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REPORT
Neuroscience Group, Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, South Dakota
Submitted 4 January 2008; accepted in final form 7 March 2008
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ABSTRACT |
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INTRODUCTION |
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). A number of experiments have produced "global" potentiation by applying drugs that initiate LTP so that a greater percentage of cells in the preparation are potentiated, making it easier to detect cellular level changes; this class of induction paradigms is typically referred to as chemical LTP (cLTP). One of the most common techniques used to elicit cLTP involves the bath-application of forskolin, an adenylate cyclase activator (Otmakhov et al. 2004; Sokolova et al. 2006). In addition, many studies use forskolin to stimulate AMPA receptor trafficking (Gomes et al. 2004; Oh et al. 2006; Yudowski et al. 2007) that is thought to mediate LTP.
The leech provides a useful model system for examining the biochemical pathways that mediate forskolin-induced synaptic potentiation. Both N-methyl-D-aspartate receptor (NMDAR)-dependent LTP and long-term depression (LTD) have been observed in the leech CNS (Burrell and Li 2008; Burrell and Sahley 2004). In addition, the CNS of the leech is well-characterized so that it is possible to record from the same neuron across multiple preparations (see review by Kristan et al. 2005). The P-to-AP synapse is composed of a pressure-sensitive mechanosensory neuron (P) and the anterior pagoda (AP) neuron, the function of which is unknown (Muller et al. 1981). This synapse is glutamatergic (Wessel et al. 1999) and has both mono- and polysynaptic components (Gu 1991). In this study, we find that forskolin induces an NMDAR-dependent potentiation of the P-to-AP synapse. This potentiation required the activation of protein kinase A (PKA) and calmodulin-dependent kinase II (CaMKII), postsynaptic increases in intracellular Ca2+, and postsynaptic exocytosis, presumably for the insertion of glutamate receptors. A portion of the data presented here has been previously reported in abstract form (Burton and Burrell 2007).
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METHODS |
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1 ml/min). Dissections and recordings were carried out in leech saline containing (in mM): 115 NaCl, 4 KCl, 1.8 CaCl2, 1 MgCl2, and 10 HEPES.
Dual intracellular recordings were made by impaling individual neurons with a glass microelectrode using a micropositioner (Model 1480; Siskiyou Inc., Grants Pass, OR). Electrodes were pulled from borosilicate capillary tubing (1.0 mm OD, 0.75 mm ID; FHC Bowdoinham, ME) to a resistance of 25–35 M
and filled with 3 M potassium acetate. Current pulses were delivered using a programmable stimulator (MultiChannel Systems STG 1004). Signals were amplified with a bridge amplifier (BA-1S; National Precision Instruments, Tamm, Germany) and then digitally converted (Digidata 1322A A/D converter) for viewing and subsequent analysis (Axoscope; Molecular Devices, Sunnyvale, CA). Individual neurons were identified based on their position, size, and action potential shape. Excitatory postsynaptic potentials (EPSPs) in the AP cell were elicited by brief, 20-ms current injections into a contralateral P-cell. To prevent the initiation of action potentials, the AP neuron was hyperpolarized to the same membrane potential during both the pre- and post tests (approximately –70 mV). Input resistance of the postsynaptic AP cell was measured throughout each experiment by injecting negative currents (0.5 nA, 500 ms). Typically, four to six EPSPs (to minimize synaptic depression) and seven to nine input resistance measurements were averaged per recording.
In all experiments, baseline EPSP amplitude and input resistance measurements were taken in normal saline. Due to the NMDAR-dependent nature of forskolin-induced cLTP in vertebrates, the efficacy of drug application was optimized by perfusing the drug in Mg2+-free saline so as to reduce the NMDAR's voltage-dependent block and facilitate LTP induction (Otmakhov et al. 2004). Accordingly, forskolin (50 µM) and rolipram (0.1 µM) were applied in Mg2+-free saline for 15 min followed by washout in normal saline for 15 min. Control experiments consisted of 15-min perfusion of Mg2+-free saline, Mg2+-free saline plus DMSO, or other drug-specific control, followed by washout in normal saline for 15 min. Ionophoretically injected drugs were delivered using 5 nA, 100-ms negative current pulses and co-applied with the 15-min bath-applied treatment. Across all experiments, the average AP resting potential was approximately –40 mV, and the average initial input resistance was 26.61 ± 0.44 (SE) M. EPSP amplitude and input resistance measurements were taken at the conclusion of each 30-min experiment and normalized to their initial values (% of baseline) and presented as the means ± SE. Cells were excluded if input resistance changed >30% from baseline. In addition, only cells with initial EPSPs <7 mV were studied, as synapses >7 mV did not potentiate, consistent with LTP observed in other leech and vertebrate synapses (Fig. 1C) (Bi and Poo 1998; Burrell and Sahley 2004; Montgomery et al. 2001).
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Bath-applied drugs were dissolved in dH2O except where noted and perfused in Mg2+-free leech saline at the following concentrations: forskolin (50 µM, Sigma, St. Louis, MO) dissolved in DMSO (final concentration 0.0005% wt/vol, Sigma); rolipram (0.1 µM, Sigma); APV (100 µM, Sigma); bis-(o-aminophenoxy)-N,N,N',N'-tetraacetic acid (BAPTA, 1 mM, Sigma) dissolved in 3 M KAc; db-cAMP (50 µM, Sigma); Rp-cAMP (50 µM, Sigma); autocamtide-2-related inhibitory peptide (AIP, 1 µM, Tocris, Ellisville, MO); botulinum neurotoxin type B light chain (0.5 µM, List Biological Laboratories, Campbell, CA) dissolved in 3 M KAc (Sigma).
Statistics
Statistical tests were conducted using Statistica analysis software (Statsoft). Statistical significance (P < 0.05) was determined using a one-way ANOVA and Least Significant Difference post hoc comparison for all experiments unless otherwise indicated. A t-test was used to determine initial EPSP amplitudes (Fig. 1C).
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RESULTS |
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Perfusion of forskolin plus rolipram in Mg2+-free leech saline for 15 min substantially increased EPSP amplitude 30 min after the initial baseline test compared with the Mg2+-free plus DMSO control (164 ± 15.4%, n = 9; 104 ± 14.2%, n = 6, P < 0.05; Fig. 1, A and B). Application of APV (100 µM), an NMDAR antagonist, completely blocked the potentiation when co-applied with forskolin and rolipram (101% ± 5.1, n = 3, P < 0.05, Fig. 1B). Potentiation was not seen in Mg2+-free or DMSO control groups at 30 min (Fig. 1B). We found differences in potentiation due to the initial EPSP amplitude, leading us to exclude synapses with baseline amplitudes >7 mV as they, on average, failed to potentiate (Fig. 1C). A similar trend has been observed during LTP in the hippocampus and at a different synapse in the leech CNS (Bi and Poo 1998; Burrell and Sahley 2004; Montgomery et al. 2001). No change in input resistance was observed between the forskolin-treated and control synapses (P > 0.05; n = 34 total experiments shown in Fig. 1B).
Synaptic facilitation requires an increase in postsynaptic intracellular Ca2+
To determine whether forskolin-induced potentiation requires a pre- or postsynaptic increase in intracellular Ca2+, the calcium chelator BAPTA was ionophoretically injected into the P (presynaptic) or AP (postsynaptic) cell during forskolin plus rolipram treatment. Injection of BAPTA into the postsynaptic AP cell blocked synaptic facilitation (106 ± 5.8%, n = 6, P < 0.05, Fig. 2C), whereas injection of BAPTA into the presynaptic P cell had no effect on forskolin-induced potentiation (143 ± 9.15%, n = 16; 153 ± 10.46%, n = 21; Fig. 2B), suggesting that this potentiation depends on an increase in postsynaptic intracellular Ca2+. Although presynaptic BAPTA reduces evoked synaptic transmission through the inhibition of vesicle release (Lu and Hawkins 2006) no change in P-to-AP EPSP was observed following BAPTA treatment of the P-cell by itself. To verify that the BAPTA reached the presynaptic terminals, EPSP measurements were taken 15 min after the pretest, coinciding with the completion of BAPTA treatment. Evoked synaptic transmission in normal saline decreased to 54 ± 0.42% (n = 3) of the pretest level (Fig. 2A). There was no significant change in input resistance for any of the BAPTA groups (P > 0.05; n = 67 total experiments shown in Fig. 2, B and C).
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Because forskolin is known to activate adenylyl cyclase, the cAMP pathway is expected to play a role in generating synaptic facilitation. Application of db-cAMP, a membrane-permeable cAMP analogue, potentiated the synaptic potentiation to a level identical to that of forskolin (163 ± 10.36%, n = 12; Fig. 3A). Because cAMP activates PKA, the role of PKA in synaptic facilitation was examined. Co-application of Rp-cAMP, a competitive inhibitor of PKA, with forskolin plus rolipram blocked forskolin-induced potentiation, yielding synaptic transmission levels nearly identical to the Rp-cAMP plus DMSO control (104 ± 12.74%, n = 10, P < 0.05, and 108 ± 10.52%, n = 13, P < 0.05; Fig. 3B; no change in input resistance, P > 0.05; n = 73 total experiments shown in Fig. 3). Taken together these experiments suggest that forskolin-induced potentiation requires activation of the cAMP/PKA signaling pathway.
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Given that CaMKII plays an important role in most forms of NMDAR-dependent LTP (see review by Miyamoto 2006), the role of CaMKII during synaptic facilitation in the leech was examined. Co-application of the CaMKII inhibitor AIP with forskolin plus rolipram blocked forskolin-induced potentiation and actually depressed the postsynaptic EPSP (65 ± 6.12%, n = 6, P < 0.05; Fig. 3C). The AIP plus forskolin group was significantly different from both the forskolin group as well as the control groups with no change in input resistance (P > 0.05; n = 73 total experiments shown in Fig. 3). AIP alone did not alter P-to-AP synaptic transmission (112 ± 7.20%, n = 8, P < 0.05). These results suggest that the induction of synaptic facilitation requires CaMKII and that inhibition of CaMKII during forskolin treatment results in synaptic depression.
Inhibition of exocytosis blocks forskolin-induced potentiation
Insertion of glutamate receptors into the postsynaptic membrane is thought to be a critical component in the expression of LTP (Hayashi et al. 2000). There are no known antibodies that recognize AMPA-type receptors in the leech; therefore an alternative approach was employed that has been used in other studies of synaptic plasticity in invertebrate glutamatergic synapses (Antonov et al. 2007; Chitwood et al. 2001; Ji and Hawkins 2003; Li et al. 2005). Botulinum toxin type B (BTX-B) inhibits exocytosis (Montecucco and Schiavo 1995), and presumably blocks insertion of AMPA receptors in the post synaptic cell. Ionophoresis of BTX-B into the postsynaptic AP-cell by itself did not affect synaptic transmission (110 ± 15.04%, n = 4, P < 0.05); However, BTX-B treatment did block forskolin-induced potentiation (84 ± 10.22%, n = 5, P < 0.05; Fig. 3D) with no effect on input resistance (P > 0.05; n = 73 total experiments shown in Fig. 3). These results are consistent with the hypothesis that forskolin-induced potentiation in the P-to-AP synapse requires the insertion of glutamate receptors.
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DISCUSSION |
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; Martin et al. 1997; Yoshihara et al. 2000), this is, to our knowledge, the first example of NMDAR-dependent chemically induced potentiation in an invertebrate CNS. Furthermore these findings indicate that forskolin-induced potentiation acts through similar mechanisms in both vertebrates and invertebrates (Otmakhov et al. 2004). In addition to being NMDAR-dependent, this synaptic potentiation in the leech requires a postsynaptic increase in intracellular Ca2+, activation of PKA and CaMKII, and appears to depend on postsynaptic exocytosis.
Methods for producing a consistent, chemically induced synaptic potentiation have a number of advantages. In vertebrate preparations, bath application of drugs are thought to potentiate a greater number of synapses (Otmakhov et al. 2004), making it possible to detect cellular-level changes during LTP that could not be resolved if only a small subset of synapses were potentiated (e.g., phosphorylation of proteins or trafficking of receptors). Also, it may allow for the study of synapses that are technically difficult to induce LTP in using standard electrophysiological techniques. In addition to forskolin, a number of other techniques have used biochemical manipulations to induce cLTP, including, manipulating postsynaptic calcium (Neveu and Zucker 1996), raising cAMP levels (Frey et al. 1993; Nguyen et al. 1994), adding glycine (Lu et al. 2001; Yudowski et al. 2007), and perfusing Mg2+-free saline alone (Bekkers and Stevens 1990; Otmakhov et al. 2004). We did not observe potentiation using only Mg2+-free saline at 30 min. The reasons for this are unknown, but one possibility is that there may be less excitatory synaptic drive during Mg2+-free conditions in the leech CNS because there are far fewer synaptic contacts compared with a mammalian brain. The number of contacts among studied synapses in the leech range from 20 to 70 (Baccus et al. 2000; Gu 1991), considerably fewer than the hundreds to thousands of synaptic connections typically found between vertebrate neurons.
It is thought that forskolin treatment induces cLTP by modulating or "sensitizing" the NMDARs so that spontaneous activity stimulates these receptors sufficiently to induce LTP. One possible mechanism is that the forskolin-induced increase in cAMP activates PKA, which modulates the NMDARs via phosphorylation of Ser897, such that calcium conductance increases (Raman et al. 1996; Skeberdis et al. 2006; Tingley et al. 1997). An alternate NMDAR sensitizing pathway has been suggested for cerebellar neurons in which Akt, not PKA, modulates this receptor (Llansola et al. 2004), but we did not find support for this theory in these experiments.
Expression of NMDAR-dependent LTP is thought to result from insertion of additional glutamate receptors in the postsynaptic membrane (Malinow and Malenka 2002). Because there are no known antibodies that recognize leech AMPA-like receptors, the potential role of glutamate receptor trafficking during cLTP in the leech was examined using botulinum toxin (BTX). BTX inhibits exocytosis by cleaving the SNARE complex (Montecucco and Schiavo 1995) and has been successfully used in a number of vertebrate (Baxter and Wyllie 2006; Kakegawa and Yuzaki 2005) and invertebrate studies (Antonov et al. 2007; Chitwood et al. 2001; Ji and Hawkins 2003; Li et al. 2005) that examined glutamate receptor trafficking. The BTX experiments show that postsynaptic exocytosis and presumably glutamate receptor insertion are necessary for forskolin-induced potentiation in the leech. Although the BAPTA and BTX results indicate that the potentiation observed here appears to be mediated postsynaptically, we cannot rule out a presynaptic component, and other studies have suggested that forskolin-induced cLTP can occur via a presynaptic mechanism (Chavez-Noriega and Stevens 1994; Huang and Hsu 2006).
This study is not the first to demonstrate NMDAR-dependent potentiation at invertebrate synapses, which has been previously observed in the CNS of both Aplysia and the leech (Antonov et al. 2003; Burrell and Sahley 2004; Lin and Glanzman 1994; Murphy and Glanzman 1997, 1999). However, the results presented here do demonstrate that techniques used to induce cLTP in vertebrates can also be used in invertebrate synapses. These findings are also significant in terms of understanding the mechanisms responsible for modulating the induction threshold for LTP. A number of studies have shown that cAMP/PKA pathways can enhance NMDAR function (Crump et al. 2001; Westphal et al. 1999), which could reduce the threshold or level of activity required to initiate LTP, sometimes referred to as metaplasticity (Abraham and Bear 1996). The observations presented here suggest that LTP in the leech may be modulated by cAMP/PKA and CaMKII signaling processes. It is known that the leech CNS possesses serotonin receptors that activate PKA (Burrell and Sahley 2005; Crisp and Muller 2006), but further studies are necessary to determine if serotonin activators of the cAMP/PKA pathway modulates LTP in the leech.
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GRANTS |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Address for reprint requests and other correspondence: B. D. Burrell, Neuroscience Group, Div. of Basic Biomedical Sciences, Sanford School of Medicine at the University of South Dakota, Vermillion, SD 57069 (E-mail: bburrell{at}usd.edu)
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ABSTRACT
INTRODUCTION
