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1Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, New York; and 2Department of Cardiac Arrhythmia, Massachusetts General Hospital, Boston, Massachusetts
Submitted 2 March 2006; accepted in final form 1 May 2006
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ABSTRACT |
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INTRODUCTION |
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-BTX) treatment, and in neuregulin (NRG)-deficient mice (Cull-Candy et al. 1980
; Plomp et al. 1992, 1994, 1995; Sandrock et al. 1997). The same type of compensatory response has been observed at Drosophila neuromuscular junctions with reduced density or efficacy of glutamate receptors (DiAntonio et al. 1999; Haghighi et al. 2003; Petersen et al. 1997). To better understand this two-way transynaptic communication, it is important to determine the temporal relationship between changes in quantal size and quantum content. We examined the relationship between functional AChR density and ACh release in postnatal day 7 (P7), P14, and adult NRG-deficient mice.
Members of the NRG family of proteins increase transcription of muscle AChR subunit genes and, ultimately, the number of AChRs in the muscle membrane (Buonanno and Fischbach 2001; Falls 2003; Rimer 2003). ARIA (acetylcholine receptor inducing activity), a type I product of the nrg-1 gene, was purified from chick brain on the basis of its ability to increase AChR synthesis in cultured chick myotubes (Falls et al. 1993; Usdin and Fischbach 1986). In cultured rat myotubes, ARIA also increases synthesis of the AChR 
-subunit that, in vivo, replaces the embryonic 
-subunuit during the second postnatal week (Fromm and Rhode 2004; Martinou et al. 1991; Missias et al. 1996).
All known neuregulins contain an epidermal growth factor (EGF)–like domain that is necessary and sufficient for activation of the erbB family of receptor tyrosine kinases (Altiok et al. 1995; Moscoso et al. 1995; Zhu et al. 1995). Type I NRG isoforms contain an immunoglobulin-like domain and, at the neuromuscular junction, this isoform accumulates in the synaptic basal lamina (Loeb 2003; Loeb et al. 1999). Targeted deletion of the immunoglobulin G (IgG)–like domain is embryonic lethal (Kramer et al. 1996). Heterozygous mice (Ig-NRG+/–) survive and a mild myasthenia can be revealed after administration of low doses of curare (Sandrock et al. 1997). Adult heterozygotes demonstrate a 30–50% decrease in AChR density as measured by spontaneous miniature endplate potential (MEPP) amplitude and 125I alpha-bungarotoxin (-BTX) binding. Ig-NRG+/– adults also exhibit an increase in the mean quantum content of nerve-evoked endplate potentials (EPPs) evoked at low rates of stimulation (1 Hz). Here we report that changes in postsynaptic neurotransmitter sensitivity and quantum content are dissociated in time during postnatal maturation of Ig-NRG–deficient mice.
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METHODS |
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Mice used in this study were rederived from mice heterozygous for a targeted disruption of the NRG-1, IgG-like domain, which had been maintained on the original mixed background (Kramer et al. 1996). Thus the mice were backcrossed once into one of the parental strains, C57Bl/6. Mice were maintained and bred under standard conditions, consistent with National Institutes of Health guidelines and approved by the Institutional Animal Care and Use Committee.
Electrophysiology
Synaptic transmission was assayed in postnatal day 7, day 14, and adult Ig-NRG heterozygous and wild-type mice. Spontaneous MEPPs and nerve-evoked EPPs were measured with intracellular microelectrodes (17–30 M
) in isolated diaphragm–phrenic nerve preparations pinned at resting length in specially designed Sylgard (DuPont)-coated Plexiglas perfusion chambers. Electrodes were placed at the edge of each endplate. Motor nerve terminals were labeled with yellow fluorescent protein (YFP) by crossing Ig-NRG+/– mice with transgenic mice expressing YFP under the control of neuron-specific elements of the thy1 gene (Feng et al. 2000), a kind gift of Joshua Sanes. Phrenic nerves were stimulated through a suction electrode. Extracellular solution [composed (in mM) of NaCl (125), NaHCO3 (26), NaH2PO4 (1.25), KCl (2.5), CaCl2 (2.0), and MgCl2 (1.0)] was bubbled with 95% O2-5% CO2 and maintained at 22°C by a specially designed temperature exchange system attached to a circulating water bath (MultiTempIII, Pharmacia Biotech). For focal extracellular recording, microelectrodes (4 M) were filled with 1 M NaCl. To determine endplate size, AChRs were labeled in live whole mounts with Texas red–or Alexa Fluor 594 (AF594)–labeled -bungarotoxin (Molecular Probes).
MEPPs occur at low frequency at young end plates and thus data were combined from many end plates in several mice in each category. EPPs were recorded in elevated extracellular Mg (12 mM) to decrease the probability of presynaptic ACh release, which eliminates action potentials and allows application of Poisson statistics (Del Castillo and Katz 1954; Sandrock et al. 1997). This strategy was adopted to avoid changes in compensation specific to Ca2+ concentration. Plomp et al. (1994) found that the relative difference in quantal content between -BTX–treated rats and controls was highly sensitive to Ca2+ concentration (i.e., the upregulation was lost as Ca2+ concentration was decreased), but was not influenced by Mg2+ concentration, even though MEPP amplitude was decreased by high Mg2+, both in -BTX–treated rats and controls; 12 Mg2+/2Ca2+ was used in our original characterization of synaptic transmission in Ig-NRG1+/– adult mice (Sandrock et al. 1997). Quantum content—the average number of vesicles released in response to each nerve impulse—was calculated for each fiber by the method of failures [m0 = ln (N/N0), where N, the total number of successive nerve impulses, is divided by N0, the number of impulses in which no EPP is recorded], and by the direct method (m1, where mean EPP amplitude per stimulus is divided by mean MEPP amplitude) when there was a sufficient number of MEPPs per fiber. Recording temperature was maintained at 26°, EPP and MEPP rise times were <1.5 ms, and amplitudes were normalized to –70 mV (adult) or to –50 mV (P7, P14). Traces were measured using Mini Analysis software (Synaptosoft). Data were analyzed using Student's unpaired t-test with Origin 7.0 (OriginLab). Differences were considered significant at P < 0.05. Measurements are expressed as means ± SE of individual end plates from three to seven preparations in each experimental group.
Quantification of mRNA
Relative mRNA expression was determined by real-time PCR using the Roche LightCycler. Total RNA was isolated from mouse spinal cord with Trizol reagent (Invitrogen), treated with RNase-free DNaseI (Promega), extracted with phenol/chloroform, precipitated with NaOAc ETOH, and dissolved in DEPC-treated distilled water (dH2O). First-strand cDNA was synthesized using reverse transcription (RT) reagent from Invitrogen. Briefly, 3 µg of cleaned total RNA in 10 µl of H2O was denatured at 65°C for 5 min, then chilled on ice for 5 min. RT mix (1.5 µl of 150 ng/µl random primer, 1.5 µl of 10 mM dNTPs, 3 µl of 1 M DTT, 6 µl of 5 x buffer, 1 µl of RNase inhibitor, in DEPC-treated H2O; total volume 18.5 µl) was added and mixed well, then incubated at 42°C for 2 min. SuperscriptII (1.5 µl, Invitrogen) was added, incubated at 42°C for 1 h, then inactivated at 70°C for 15 min. The 20-µl real-time PCR reaction contained 2 µl cDNA, 2 µl mM MgCl, 0.25 µM each forward and reverse primers, and 2 µl FastStart DNA Master SYBR Green I (Roche) in dH2O. Primer sequences were as follows:EGF-NRG
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RESULTS |
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; Plomp et al. 1994). The decrease in Ig-NRG+/– MEPP amplitude at P7 (20–25%) is comparable to our previous finding in adult Ig-NRG+/– mice (Sandrock et al. 1997).
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). We selected singly innervated fibers by including only those junctions that exhibited smoothly rising EPPs. Nevertheless it is possible that some multiply innervated fibers were included in our sample. Because multiple innervation increases quantal content (Santafe et al. 2001), the reduction at P7 may be greater than we report here. Thus at P7, the decrease in MEPP amplitude was not accompanied by an increase in transmitter release.
Transmitter release clearly was increased in adult Ig-NRG+/– mice. Mean evoked EPP amplitude was increased by 73%, as was mean quantum content (Fig. 2A and Table 1). Based on our earlier studies, we expected the increase in transmitter release to be accompanied by a decrease in quantal size. However, in this series of experiments, MEPP amplitudes recorded in adult Ig-NRG+/– mice were not different from control (Fig. 2B). This was observed both in 1 and in 12 mM Mg. Representative traces are shown in Fig. 2C. We confirmed that Ig-NRG mRNA was reduced in our Ig-NRG+/– mice by quantitative RT-PCR. Comparison with wild-type adults showed that transcripts containing the NRG IgG-like domain were decreased by about 45% (het/wt, 0.54 ± 0.06 in nine pairs). IgG-containing isoforms represent only about 10% of NRG message in motor neurons (Corfas et al. 1995). As expected, total NRG mRNA (messages containing the EGF-like domain) showed little change (het/wt, EGF-NRG, 0.90 ± 0.11). Thus in adult Ig-NRG+/– mice, we found a dissociation between quantal size and quantal content. In contrast to P7, transmitter release was increased despite normal MEPP amplitude.
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; Sakmann and Brenner 1978). During the second postnatal week, the embryonic -subunit characterized by a relatively long mean channel open time (4.5 ms), is replaced by the adult -subunit characterized by a brief open time (1.4 ms) and a small increase in channel conductance (1.5-fold). Thus if -subunit expression persisted in adult Ig-NRG+/– mice, it is possible that MEPP amplitude might overestimate receptor density if channel open time was more significant than peak conductance in determining net synaptic current. To test this possibility, we analyzed the decay of miniature end-plate currents (MEPCs) detected by focal extracellular recording. Both Ig-NRG+/– and wt MEPCs showed the rapid decay characteristic of adult receptors (Fig. 3). Representative traces are shown in Fig. 3A and composite histograms of 
1 are shown in Fig. 3B. In adult muscles, there was no difference in AChR -subunit mRNA levels between wt and Ig-NRG+/– mice (Fig. 3C).
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; Katz and Thesleff 1957). We found no difference in imput resistance measured directly in a subset of adult Ig-NRG+/– and wild-type fibers by injecting 10 nA of current through an electrode placed adjacent to the end plate and recording within 100 µm of the first electrode (1.01 ± 0.04 M, in 2 wt mice, 17 fibers; 1.03 ± 0.04 in 2 het mice, 24 fibers, P = 0.6). Fiber diameters were measured in bright field images obtained near end plates before electrophysiological recording (Fig. 4A). Heterozygous and wild-type fiber diameters were similar both in adult mice and in neonatal mice (Fig. 4B and Table 1). Examples of end plates viewed en-face illustrate a variety of morphologies evident in adult mouse diaphragm (Fig. 4C; Prakash and Sieck 1998). We compared Texas-red -bungarotoxin–labeled end plates by confocal microscopy in three het (47 fibers) and three wt (44 fibers) mice. No significant difference was observed in total end-plate area (het = 4,205 ± 256; wt = 4,356 ± 314), end-plate length (het = 73.96 ± 2.2; wt = 74.48 ± 2.75), or end-plate width (het = 55.45 ± 1.96; wt = 56.23 ± 2.14). Taken together, these results suggest that the normal MEPP amplitudes recorded in adult Ig-NRG+/– mice did not arise from differences in receptor subunit composition, muscle fiber diameter, or end-plate size.
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- to -AChR subunit switch is virtually complete (Missias et al. 1996; Sanes and Lichtman 2001). Mean MEPP amplitude was similar to control in P14 NRG+/– mice (Fig. 5 and Table 1). Evoked EPP amplitudes and mean quantum content were 20% lower than control, although this difference was not statistically significant. The relative increase in Ig-NRG+/– MEPP amplitude compared with wild-type values and the relatively large variance in mean EPP amplitudes suggest that P14 may reflect a transition between the neonatal and adult response to decreased Ig-NRG expression.
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DISCUSSION |
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Although dissociated in time, both quantal size and quantum content were influenced by Ig-NRG expression. The simplest interpretation of these results is that type I NRG can influence ACh release at the neuromuscular junction independently of its effects on postsynaptic AChRs. At the nerve terminal, NRG may modulate the surface membrane expression or trafficking of channels that regulate transmitter release, such as voltage-dependent potassium or calcium channels, or muscarinic AChRs (Ford et al. 2003; Rosato Siri and Uchitel 1999; Santafe et al. 2003).
At the postsynaptic membrane, decreased Ig-NRG gene expression results in decreased MEPP amplitude in P7 mice. This is consistent with known actions of NRG1 on AChR transcription in muscle fibers (Buonanno and Fischbach 2001). In the experiments reported here, the appearance of MEPPs of normal amplitude in Ig-NRG+/– adults, rather than the low-amplitude MEPPs observed previously (Sandrock et al. 1997), probably reflects the difference in genetic background in our rederived colony. Several factors may modulate the effects of reduced Ig-NRG expression. During the first 2 wk after birth, the mammalian neuromuscular junction changes dramatically. By P14, motor endplates become singly innervated, subsynaptic nuclei accumulate, embryonic AChRs are replaced by adult receptors, and the postsynaptic membrane develops deep folds with AChRs concentrated in the crests and sodium channels in the troughs (Brenner et al. 1994; Kues et al. 1995; Sanes and Lichtman 2001; Zhu et al. 1995). In addition, NRG protein, diffusely distributed in the basal lamina at birth, becomes concentrated at the endplate in the adult pattern (Loeb et al. 1999; Missias et al. 1997; Moscoso et al. 1995; Sandrock et al. 1995). Thus the efficacy of Ig-NRG signaling may be increased in heterozygous mice, despite reduced expression of Ig-NRG mRNA, by genetic changes that increase the release of NRG from nerve terminals or the accumulation of Ig-NRG isoforms in the synaptic cleft (Loeb 2003). Moreover, AChR expression, turnover, or stabilization may also be affected by the expression of other signaling molecules, including CGRP or NRG-2 (Fontaine et al. 1987; Lai and Ip 2003a,b; Meyer et al. 1997; New and Mudge 1986; Rimer et al. 2004).
It has been shown repeatedly that the phenotype of genetically altered mice, including mice with altered erbB2 receptors, may reflect differences in background genes as well as in the targeted gene (Andrechek et al. 2002; Crawley et al. 1997), and strain-specific differences in gene expression and synaptic properties have been reported (Fernandes et al. 2004; Nguyen et al. 2000). Taken together, our results suggest that in the postsynaptic membrane, MEPP amplitude is not determined simply by the level of Ig-NRG expression, but may be influenced by additional genes. By contrast, the presynaptic increase in transmitter release in Ig-NRG–deficient adult mice appears to be more robust since this phenotype was observed in two different genetic backgrounds. The mechanisms responsible, and their developmental regulation, are under investigation.
The observed dissociation between postsynaptic and presynaptic changes in Ig-NRG+/– mice also may be explained by an alternative hypothesis. A slow presynaptic response may be triggered by the decreased postsynaptic transmitter sensitivity observed during the first postnatal week in Ig-NRG+/– mice. A delay in presynaptic compensation for decreased quantal size was seen in TIMG rats chronically treated with -bungarotoxin (Plomp et al. 1992). Receptor density was decreased within 3 h of the first injection. Transmitter release increased gradually during the first week and plateaued 2 to 3 wk later. This time course is consistent with our results. Whether the increased transmitter release observed in TIMG rats would have been maintained if treatment had stopped and quantal size returned to control levels—as it had in our adult Ig-NRG deficient mice—is not known. However, results in Drosophila neuromuscular junctions suggest a "one-way" mechanism of presynaptic compensation during normal development. When quantal size was experimentally increased in Drosophila end plates there was no homeostatic decrease in transmitter release (Davis et al. 1998; DiAntonio et al. 1999; Petersen et al. 1997). Thus in Ig-NRG+/– adult muscle fibers, as in Drosophila muscle, transmitter release may remain elevated despite an increase in quantal size. One attractive hypothesis is that regulation of synaptic efficacy may be set by early activity-dependent events (Davis and Bezprozvanny 2001; Landmesser 1998).
CaMKII has been identified as a postsynaptic regulator of retrograde signaling in Drosophila muscle with altered postsynaptic receptor density (Haghighi et al. 2003) and is required for the increased transmitter release observed in toxin-induced myasthenic (TIMG) rats (Plomp and Molenaar 1996). The size of the end plate is not altered in either system. It is possible that CaMKII is also involved in the regulation of transmitter release in NRG-deficient mice. Opposite actions of this kinase have been observed: inhibition of CaMKII increases transmitter release in DGluRIIA mutants, but inhibition of CaMKII decreases transmitter release in TIMG rats. Inhibition of CaMKII has no effect on transmitter release in wild-type fly or rat muscle. It will be interesting to determine whether these two actions are evident at different developmental stages in NRG-deficient mice.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Address for reprint requests and other correspondence: M. A. Mann. College of Physicians and Surgeons, Columbia University, 630 West 168th Street BB1102, New York, NY 10032 (E-mail: mam2012{at}columbia.edu)
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ABSTRACT
INTRODUCTION
