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Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, Florida 32610
Submitted 1 December 2003; accepted in final form 29 January 2004
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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; Muller and Connor 1991; Sabatini et al. 2001; Svoboda et al. 1999; Wickens 1988; Yuste et al. 2000). Alternatively, intracellular Ca2+ can have distal influences due to the propagation of Ca2+ waves (Jaffe and Brown 1994; Kapur et al. 2001; Miller et al. 1996; Nakamura et al. 1999) or membrane effects that influence cell excitability and the integration of electrical potentials (Disterhoft et al. 1996; Foster and Kumar 2002; Johnston et al. 2003; Landfield and Pitler 1984; Norris et al. 1998a; Sah and Bekkers 1996). Several sources of intracellular Ca2+ are available, including ligand-gated glutamate receptors such as the N-methyl-D-aspartate (NMDA) receptors, voltage-dependent Ca2+ channels (VDCCs), and release from intracellular Ca2+ stores (ICS). It is generally accepted that, at CA1 synapses, NMDA receptors provide the foremost source of Ca2+ for LTP induction for stimulation frequencies near the threshold for synaptic modification (Cavus and Teyler 1996; Johnston et al. 1992). However, the level of Ca2+ in dendritic spines can be influenced by VDCCs, ICS, and other glutamate receptors (Christie et al. 1996a,b, 1997; Dingledine et al. 1999; Jaffe et al. 1994; Korkotian and Segal 1999). Recent studies have suggested that VDCCs and ICS are involved in regulating the threshold for induction of synaptic plasticity in young adult animals (Foster and Kumar 2002; Foster and Norris 1997; Kamsler and Segal 2003; Nishiyama et al. 2000; Norris et al. 1998a; Raymond and Redman 2002; Rose and Konnerth 2001; Wilsch et al. 1998).
The relationship between Ca2+ sources and synaptic plasticity thresholds is particularly relevant to studies of aging since changes in synapse modifiability have been linked to dysregulation of Ca2+ homeostasis (Foster and Kumar 2002; Foster and Norris 1997). Over the course of aging, there is a shift in the influence of VDCCs on the induction of synaptic plasticity, particularly for stimulation patterns that are near the threshold for synaptic modification (Foster 1999; Norris et al. 1998a; Shankar et al. 1998; Watabe and O'Dell 2003). In addition, L-channels are closely linked to the Ca2+-dependent, K+-mediated afterhyperpolarization (AHP) (Disterhoft et al. 1996; Kumar and Foster 2002; Landfield and Pitler 1984; Power et al. 2002; Thibault and Landfield 1996; Wu et al. 2002), and the increase in the AHP during senescence is associated with an increased threshold for LTP, possibly due to weakened synaptic integration (Kumar and Foster 2002; Norris et al. 1998a). Studies in neonate and juvenile animals indicate that Ca2+ release from ICS contributes to LTP induction for stimulation near the threshold for induction (Behnisch and Reymann 1995; Harvey and Collingridge 1992; Obenaus et al. 1989; Raymond and Redman 2002), possibly by contributing to Ca2+ levels in dendritic spines (Emptage et al. 1999; Nishiyama et al. 2000). However, ICS also contribute to the AHP (Shah and Haylett 2000), suggesting that this source of Ca2+ may be a factor in altered synaptic plasticity thresholds during aging. Thus this study was designed to investigate the role of ICS in mediating age-related changes in the threshold for LTP induction.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Procedures involving animal subjects have been reviewed and approved by Institutional Animal Care and Use Committee. Male Fischer 344 rats, young (5–8 mo; n = 20) and old (22–24 mo; n = 41), were group housed (1–2/cage), maintained on a 12:12 h light schedule, and provided ad libitum access to food and water.
Hippocampal slice preparation
Rats were killed with CO2, hippocampi were dissected, and slices (
400 µm) were cut parallel to the alvear fibers with a Vibratome (Technical Products International, St. Louis, MO). Slices were transferred to a standard interface-recording chamber that was continuously perfused (1 ml/min) with oxygenated artificial cerebrospinal fluid (ACSF) containing (in mM) 124 NaCl, 2 KCl, 1.25 KH2PO4, 2 MgSO4, 2 CaCl2, 26 NaHCO3, and 10 glucose. Slices were maintained at 30–32° C, and humidified air (95% O2-5% CO2) was blown over the slices.
Electrophysiological recordings
Extracellular synaptic field potentials from CA3–CA1 synaptic contacts were recorded with glass micropipettes (4–6M
) filled with ACSF. Stimulating electrodes (stainless steel, tip diameter 0.13 mm) were positioned on either side (1 mm) of a recording electrode localized to the middle of stratum radiatum, and single diphasic stimulus pulses were alternated between pathways such that each pathway was activated at 0.033 Hz. One stimulating electrode activated a control pathway used to insure that the effects of pattern stimulation were specific to activated synapses and not due to a change in slice health (Norris et al. 1996). Stimulation intensity was set to elicit a 1- to 2-mV excitatory postsynaptic potential (EPSP) response. Drug application to the slices occurred 
35–120 min prior to pattern stimulation, and stable response baseline in the presence of drug was collected for 20 min prior to delivery of pattern stimulation. Following pattern stimulation to induce synaptic modification, the response was recorded for 60 min (Norris et al. 1996, 1998a). Synaptic modification was induced by pattern stimulation (5 Hz, 900 pulses) delivered to the Schaffer collaterals. The signals were amplified, filtered between 1 Hz and 1 kHz, and stored on computer disk for off-line analysis (Data Wave Technologies, Longmont, CO). Two cursors were placed around the initial descending phase of the wave-form, and the maximum slope (mV/ms) of the EPSP was determined by a computer algorithm that found the maximum change across all sets of consecutively recorded points (20-kHz sampling rate) between the two cursors. Changes in transmission properties induced by pattern stimulation or application of drug were calculated as the percent change from the averaged baseline response collected 10 min prior to pattern stimulation or drug application.
Intracellular recordings were performed from CA1 pyramidal neurons to record AHPs and EPSPs. Microelectrodes were pulled from thin-wall 1.0-mm microfiber-filled borosilicate capillaries using a Flaming/Brown horizontal micropipette puller (Sutter Instruments, San Rafael, CA). The resistance of microelectrodes when filled with 3 M potassium acetate was 50–100 M. Microelectrodes were visually positioned in the CA1 pyramidal cell layer using a dissecting microscope (SZH10, Optical Elements Corp., Washington, DC). The signals were amplified by an Axoclamp 2B amplifier (Axon Instruments, Union City, CA), and recordings (continuous bridge mode) were sampled at 5 kHz and stored on computer disk for off-line analysis (Data Wave Technologies).
Only neurons with a resting membrane potential less than –57 mV, an input resistance >20 M, and an action potential amplitude rising 70 mV above the point of spike initiation were included in the analysis as described earlier (Kumar and Foster 2002). Resting membrane potential was maintained between –57 and –84 mV with current injection. Voltage deflections resulting from hyperpolarizing current pulses (100 ms, 0.2 nA) were used to determine input resistance. Depolarizing current pulses (100 ms, 0.1–0.6 nA) were delivered every 20 s through the intracellular electrode to elicit a sodium spike bursts of five to six action potentials. The AHPs in the control and experimental conditions were elicited at the same membrane potential by manually clamping the potential with DC current injection (0.1–0.5 nA). The AHP amplitude was measured as the difference between the membrane potential during the 100-ms period, immediately before the onset of the depolarizing current and the membrane potential 500 ms after the offset of the depolarizing current. The amplitude and duration of the AHP were compared before and during drug administration in the same cell. For each cell, several (>10) consecutive AHPs were measured in each experimental condition, and the values were averaged for data analysis or statistical comparison. To record the NMDA receptor-mediated component of CA3–CA1 synaptic transmission, slices were incubated in low extracellular Mg2+ (0.5 mM), 6, 7-dinitroquinoxaline-2,3-dione (DNQX, 30 µM), and picrotoxin (10 µM).
Cyclopiazonic acid (CPA, Tocris, Ballwin, MO), Bay K8644, thapsigargin, and DNQX (Sigma, St. Louis, MO) were initially dissolved in a small amount of dimethyl sulfoxide (DMSO) and diluted by ACSF to a final DMSO concentration of 0.001% and a final concentration of CPA, Bay K8644, thapsigargin, and DNQX of 3, 1, 1, and 30 µM, respectively. The metabotropic receptor antagonist, (s)-
-methyl-4-carboxyphenylglycine (MCPG, 500 µM, Tocris, Ballwin, MO), was initially dissolved in a small amount of 1 M NaOH (150 µl for 50 mg of MCPG) and further diluted with ACSF; pH was adjusted to 7.42 ± 0.2. Picrotoxin (Sigma) was initially dissolved in a small amount of ethanol and further diluted in ACSF to reach final concentration of 10 µM. FK506 (CalBiochem, La Jolla, CA) was initially dissolved in DMSO and diluted in potassium acetate (3 M) to a final DMSO concentration of 0.001% and FK506 of 50 µM. Ryanodine and AP-5 (Sigma) were dissolved directly in ACSF. Suitable precautions were taken to ensure that ryanodine was protected from exposure to light.
For synaptic plasticity studies, the mean percent changes in the slope of the extracellular synaptic response were measured 55–60 min after 5-Hz stimulation for both control and tetanized pathways. ANOVA, repeated across the two pathways, determined effects of patterned stimulation and age. Post hoc analyses were conducted using Scheffe tests, with significance set at P < 0.05. Where stated, n represents the number of slices used in each set of experiment.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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An episode of pattern stimulation (5 Hz, 900 pulses) produced an initial short-lasting (10 min) depression in slices from young (n = 10) and old (n = 18) rats, which returned to baseline over the next 60 min. The percent change for both age groups [young, 108.3 ± 3.9% (SE); old, 101.8 ± 2.4%] was not significantly different from their respective nontest pathway in either group, and the change in the synaptic response was not significantly different between young and old rats.
An age-dependent shift in susceptibility to LTP induction was observed following ICS depletion by thapsigargin. Pattern stimulation in presence of thapsigargin (1 µM) resulted in a significant increase in synaptic strength relative to the control (nontetanized) pathways [F(1, 15) = 9.85, P < 0.01]. Post hoc comparisons between responses in test and control pathways within each age group indicated that pattern stimulation in slices from old animals (n = 9) resulted in an enhancement of synaptic transmission at the 60-min time point (Fig. 1A). In contrast, pattern stimulation to slices from young rats treated with thapsigargin did not produce a significant change in synaptic strength (n = 8, Fig. 1B).
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The specific source of Ca2+ from ICS that mediate age-related differences can be investigated by blocking Ca2+-induced Ca2+ release from intracellular stores through blockade of ryanodine receptors or blockade of metabotropic receptor-induce inositol 1,4,5-trisphosphate (IP3) formation, which mobilizes Ca2+ from intracellular stores in dendritic spines through IP3 receptors (Takechi et al. 1998). In the presence of ryanodine (20 µM), 5-Hz pattern stimulation resulted in an age by pathway interaction [F(1, 8) = 9.77, P < 0.05], and post hoc comparisons indicated that old animals exhibited significant growth in the response of the test pathway relative to the control pathway (Fig. 1E). However, pattern stimulation in the presence of ryanodine did not alter the synaptic response in slices from young rats (n = 5, Fig. 1F). The LTP induced by pattern stimulation in presence of ryanodine was NMDA receptor sensitive such that addition of the NMDA receptor antagonist, AP-5 (100 µM), to slices from old rats blocked the induction of LTP (105 ± 3%, n = 7). Finally, LTP induction was not observed in slices of old animals for 5-Hz pattern stimulation in the presence of the metabotropic receptor antagonist, MCPG (500 µM; 108 ± 4%, n = 7).
Mechanisms for facilitation of LTP following inhibition of intracellular stores: reduced AHP and increased NMDA receptor function
Previous work suggests that the LTP threshold for older animals may be regulated by the amplitude of the Ca2+-dependent AHP (Kumar and Foster 2002; Norris et al. 1998a). To determine whether a similar mechanism might contribute to facilitation of synaptic enhancement following blockade of ICS, the Ca2+-dependent K+-mediated AHP was examined. A total of 33 cells from old animals and 11 cells from young animals were acceptable according to our criteria. The input resistance, resting membrane potential, and spike amplitude were not different between age groups, and no significant differences in the intrinsic membrane properties (input resistance, resting membrane potential, and spike amplitude) were observed across the various treatment conditions (Table 1). Nevertheless, in confirmation of previous reports (Disterhoft et al. 1996; Kumar and Foster 2002; Landfield and Pitler 1984; Power et al. 2002), the AHP was significantly increased [F(1, 23) = 13.67, P < 0.001] in old (6.91 ± 0.39 mV, n = 19), relative to young, animals (3.79 ± 0.85 mV, n = 6). Figure 2 shows that application of CPA (3 µM) or ryanodine (20 µM) resulted in a rapid (5–10 min) reduction in the AHP in cells from old animals. Compared with control conditions, AHP amplitude decreased 44.5 ± 5.4% and 40.2 ± 4.5% for cells exposed to CPA (n = 5) or ryanodine (n = 5), respectively, and was significantly different (P < 0.0001) from the control condition. The CPA-mediated reduction in the AHP in young animals was highly variable and considerably less than that for old animals (15.57 ± 15.7%, n = 3). Finally, the reduction in the AHP was specific to ryanodine receptors, since blockade of metabotropic glutamate receptors (mGluRs) by application of MCPG (500 µM) resulted in a slight increase in the AHP amplitude in old rats (4.23 ± 2.27%, n = 3). Similarly, application of drug vehicle, DMSO (n = 4), or NaOH (n = 2) had no effect on the AHP amplitude.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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In contrast to a number of studies that indicate an age-related impairment of LTP induction (Foster 1999), this study demonstrates an age-related facilitation of LTP, which was revealed when release of Ca2+ from ICS was pharmacologically blocked through depletion of ICS (thapsigargin, CPA) or blockade of Ca2+-induced Ca2+ release (ryanodine). The findings are contrary to those observed for studies examining LTP in young animals, which indicate a contribution of ICS, including ryanodine receptor-gated calcium pools, in the induction of LTP for weak stimulation (Behnisch and Reymann 1995; Harvey and Collingridge 1992; Raymond and Redman 2002; Reyes and Stanton 1996; Wang et al. 1996). One model suggests that, at least for juveniles, Ca2+ influx through NMDA receptors and VDCCs, in concert with mGluR-IP3–mediated Ca2+ release from internal stores, is able to access Ca2+-induced Ca2+ release at synapses of neonatal animals (Nishiyama et al. 2000). The results of this study indicate that the role of Ca2+-induced Ca2+ release in regulating the level of Ca2+ at the postsynaptic membrane may be minimized with advanced age. A reduction in the contribution of ICS to the rise in Ca2+ in the dendritic spine could result from an age-related decline in NMDA receptor function (Clark et al. 1992; Nicolle et al. 1996; Wenk and Barnes 2000). Indeed, controversy concerning whether Ca2+ influx through NMDA receptors initiates Ca2+-induced Ca2+ release for ICS may be due to the experimental variables including developmental state (Emptage et al. 1999; Kovalchuk et al. 2000; Mainen et al. 1999). In addition, changes in the proximity of the endoplasmic reticulum relative to the spine could limit ICS as a Ca2+ source during synaptic activation (Nimchinsky et al. 2002; Spacek and Harris 1997; Yuste et al. 1999).
Under similar recording conditions as employed in this study, a slow onset LTP, induced by stimulation patterns near the threshold for LTP (i.e., 900 pulses at 5 Hz) can be observed in old animals following blockade of L-channels (Norris et al. 1998a). It seems counterintuitive that blockade of Ca2+ sources, could facilitate LTP, a process that depends on a substantial rise in intracellular Ca2+. One possibility is that the age-related difference in LTP induction following application of Ca2+ pump inhibitors may have been due to reduced rate of Ca2+ clearance as a result of blockade of Ca2+ pumps (Kovalchuk et al. 2000; Markram et al. 1995) combined with increased Ca2+ entry through L-channels and impaired Ca2+ buffering in old animals (Thibault et al. 1998). However, this does not seem likely since ryanodine, which blocks release rather than the Ca2+ pump, also facilitated LTP. Furthermore, the LTP was specific to the pathway that received 5-Hz stimulation and was sensitive to NMDA receptor blockade, suggesting that it was not generalized as would be expected from increased VDCC activation and impaired buffering. Moreover, increasing L-channel activity via the L-channel agonist, Bay K8644, blocked the facilitation of LTP by CPA, demonstrating that increased influx through L-channel did not mediate the induction of LTP.
Voltage-dependent ion channels can control the induction of synaptic plasticity by regulating dendritic excitability (Johnston et al. 2003; Magee and Johnston 1997). The fact that LTP induction was readily modified by manipulations that influence the AHP indicates that regulation of the LTP threshold in old animals is closely coupled to changes in postsynaptic excitability involving Ca2+-dependent K+ channel activity. The shape of the AHP is influenced by release of Ca2+ from ICS (Borde et al. 2000), and this source of Ca2+ may contribute to the enhancement of the AHP during senescence (Kumar and Foster 2002; Landfield and Pitler 1984; Power et al. 2002). The results are consistent with the notion that augmentation of the hyperpolarization in old animals limits synaptic integration and depolarization required for NMDA receptor activation and LTP induction (Behnisch and Reymann 1998; Cohen et al. 1999; Foster and Kumar 2002; Foster and Norris 1997; Norris et al. 1998a; Sah and Bekkers 1996). The results suggest that during aging, ICS and VDCCs inhibit LTP induction by increasing the AHP and the level of stimulation required for LTP-induction. In this regard, the decreased excitability imposed by the larger Ca2+-dependent AHP may represent compensatory mechanisms restricting Ca2+ influx through NMDA receptors, disallowing enhanced LTP induction, and preventing the accumulation of toxic Ca2+ levels in the dendrite.
In this study, inhibition of ICS increased NMDA receptor responses specifically in old animals, and enhancement of the synaptic NMDA receptor response was blocked by including FK506 in the recording pipette. FK506 can influence several cellular processes including inhibiting peptidylprolyl isomerase activity and disrupting Ca2+ channels to increase release of Ca2+ from ICS (Brillantes et al. 1994). It is unclear how enhanced peptidylprolyl isomerase activity or decreased release for ICS could mediate differences in NMDA receptor function during aging, unless possibly through the regulation of the balance of Ca2+-dependent phosphatase/kinase activity. Indeed, several lines of evidence suggest that the effects are mediated by FK506 effects on the balance of kinase/phosphatase activity possibly involving the inhibition of the Ca2+-dependent phosphatase, calcineurin. First, activation of calcineurin decreases NMDA receptor function in younger animals (Lieberman and Mody 1994; Tong et al. 1995). Second, an increase in phosphatase activity is thought to act on glutamate receptors to reduce synaptic strength in aged animals (Foster et al. 2001; Norris et al. 1998b). While phosphatase activity was not measured in this study, previous work indicates that NMDA receptor function is regulated through ICS by means of calcineurin activation (Tong and Jahr 1994). Moreover, the balance of kinase/phosphatase activity adjusts dendritic excitability (Migliore et al. 1999; Schrader et al. 2002), and augmented calcineurin activity of old animals may underlie increased L-channel activity (Norris et al. 2002). Accordingly, elevated phosphatase activity during aging could explain the hypothesized shift in Ca2+ sources, increasing and decreasing the L-channel and NMDA receptor contribution, respectively (Foster 1999). Indeed, the age-associated enhancement of the AHP and decreased NMDA receptor activation are thought to underlie changes in the frequency-response function for synaptic plasticity, resulting in a pronounced plateau region for intermediate stimulation frequencies near the threshold for LTP induction (Foster 1999; Foster and Norris 1997). Together, the results are consistent with the notion that ICS contribute to altered Ca2+ regulation, leading to a shift in the balance of phosphatase/kinase activity and decreased NMDA receptor function during aging. As such, 5-Hz stimulation during ICS inhibition may have normalized or stabilized kinase/phosphatase activity, permitting the growth of synaptic strength selectively in old animals. While whole cell patch-clamp studies of synaptic function are extremely difficult in old brains, such studies are needed to confirm the findings and may provide more accurate measures of ICS regulation of NMDA receptor function.
A change in ionotropic glutamate receptor or mGluR function is likely to contribute to altered Ca2+ regulation and a shift in synaptic plasticity with age (Carlson et al. 2000; Foster and Kumar 2002; Hof et al. 2002; Pagliusi et al. 1994; Rosenzweig and Barnes 2003). While the results of studies using MCPG do not exclude a role for IP3 receptors in altered synaptic plasticity with age, the inability of MCPG to facilitate LTP indicates that the mGluR-IP3 pathway does not participate in inhibiting LTP under our experimental conditions. Other researchers have noted developmental changes in the mGluR-IP3 pathway such that activation of this pathway can reduced cell excitability, decrease LTP and promote depression of synaptic transmission in neonates (Nishiyama et al. 2000), while in juvenile or young adult animals, the LTP threshold is reduced by activation of mGluRs (Brown et al. 2000; Cohen et al. 1999; Matias et al. 2002; Thomas et al. 1996). Under conditions in which mGluR activation facilitates LTP induction, an increased cell excitability involving a reduction in the AHP and increased current through NMDA receptors is observed as well (Cohen et al. 1999; Madison and Nicoll 1986; Pisani et al. 1997; Thomas et al. 1998). In contrast, this study indicates that, under our experimental conditions, ICS have only a modest influence on the AHP in young animals. It is possible that the effect of ICS on the AHP and LTP may be more relevant under conditions in which the AHP is enhanced, such as increasing the level of Ca2+ in the medium (Kumar and Foster 2002; Norris et al. 1996) or increasing L-channel function (Thibault et al. 2001). Regardless, the results emphasize the importance of changes in the role of ICS for Ca2+ dysregulations during aging.
In considering the implications of ICS in Ca2+ homeostasis, other researchers have noted that overfilling of ICS may represent the fundamental cellular defect linking altered Ca2+ signaling to pathogenesis of age-related neurodegenerative diseases (Leissring et al. 2000). For neurons of the basal forebrain, increased intracellular buffering can act as a compensatory mechanism limiting ICS filling in old animals (Murchison and Griffith 1999). ICS of hippocampal neurons may be more susceptible to overfilling since most studies suggest that Ca2+ buffering is impaired in the hippocampus (Thibault et al. 1998). Furthermore, the increased in VDCC activity in old hippocampal neurons could increase ICS filling (Garaschuk et al. 1997). Moreover, release of Ca2+ through ryanodine receptor activation can contribute to enhanced L-channel activity in old animals (Thibault and Landfield 1996; Chavis et al. 1996) suggesting a positive feedback mechanism. It will be important for future studies to determine whether alterations in ICS include a shift in the location, sink-source activity, or filling of ICS and whether these changes contribute to altered Ca2+ homeostasis or provide compensation for Ca2+ dysregulation to limit runaway synaptic plasticity and Ca2+-mediated toxicity.
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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This work was supported by National Institute on Aging Grant AG-14979 and the Evelyn F. McKnight Brain Research Grant.
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FOOTNOTES |
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Address for reprint requests and other correspondence: T. C. Foster, Dept. of Neuroscience, McKnight Brain Institute, Univ. of Florida, PO Box 100244, Gainesville, FL 32610–0244 (E-mail: Foster{at}mbi.ufl.edu).
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) and test (
) pathways. Thapsigargin (A) and CPA (C) facilitate LTP induction in slices from old animals. No effect of pattern stimulation was observed for young animals in the presence of thapsigargin (B) and CPA (D). Ryanodine (20 µM) facilitated LTP induction in slices from old (E) but not young rats (F). Error bars equal mean ± SE and alternate every 5 sweeps in this and subsequent figures.
, n = 7) and was blocked in old animals by including FK-506 (50 µM,