizzard 1981; Rudman et al. 1981). These early studies in humans have been extended to other mammals (Florini et al. 1981; Sonntag et al. 1980), and today the decline in high-amplitude growth hormone secretion and plasma IGF-1 concentrations are some of the most robust and well-characterized endocrine alterations that occur with age.
In an effort to address whether age-related downregulation of growth hormone and IGF-1 have physiological consequences, investigators have administered growth hormone to aged animals and humans. These studies revealed that age-related decreases in lean muscle mass, bone mass, immune function, and skin thickness are ameliorated by growth hormone administration (Andersen et al. 2000; Davila et al. 1987; Rudman et al. 1990; Sonntag et al. 1985; Sugimoto et al. 2002). However, the effects of growth hormone replacement on the aging brain are only beginning to be understood. Although investigators debate the cognitive benefits of growth hormone replacement in aged humans, studies using the Morris water maze have demonstrated that treatment with growth hormone releasing hormone (GHRH) from 9 to 30 mo of age prevents age-related cognitive decline in aged Brown Norway x F344 rats (Thornton et al. 2000). In a similar study, 28-day intracerebroventricular (i.c.v.) infusion of IGF-1 attenuated age-related memory deficits (Markowska et al. 1998). More recently, we observed that aged (28 mo-old) Brown Norway x Fisher rats demonstrate impairments in spatial learning compared with adult (8-mo-old) animals, and that 4-mo systemic treatment with porcine growth hormone attenuates these impairments (Ramsey et al. 2004).
While the mechanism by which upregulation of growth hormone and IGF-1 benefits learning and memory in aged rodents is unknown, administration of growth hormone for 28 days was found to increase microvascular density in aged animals (Sonntag et al. 2000b). Furthermore, 28-day i.c.v. infusion of IGF-1 to aged Brown Norway x F344 rats increases hippocampal N-methyl-D-aspartate receptor subunits 2A and 2B (NMDA R2A and R2B) subunit expression (Sonntag et al. 2000a), a finding made especially important by a report by Clayton et al. (2002) that ablation of R2B subunit abolishes hippocampal long-term potentiation (LTP) and impairs spatial learning in young animals. Twenty-eight-day IGF-1 treatment also increased rates of local cerebral glucose utilization, a function believed to be correlated with neuronal activity (Lynch et al. 2001). Furthermore, administration of IGF-I to old rats ameliorates the decline in hippocampal neurogenesis associated with aging (Lichtenwalner et al. 2001) and increases the complexity of hippocampal synapses (Shi et al. 2005).
Although the aforementioned studies provide some insights into long-term mechanisms by which upregulation of growth hormone and IGF-1 may improve learning and memory, few studies have focused on the acute effects of IGF-1 in the mammalian brain. The goal of the current study was to assess the acute actions of IGF-1 in the hippocampus, a brain region recognized as an important contributor to learning and memory (reviewed in Gallagher and Rapp 1997). The current study demonstrates that des-IGF-1, an analog of IGF-1 that does not interact with IGF-1 binding proteins (Clemmons et al. 1992), acutely enhances AMPA receptor-mediated hippocampal excitatory transmission via a postsynaptic mechanism. Our findings may offer important clues to the early changes underlying the cognitive benefits of growth hormone/IGF-1 treatment in aged animals.
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METHODS |
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Male Sprague-Dawley rats (20–40 days old) were anesthetized with halothane and killed by decapitation according to a protocol approved by the Institutional Animal Care and Use Committee of Wake Forest University School of Medicine. Coronal hippocampal slices (400 µm) were prepared using a vibrating tissue slicer (Leica VT1000S; Vashaw Scientific, Atlanta, GA). Slices were then maintained at room temperature in oxygenated artificial cerebrospinal fluid (ACSF) containing (in mM) 124 NaCl, 3.3 KCl, 2.4 MgCl2, 2.5 CaCl2, 1.2 KH2PO4, 10 D-glucose, and 25.9 NaHCO3, saturated with 95% O2-5% CO2. During recordings, slices were perfused with oxygenated ACSF at a flow rate of 2 ml/min.
Drug preparation
Drugs used in the pharmacological isolation of evoked currents included the NMDA receptor antagonist D-(–)-2-amino-5-phosphonovaleric acid (APV), the GABAA receptor antagonist bicuculline methylbromide (BIC), and the AMPA/KA receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX) (all from Sigma, St. Louis, MO). DNQX was prepared as a stock solution in dimethyl sulfoxide (DMSO; final concentration DMSO <0.05%). APV and BIC were prepared as stock solutions in deionized water.
Human des(1–3)-IGF-1 (Gropep, Thebarton, South Australia) was prepared as a stock solution in 0.1 N glacial acetic acid (final concentration 0.1 N acetic acid <0.005%). Des-IGF-1 was used in these experiments to avoid interactions with IGF binding proteins (Clemmons et al. 1992) that normally sequester circulating IGF-1. Drugs used to examine the signaling components involved in IGF-1-mediated effects were the broad-spectrum tyrosine kinase inhibitor, genistein, phosphoinositide 3-kinase (PI3K) inhibitors, wortmannin and 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY 294002). These inhibitors were made up as stock solutions in dimethyl sulfoxide (DMSO; final concentration DMSO <0.05%). During recordings, all drugs were applied through the ACSF in known concentrations via calibrated syringe pumps (Razel; Stamford, CT).
Patch-clamp recordings
Methods for whole cell recordings were similar to those reported previously (Crowder et al. 2002). Briefly, electrodes were prepared from filamented borosilicate glass capillary tubes (0.86 mm ID) using a horizontal micropipette puller (Sutter P-97; Sutter, Novato, CA). Electrodes were filled with a recording solution containing (in mM) 130 K-gluconate, 10 KCl2, 5 N-(2,6-dimethyl-phenylcarbamoylmethyl)-triethylammonium bromide (QX-314), 1 ethylene glycol-bis-(
-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), 0.1 CaCl2, 2 Mg-ATP, 0.2 tris-GTP, and 10 HEPES (free acid). Whole cell patch-clamp recordings were made at room temperature from CA1 pyramidal neurons. AMPA-mediated excitatory postsynaptic currents (EPSCs) were recorded from neurons voltage clamped at –70 mV in the presence of APV and BIC. NMDA-mediated EPSCs were recorded from neurons voltage clamped at –30 mV (to reduce the voltage-dependent magnesium block on the channel) in the presence of DNQX and BIC. Unless otherwise indicated, synaptic currents were evoked every 20 s by electrical stimulation (0.2-ms duration) of tissue adjacent to the recording electrode using a concentric bipolar stimulating electrode (FHC, Bowdoinham, ME). In one experiment, AMPA (10 µM) was applied directly to the soma of CA1 pyramidal neurons using a Picospritzer III (General Valve, Fairfield, NJ). Recordings were acquired with an Axoclamp 2B amplifier, digitized (Digidata 1200B; Axon Instruments, Foster City, CA) and analyzed on- and off-line using an IBM compatible PC computer and pClamp 8.0 software (Axon Instruments, Foster City, CA).
Field recordings
Field excitatory postsynaptic potentials (fEPSPs) were obtained using the same equipment and under the same conditions as those described for patch-clamp recordings, except the recording electrodes were placed in the apical dendritic field (stratum radiatum). Stimulation was adjusted to elicit 
30% of the maximal slope prior to des-IGF-1 application.
Statistics
Des-IGF-1 effects on the amplitude of EPSCs (pA) and slope of fEPSPs (mV/ms) were defined as percent of control (predrug) values. Concentration-response curves were analyzed by one-way ANOVA (concentration) followed by the Newman-Keuls test for pairwise comparisons, where appropriate. Paired Student's t-test were used to compare des-IGF-1 effects with predrug values. Inhibitor effects on des-IGF-1-mediated changes in fEPSP slope were analyzed by one-way ANOVA (inhibitor) followed by Dunnett's post hoc test for comparison to des-IGF-1 alone. Statistical significance was defined as P < 0.05.
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RESULTS |
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Application of des-IGF-1 for 15 min resulted in a concentration-dependent increase in the slope of CA1 fEPSPs by 39 ± 6% (Fig. 1A). At a concentration of 40 ng/ml, the des-IGF-1-induced potentiation was initiated within 5 min of the start of des-IGF-1 application and partially recovered during a 15-min washout period (n = 10; Fig. 1A). The synaptic response remained significantly increased compared with pre-des-IGF-1 baseline values (15 ± 4%; P < 0.01). The potentiation reached statistical significance at 
10 ng/ml (n 7). A statistically significant difference in the magnitude of the potentiation was observed between responses at 5 and 20 ng/ml (P < 0.02) as well as between 5 and 40 ng/ml (P < 0.04). The response reached a plateau at 20 ng/ml suggesting a maximum possible potentiation of 40% (Fig. 1B).
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We performed two complementary experiments using whole cell patch recordings of CA1 pyramidal neurons to determine whether des-IGF-1 enhanced AMPA-mediated synaptic transmission via a pre- or postsynaptic mechanism. In the first experiment, we examined whether des-IGF-1 application altered the release probability for glutamate by determining the effect of des-IGF-1 on paired-pulse facilitation (PPF) of pharmacologically isolated AMPA EPSCs. Two stimuli were paired with an interstimulus interval of 50 ms such that the second EPSC (peak 2) was potentiated by the first EPSC (peak 1). We then calculated the ratio of peak 2/peak 1 in the absence and presence of 40 ng/ml des-IGF-1. The average amplitudes of both peaks 1 and 2 were increased by the application of des-IGF-1, and the paired-pulse ratio was not significantly altered (n = 8; Fig. 2).
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We utilized whole cell patch-clamp recordings in the CA1 pyramidal layer to determine which receptor system(s) were responsible for the enhancement of fEPSPs by des-IGF-1. A 15-min application of des-IGF-1 (40 ng/ml) increased the amplitude of pharmacologically isolated AMPA EPSCs by 34 ± 7% (n = 10), a change that reached statistical significance (P < 0.05). In contrast, des-IGF-1 application did not significantly enhance pharmacologically isolated NMDA EPSCs (n = 7; Fig. 4).
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To gain insight into which elements in the IGF-1 receptor signaling cascade are responsible for the observed enhancement of CA1 fEPSPs and EPSCs, we treated hippocampal slices with the broad-spectrum tyrosine kinase inhibitor, genistein (220 µM), or the PI3K inhibitors, wortmannin (1 µM) or LY 294002 (10 µM), for 20 min prior to and continuing throughout des-IGF-1 application (40 ng/ml). A des-IGF-1-mediated potentiation was not observed in the continuous presence of genistein (n = 6) (Fig. 5, A and D). In fact, fEPSP slope significantly decreased during des-IGF-1 application (P < 0.01) but did not recover on cessation of hormone application. In addition, genistein inhibited fEPSP slope to the same extent in the absence of des-IGF-1 application (genistein + des-IGF-1: 38 ± 6% inhibition, genistein alone: 40 ± 5% inhibition, P > 0.05, data not shown). Therefore we attributed the apparent inhibition to an independent effect of genistein on excitatory transmission (Fig. 5, A and D). Pretreatment with wortmannin (n = 5) or LY 294002 (n = 6) significantly reduced des-IGF-1-mediated potentiation of fEPSP slope (wortmannin: 14 ± 2% potentiation; LY 294002: 7 ± 5% potentiation; Fig. 5, B–D) and application of either of these PI3K inhibitors alone for 20 min had no significant effect on fEPSP slope (wortmannin: 9 ± 6%, n = 5; LY 294002: 5 ± 7%, n = 4, data not shown).
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DISCUSSION |
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35% but had no effect on EPSCs mediated by NMDA receptors. Finally, experiments using inhibitors of downstream effectors of the IGF-1 receptor demonstrated that the acute effects of des-IGF-1 on excitatory transmission in the CA1 region were tyrosine-kinase-dependent and predominantly mediated by PI3K. Thus activation of AMPA receptors represents one of the earliest neuronal effects of IGF-1 and could potentially initiate many of the long-term effects of this peptide on brain function.
This study follows several other investigations into acute IGF-1 action in brain tissues. External application of IGF-1 (50 ng/ml) induced an attenuation of AMPA receptor-mediated currents via increased AMPA receptor internalization but had no effect on NMDAR-mediated currents in cultured cerebellar granule neurons (Wang and Linden 2000). However, acute in vitro application of IGF-1 (75 ng/ml) potentiated kainate receptor-mediated currents via a PI3K-dependent mechanism in the same cell type (Gonzalez et al. 2001). Additionally, Nunez et al. (2003) reported that systemic administration of IGF-I (10 µg) elicited a prolonged increase in the excitability of dorsal column nuclei (DCN) cells in vivo. The same group observed that in a slice preparation, IGF-I (75 ng/ml) induced a sustained depolarization of 2–5 mV in 81% of DCN neurons and increased evoked EPSP peak amplitude and rising slope by a presynaptic process dependent on MAPK activation (Nunez et al. 2003). These studies demonstrate the diverse electrophysiological actions of IGF-1 and suggest that the effects of IGF-1 on excitatory neurotransmission may differ with respect to brain region.
The des-IGF-1-mediated enhancement that we observed at hippocampal excitatory synapses is consistent with the known actions of some other growth factors, though specific mechanisms of action may differ. Like IGF-1, BDNF and other neurotrophins act over hours or days to promote neuronal differentiation and survival but are able to exert critical effects on synaptic transmission and plasticity within minutes. Neurotrophins bind to one of three receptors in the trk family, which, like IGF-1 receptors, possess tyrosine kinase activity. Trk and IGF-1 receptors also share many downstream effectors including ras and MAPK, PI3K, and Akt, as well as the adaptor proteins shc and Grb2 (Friedman and Greene 1999). Several groups have reported that acute application of BDNF to hippocampal slices increases the strength of glutamatergic synaptic transmission at Schaffer collateral-CA1 synapses (Kang and Schuman 1995; Scharfman 1997). Other work in hippocampal neuronal cultures has suggested that BDNF acts presynaptically to enhance AMPA receptor-mediated currents (Lessmann et al. 1994). Our current findings suggest that des-IGF-1 acts postsynaptically to facilitate AMPAR-mediated synaptic transmission. The acute actions of des-IGF-1 at AMPA receptors may complement the long-term alterations in NMDAR composition to augment excitatory processes.
Our results demonstrate a postsynaptic and AMPAR-specific mechanism for acute enhancement of CA1 fEPSPs and EPSCs by des-IGF-1. However, there are many possible mechanisms by which des-IGF-1 may increase AMPA-mediated synaptic transmission. These include changes in the activity of cellular machinery responsible for endocytosis and exocytosis of AMPARs, which regulates synaptic strength by influencing the number of AMPARs at the synapse (Esteban 2003; Malinow et al. 2000; Zamanillo et al. 1999). For instance, des-IGF-1 application may alter the activity of N-ethylmaleimide-sensitive fusion protein (NSF), glutamate receptor AMPAR binding protein (GRIP), protein interacting with C-kinase-1 (PICK1), or stargazin, which are involved in synaptic targeting, surface translocation, and anchoring of AMPA receptors in the plasma membrane (Dong et al. 1997; Osten et al. 2000; Rothman 1994; Schnell et al. 2002; Xia et al. 1999). Altered phosphorylation or any other change that increases the ability of these proteins to interact with AMPARs and one another may result in increased density of AMPARs in the synaptic membrane (Bredt and Nicoll 2003; Esteban et al. 2003). Des-IGF-1-mediated inhibition of endocytotic mechanisms may also cause an increase in surface expression of AMPA receptors consistent with potentiation of AMPA-mediated excitatory transmission. For example, alterations in the function of clathrin may hinder removal of AMPARs from the membrane (Cremona and De Camilli 1997). Phosphorylation of GluR subunits directly or via downstream effectors of the IGF-1 signaling cascade may also regulate AMPA receptor trafficking. Activation of the IGF-1 receptor may also result in mobilization of calcium from intracellular stores and subsequent targeting of AMPA receptors to the synaptic membrane by mechanisms involving calcium-dependent enzymes (Barria et al. 1997a,b; Benke et al. 1998).
Although any of the aforementioned mechanisms of AMPA current enhancement could contribute to the observed potentiation by des-IGF-1, the partial dependence of the des-IGF-1-induced effect on PI3K is consistent with the established role of PI3K in membrane insertion of AMPARs during expression of LTP at CA1 synapses (Man et al. 2003; Sanna et al. 2002). Although the PI3K/Akt pathway is a well-documented cascade initiated by activation of the IGF-1 receptor (De Meyts et al. 1995; Zheng and Quirion 2004), future studies will determine whether the ras/MAPK branch of the IGF-1 receptor signaling pathway also contributes to enhancement of AMPAR currents.
Regardless of the intracellular signaling involved, the action of des-IGF-1 at hippocampal AMPARs presents an additional mechanism by which growth hormone and IGF-1 treatments may attenuate cognitive deficits in aged animals (Markowska et al. 1998; Thornton et al. 2000). In fact, a number of studies have suggested that positive AMPA receptor modulators improve learning and memory in laboratory animals (Davis et al. 1997; Granger et al. 1993; Hampson et al. 1998; Larson et al. 1995; Shors et al. 1995; Staubli et al. 1994). Furthermore, oral administration of the ampakine, CX516, improved recall of nonsense syllables in older humans (Lynch et al. 1997), and improved memory in healthy males 20 to 35 yr of age (Ingvar et al. 1997). We have confirmed that aged hippocampal tissue responds to acute des-IGF-1 exposure in a manner similar to young hippocampal tissue (M. M. Ramsey and J. L. Weiner, unpublished observations), which suggests that the current mechanistic findings may apply to the aged brain as well. It also provides additional evidence that the cognitive benefits imparted by growth hormone/IGF-1 replacement may be mediated, in part, by acute actions of IGF-1 in the aged hippocampus.
Although past behavioral studies in our laboratory have suggested that growth hormone/IGF-1-mediated cognitive improvements in aged rats are due to long-term changes, the acute enhancement of AMPAR-mediated currents, as observed here with des-IGF-1 application, may provide a direct contribution to learning and memory benefits. Furthermore, the acute effects of des-IGF-1 on AMPA receptor currents may initiate long-term changes that contribute to cognitive improvements. For example, AMPARs are crucial for the maintenance of long-term potentiation (LTP), and AMPAR activity can initiate the synthesis of peptides including BDNF (Lauterborn et al. 2003; Legutko et al. 2001; Mackowiak et al. 2002), a growth factor required for hippocampal LTP (Korte et al. 1995; Patterson et al. 1996). In fact, Xiong et al. (2002) reported that AMPA receptor activity is required for induction of BDNF by NT-4/5 (Xiong et al. 2002). Additionally, AMPA receptor activation increases energy demand in the CA1 region via depolarization-induced activation of the Na+/K+-ATPase, which results in activation of oxidative phosphorylation and the TCA cycle (Kasischke et al. 2004). These acute actions of des-IGF-1 may complement long-term changes observed with IGF-1 treatment, including increases in the abundance of hippocampal NMDAR subunits 2A and 2B (Sonntag et al. 2000a), which may enhance NMDAR activity and facilitate LTP induction.
In summary, the current investigation characterized the acute action of des-IGF-1 on excitatory transmission in the CA1 region of rat hippocampus. We hypothesize that both acute and chronic elevations in plasma IGF-1 contribute to the improved cognitive performance in aged animals treated chronically with GHRH, growth hormone, or IGF-1. While a direct contribution of acute elevations in plasma IGF-1 to cognitive benefits has not been established, it is certain that acute actions of IGF-1, perhaps at AMPARs, initiate changes in protein expression and synaptic structure that, in turn, initiate long-term events resulting in learning and memory enhancement.
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FOOTNOTES |
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Address for reprint requests and other correspondence: J. L. Weiner, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC 27157-1083 (E-mail: jweiner{at}wfubmc.edu)
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, significant difference from response at 5 ng/ml (P < 0.05).
