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REPORT
1-Induced Long-Term Changes in Neuronal Excitability in Aplysia Sensory Neurons Depend on MAPK
1Department of Neurobiology and Anatomy, W. M. Keck Center for the Neurobiology of Learning and Memory, University of Texas Medical School at Houston; and 2Department of Biology and Biochemistry, University of Houston, Houston, Texas
Submitted 20 July 2005; accepted in final form 18 January 2006
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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1) plays important roles in the early development of the nervous system and has been implicated in neuronal plasticity in adult organisms. It induces long-term increases in sensory neuron excitability in Aplysia as well as a long-term enhancement of synaptic efficacy at sensorimotor synapses. In addition, TGF-1 acutely regulates synapsin phosphorylation and reduces synaptic depression induced by low-frequency stimuli. Because of the critical role of MAPK in other forms of long-term plasticity in Aplysia, we examined the role of MAPK in TGF-1-induced long-term changes in neuronal excitability. Prolonged (6 h) exposure to TGF-1 induced long-term increases in excitability. We confirmed this finding and now report that exposure to TGF-1 was sufficient to activate MAPK and increase nuclear levels of active MAPK. Moreover, TGF-1 enhanced phosphorylation of the Aplysia transcriptional activator cAMP response element binding protein (CREB)1, a homologue to vertebrate CREB. Both the TGF-1-induced long-term changes in neuronal excitability and the phosphorylation of CREB1 were blocked in the presence of an inhibitor of the MAPK cascade, confirming a role for MAPK in long-term modulation of sensory neuron function. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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; Lu 2003). A role for the cytokine TGF-1 in neuronal plasticity has also emerged. Recombinant TGF-1 induces long-term facilitation of Aplysia sensory-motor synapses (Zhang et al. 1997). Moreover, 5-HT-induced long-term facilitation is blocked by a soluble fragment of the TGF-1 type II receptor, which presumably acts by scavenging an endogenous TGF-1-like molecule. TGF-1 also induces long-term increases in neuronal excitability in Aplysia (Chin et al. 1999; Farr et al. 1999). Short-term modulation is also induced by TGF-1. Synaptic depression is reduced, in association with regulation of synapsin function (Chin et al. 2002). Finally, mice deficient in Smad, a component of the TGF-1 signaling pathway, have impaired spatial memory (Frankland et al. 2001).
The TGF-1 superfamily controls an array of cellular processes regulating development, growth, homeostasis, extracellular matrix production and regulation and wound repair (reviewed in Massagué, 1998; ten Dijke and Hill 2004). Recently, the regulation and roles of TGF-1 signaling in neurons have been investigated extensively (reviewed in Bottner et al. 2000; Sanyal et al. 2004). It has become clear that the pathways activated by TGF-1 in neurons overlap with those engaged by other factors that modulate neuronal and synaptic plasticity. Of particular interest are the MAPK pathway and the transcriptional activator cAMP response element binding protein (CREB), which have both been widely implicated for their roles in activity-dependent plasticity. TGF-1 transiently activates MAPK in chick ciliary ganglion neurons, which is necessary for acute and sustained effects of TGF-1 on KCa channel expression (Lhuillier and Dryer 2000). In addition, a number of studies have implicated MAPK as being an important mediator of TGF-1 signaling (reviewed in Mulder 2000). TGF-1 also activates the MAPK pathway in Aplysia sensory neurons, which is critical for the TGF-1-mediated reduction in synaptic depression at the sensorimotor synapse (Chin et al. 2002). The MAPK pathway plays a crucial role in the synaptic plasticity underlying learning and memory in both invertebrates and vertebrates (reviewed in Sweatt 2004). Among the targets of the MAPK pathway is the transcription factor CREB, which has been well-characterized for its role in long-term plasticity (reviewed in Lonze and Ginty 2002). CREB is also engaged by TGF-1 signaling (Liu et al. 2005; Warner et al. 2003; Zhang et al. 2004), representing a point of convergence between activity-dependent and neurotrophin/cytokine-dependent modulation of neuronal function. Of particular interest to the present study, long-term facilitation of Aplysia sensorimotor synapses induced by 5-HT involves the activation of MAPK and CREB1 (Bartsch et al. 1998; Martin et al. 1997; Michael et al. 1998; Purcell et al. 2003; Sharma et al. 2003).
In the present study, we demonstrate that TGF-1 induces the activation and increased nuclear localization of MAPK in sensory neurons and that this activation is necessary for TGF-1 to induce long-term changes in neuronal excitability. Moreover, the transcription factor CREB1 is activated by TGF-1 in a MAPK-dependent manner, suggesting that it may play a role in long-term changes induced by TGF-1. These results underscore the role of TGF-1 in modulating neuronal properties and the engagement of the MAPK/CREB signaling pathway in long-term neuronal plasticity.
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METHODS |
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and Chin et al. (2002). Mechanoafferent sensory neurons from the ventral-caudal cluster of the pleural ganglia were isolated and allowed to grow for 3–5 days at 18°C before experiments were begun. For immunocytochemistry, neurons were fixed in 4% paraformaldehyde in PBS containing 30% sucrose and incubated with anti-dually-phosphorylated MAPK (1:2500, Promega) or anti-phosphorylated CREB1 (1:1000) followed by tetramethylrhodamine-conjugated goat-anti-rabbit IgG. The anti-dually-phosphorylated MAPK antibody is specific for Aplysia MAPK (Fioravante et al. 2006). The rabbit polyclonal anti-phosphorylated-CREB1 (pCREB1) antibody was raised against Ser85-phosphorylated Aplysia CREB1 as previously described (Mohamed et al. 2005). Immunofluorescence was viewed with a confocal microscope (Biorad, MRC 1024MP). A z-series of optical sections through the cell body (0.25 µm increments) were taken, and the section through the middle of the nucleus was used for analysis of mean fluorescence intensities by means of ImageTool 2.1 software (Univ. of Texas Health Science Center at San Antonio). Eight to 10 neurons on each coverslip were analyzed, and measurements from neurons on the same coverslip were averaged. For electrophysiology, all recordings were performed at 22°C in solution containing 50% L15 and 50% ASW. Neurons were impaled with one microelectrode (resistance approximately 10 M
). Resting potential and input resistance were measured, and the neuron was held at –45 mV by passing current. Excitability was measured by counting the number of action potentials triggered by a 1-nA, 2-s depolarizing current pulse. Measurements from cells in one dish were averaged (2–3 cells per dish). After baseline measurements, cells were treated with TGF-1 (1 ng/ml), U0126 (20 µM in 0.2% DMSO, Promega), or 0.2% DMSO alone for 1 h prior to application of TGF-1 or BSA for 5 min (short-term experiments) or 6 h (long-term experiments). After the treatment, neurons were rinsed and returned to culture media. Excitability was assessed either 5 min later (short term) or 24 h later (long term). The individual performing the electrophysiological tests did not know which treatment the neurons had received. |
RESULTS |
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1 for 6 h exhibited increased excitability measured 24 h later (Chin et al. 1999). Farr et al. (1999) also showed that TGF-1 increased the excitability of Aplysia sensory neurons measured 24 h after treatment. Moreover, injection of active MAPK into sensory neurons induced long-term increases in neuronal excitability (Sung et al. 2001). On the basis of the ability of both TGF-1 and MAPK to induce long-term changes in excitability, we examined whether MAPK activity was necessary for the long-term regulation of neuronal excitability by TGF-1. U0126, a specific inhibitor of MEK, an upstream activator of MAPK (Favata et al. 1998), inhibits the activation of MAPK in Aplysia sensory neurons (Chin et al. 2002). Using isolated sensory neurons grown in culture, we replicated our previous finding that TGF-1 increases neuronal excitability measured 24 h after 6 h treatment with TGF-1 (Chin et al. 1999). TGF-1 increased the excitability of neurons by 238 ± 30% (mean ± SE) of baseline (Fig. 1A1, n = 7, representing 18 neurons). However, the excitability of neurons treated with U0126 + TGF-1 was only 151 ± 24% of baseline (Fig. 1A2, n = 8, representing 20 neurons). The excitability of neurons treated with U0126 + BSA was 147 ± 13% (Fig. 1A3, n = 7, representing 18 neurons) indicating that the effect of U0126 + TGF-1 was the same as the effect of U0126 + BSA. A two-way analysis of variance (ANOVA), repeated measures design, revealed a significant difference among these three groups (F2,19 = 4.65, P < 0.05), and Tukey post hoc tests revealed that the group of neurons treated with DMSO + TGF-1 was significantly different from the other two groups. These results indicate that MAPK plays a critical role in the induction of long-term changes in excitability by TGF-1.
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1 acutely stimulates MAPK activation in sensory neurons (Chin et al. 2002), we examined whether acute (5 min) exposure to TGF-1 was sufficient to induce short-term changes in excitability. These experiments were performed in a manner identical to that described above, but the excitability of sensory neurons was immediately retested after the end of the 5 min treatment with TGF-1. Five minutes of treatment with TGF-1 did not alter sensory neuron excitability (111 ± 17%, mean ± SE, for TGF-1 vs. 95 ± 11% for BSA, n = 8, t14 = 0.81, P = 0.43). We also examined whether the brief, 5-min treatment would induce the long-term increase in neuronal excitability. Twenty-four hours after the 5-min treatment, the excitability of the sensory neurons was not different from that of BSA-treated controls (149 ± 27%, mean ± SE, for TGF-1 vs. 146 ± 24% for BSA, n = 4, t6 = 0.89, P = 0.41).
On MAPK phosphorylation and activation, a portion of the active MAPK pool translocates to the nucleus to modulate transcription factor targets (reviewed in Chang and Karin 2001). Stimuli that induce many forms of long-term neuronal and synaptic plasticity stimulate MAPK activation and lead to increased nuclear levels of active MAPK. Because we and others have shown that TGF-1 induces long-term forms of neuronal plasticity, we examined whether TGF-1 increased nuclear levels of active MAPK. We previously showed that TGF-1 quickly (within 5 min) activates MAPK in an MEK-dependent manner (Chin et al. 2002), but we did not know whether activation represented increased nuclear levels of active MAPK. Although we observed the electrophysiological effects of TGF-1 observed only after prolonged treatment (Fig. 1), we hypothesized that transcriptional events necessary for these long-term effects are initiated earlier. Therefore we treated cultured neurons with TGF-1 for 5 min, 30 min, or 6 h and then processed the neurons for immunofluorescence staining. Neurons treated with TGF-1 for 5 min and 30 min exhibited higher levels of dually phosphorylated MAPK in both nuclear and cytoplasmic compartments compared with BSA-treated control neurons (Fig. 2, A and B). Nuclear staining was increased by 21 ± 3% (mean ± SE) after 5 min treatment with TGF-1 (n = 3, representing 32 BSA-treated neurons and 30 TGF-1–treated neurons, t2 = 6.57, P < 0.05) and by 25 ± 12% after 30 min treatment (n = 4, representing 25 BSA-treated neurons and 23 TGF-1–treated neurons, t3 = 2.8, P < 0.05). TGF-1 also increased cytoplasmic staining by 10 ± 2% (mean ± SE) after 5 min (t2 = 3.91, P < 0.05), and there was a trend for an increase after 30 min (20 ± 12%, t3 = 2.03, P = 0.067). By 6 h of TGF-1 treatment, both nuclear and cytoplasmic MAPK were back to basal levels. These findings indicate that, as predicted, TGF-1 rapidly activates MAPK and increases nuclear levels of active MAPK. This translocation of activated MAPK is sustained for 
30 min, consistent with the hypothesis that there is a temporal threshold required to induce transcriptional events necessary to induce long-term changes in neuronal excitability.
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). In many systems, the MAPK pathway, including intermediates such as RSK1, leads to phosphorylation and activation of CREB and promotes its ability to activate transcription (Hardingham et al. 2001; Wu et al. 2001). The initiation of transcriptional events by CREB1, the Aplysia isoform of CREB, is negatively regulated by CREB2, the Aplysia isoform of the transcriptional repressor ATF1 (reviewed in Kandel 2001). To determine whether CREB1 may play a role in TGF-1-induced long-term neuronal plasticity, we examined whether TGF-1 treatment resulted in CREB1 phosphorylation and increased nuclear staining. We found that whereas 5 min treatment with TGF-1 was not sufficient to significantly increase nuclear phospho-CREB1 staining (1 ± 8%, mean ± SE; n = 4, representing 23 BSA-treated and 20 TGF-1–treated neurons, t3 = 0.34, P = 0.38), 30 min treatment with TGF-1 significantly increased nuclear phospho-CREB1 staining (15 ± 4%, n = 4, representing 20 BSA-treated and 18 TGF-1–treated neurons, t3 = 3.24, P < 0.05). TGF-1-induced increases in nuclear phospho-CREB1 levels were dependent on the MAPK pathway, as we found that the increase in nuclear phospho-CREB1 was blocked with U0126 even when induced by a higher concentration (10 ng/ml) of TGF-1 (33 ± 10%, mean ± SE, increase in TGF-1–treated vs. 2 ± 6% increase in U0126+TGF-1–treated neurons, n = 5, representing 41 DMSO+BSA-treated, 42 DMSO+TGF-1–treated, 42 U0126+BSA-treated and 47 U0126+TGF-1–treated neurons). ANOVA revealed a significant effect of treatment between the three groups, and Tukey post hoc tests revealed that the group of neurons treated with DMSO + TGF-1 was significantly different from the other two groups (F2,12 = 5.00, P < 0.05, Fig. 3C).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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) for the induction of long-term changes in the excitability of sensory neurons by TGF-1. Moreover, TGF-1 leads to an activation of MAPK in sensory neurons (Fig. 2 and Chin et al. 2002) and results in increased nuclear levels of active MAPK (Fig. 2). The rapid activation of MAPK by TGF-1 is in contrast to a much slower activation by 5-HT, with undetectable activation at the end of a 5-min pulse of 5-HT and a graded activation/translocation with additional pulses of 5-HT (Martin et al. 1997; Michael et al. 1998; Sharma et al. 2003). Although a 5-min treatment of TGF-1 was sufficient to activate MAPK and cause an increase in nuclear levels of activated MAPK (Fig. 2), a 6-h treatment was necessary to induce a long-term change in excitability (Fig. 1). Presumably, at some point during the 6-h treatment, levels of activated MAPK became sufficient to activate gene expression necessary for long-term changes in excitability. This hypothesis is supported by our finding that whereas 5 min treatment with TGF-1 did not increase nuclear levels of phospho-CREB1, 30 min treatment with TGF-1 did increase nuclear levels of phospho-CREB1 in a MAPK-dependent manner. Such an increase in nuclear phospho-CREB1 suggests that 30 min of TGF-1 treatment is necessary to induce the transcriptional events necessary for long-term increases in neuronal excitability. By 6 h of TGF-1 treatment, events necessary for long-term changes in excitability have been achieved, and active MAPK levels are back to basal levels.
The intermediate steps between the activation of the TGF-1 receptor and the activation of MAPK are not known. The most likely possibility is that the activated receptor leads directly to the activation of MAPK through Ras (Derynk and Zhang 2003). However, PKC is also known to couple to the MAPK pathway (reviewed in Sweatt 2004). An alternative possibility that needs to be examined is that TGF-1 engages the PKC cascade. PKC is activated by TGF-1 (Farr et al. 1999) and induces long-term changes in sensory neuron excitability (Manseau et al. 1998), and at least one MAPK-dependent protein phosphorylation in Aplysia is blocked by a PKC inhibitor (Yamamoto et al. 1999).
The neurotrophins have been well characterized for their roles in development as well as in adult organisms (Kojima et al. 2002; Lu 2003; Tyler et al. 2002). Although each of these growth factors can have distinct effects in neuronal plasticity, one common factor in the signaling mechanisms of both neurotrophins and cytokines seems to be the engagement of the MAPK pathway. Our results implicating MAPK in TGF-1-induced long-term changes in sensory neuron excitability in Aplysia add to this body of evidence. In addition, the present results provide a starting point from which to begin examining the substrate proteins such as CREB1 that are the targets of MAPK-dependent phosphorylation and the ways those proteins lead to the induction and expression of long-term changes induced by TGF-.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Address for reprint requests and other correspondence: J. H. Byrne, Department of Neurobiology and Anatomy, University of Texas-Houston Medical School, Houston, Texas 77030 (E-mail: john.h.byrne{at}uth.tmc.edu)
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