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1Institute of Neuroscience, University of Oregon, Eugene, Oregon; and 2Howard Hughes Medical Institute, Columbia University Medical Center, New York, New York
Submitted 17 January 2006; accepted in final form 30 March 2006
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ABSTRACT |
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INTRODUCTION |
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; Lockery and Spitzer 1992; Vabnick and Shrager 1998). It is presumed that changes in ionic currents reflect the execution of specific genetic programs but little is known about which genes and regulatory mechanisms are involved. The nematode Caenorhabditis elegans is a good model organism with which to address this question because it allows the combination of biophysical techniques with genetic manipulations to study the regulation of neuronal function during development in identified neurons (Francis et al. 2003; Hobert 2003).
A neuron class of particular interest in C. elegans is AIY, which consists of two left–right symmetrical neurons. AIY interneurons are involved in a number of different behaviors, including locomotion (Gray et al. 2005; Tsalik and Hobert 2003), chemotaxis (Hirotsu and Iino 2005; Remy and Hobert 2005; Tsalik and Hobert 2003), thermotaxis (Mori and Ohshima 1995; Ryu and Samuel 2002), odor adaptation (Hirotsu and Iino 2005), and associative learning (Gomez et al. 2001; Remy and Hobert 2005). In addition, certain aspects of its development have been studied at the genetic level (Altun-Gultekin et al. 2001; Wenick and Hobert 2004). The adult phenotype of AIY is reached progressively through a cascade of transcription factors. At the top of this cascade, the LIM homeobox gene ttx-3 regulates many class-specific aspects of AIY's identity, including its axonal morphology and the expression of neurotransmitter receptors (Altun-Gultekin et al. 2001; Wenick and Hobert 2004). In contrast, pan-neuronal markers are preserved in ttx-3 mutants, suggesting that the product of this gene is mostly involved in specifying the AIY neuronal subtype. Abnormal development in ttx-3 mutants leads to abnormal AIY-mediated behavior (Mori and Ohshima 1995; Remy and Hobert 2005; Tsalik and Hobert 2003). Thus the ttx-3–mediated control of AIY development has important implications for adaptive behavior in C. elegans.
Although many genes involved in AIY's development have been characterized, almost nothing is known about the maturation of its electrical properties and how these properties are affected by mutations in genes responsible for AIY's identity. We therefore analyzed capacitance and whole cell voltage-dependent current in AIY during larval development in wild-type (WT) animals, and also in animals in which specific AIY-expressed genes were genetically removed. We found that there is an age-dependent maturation in the electrical properties of AIY and that this maturation is altered in animals that lack a LIM homeobox gene, ttx-3, and a specific target of this transcription factor, the IgSF member wrk-1. In particular, AIY interneurons undergo an increase in cell capacitance during larval development, without a concomitant increase in steady-state current amplitude. Furthermore, the time course of net outward currents changes from a slowly activating, sustained current to a rapidly activating, decaying current as the animals age.
We found that in the case of the ttx-3 and wrk-1 mutants, AIY matured precociously, implying that the more mature state is a default state that AIY adopts in the absence of ttx-3 and wrk-1 function. The mutants also showed that developmental changes in capacitance can be genetically dissociated from changes in the time course of outward currents.
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METHODS |
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The following C. elegans strains were used for the electrophysiological experiments: ttx-3(ks5) (Moni and Oshima 1995), ser-2(pk1357) (Tsalik and Hobert 2003), wrk-1(ok695), wrk-1(tm1099) (Boulin T, Pocock R, and Hobert O, unpublished observations). All animals contained the mgIs18 transgene (ttx-3prom 
gfp) in the background to visualize the AIY interneurons with gfp (Altun-Gultekin et al. 2001); mgIs18 animals served as WT control. We used the hypomorphic ks5 mutant allele of ttx-3, rather than available null alleles, because in null alleles gfp expression from the mgIs18 array is completely lost, thus precluding the identification of AIY for recording. The two wrk-1 mutant alleles will be described elsewhere. Briefly, both are deletion alleles with ok695 being a likely null allele.
Animals were grown in mixed-stage cultures at 20°C on 1.7% agar-filled plates containing nematode growth medium seeded with Escherichia coli strain OP50 (Brenner 1974). We performed recordings at the four larval stages (L1 to L4) that characterize postembryonic C. elegans development (animals ranging in size from 200 to 628 µm). We did not record from adult animals because of the difficulty of exposing AIY for electrophysiological recordings at this stage. The following numbers of AIY recordings were obtained from these strains: wild-type, 14; ttx-3(ks5), 18; ser-2(pk1357), 12; wrk-1(ok695), 17; wrk-1(tm1099), 10.
Expression pattern
A 4-kb portion of the upstream regulatory region of wrk-1 (F41D9.3) was fused to gfp using a PCR fusion technique and injected with pha-1(+) DNA into pha-1 mutants (Aurelio et al. 2002). Three independent arrays (otEx202–otEx204) showed similar expression patterns, unpublished observations). Expression in AIY was assessed using the otIs133 transgene, which labels the AIY interneurons with dsRed2 (Wenick and Hobert 2004). To assess wrk-1 regulation by ttx-3, the otEx203 array was crossed into a ttx-3(ot22) mutant background.
Electrophysiology
Animals were prepared and dissected as previously described (Goodman et al. 1998; Lockery and Goodman 1998). Whole cell patch-clamp recordings were performed using electrodes manufactured from borosilicate glass (Sutter BF120-69-10, Novato, CA) and filled with (in mM): 125 K gluconate, 18 KCl, 4 NaCl, 1 MgCl2, 0.6 CaCl2, 10 HEPES, and 10 EGTA (pH 7.2). External saline contained (in mM): 145 NaCl, 5 KCl, 1 CaCl2, 5 MgCl2, and 10 HEPES (pH 7.2). Membrane currents were amplified with a modified Axopatch 200A (Axon Instruments, Foster City, CA), filtered at 10 kHz, and digitized at 25 kHz. Currents were further filtered at 2 kHz off-line. Membrane currents were leak subtracted and voltages were corrected for liquid junction potentials. AIY interneurons were identified by GFP expression (see Strains). Steady-state current amplitude was measured as the average value during the last 5 ms of the voltage pulse. The early-to-late current ratio was defined as the ratio of the average current in the 5-ms time window beginning at t = 5 ms and the average current during the last 5 ms of the voltage pulse. Recordings were performed randomly on either the left or right AIY neurons.
Statistics
Data values are expressed as means ± SE. Statistical analysis was performed with SPSS 11.0 software (SPSS, Chicago, IL). Statistical significance was assessed using a one-way ANOVA (Figs. 1, A and E; 2, A and D; 4A; 5C; 6B; and 7, A and D), a one-way ANOVA for repeated measures (Figs. 1B, 2B, 4B, and 6B), and a two-way ANOVA for repeated measures (comparison of WT and mutant IV curves). Statistical results are expressed in the form F(a,b) = c, where a and b are the degrees of freedom in the ANOVA, and c is the value of the F statistic.
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RESULTS |
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To study the development of AIY's electrical properties, we measured whole cell capacitance and net membrane current as a function of developmental stage, using animal length as an approximate marker of stage. Animals were divided into two groups: L1 larvae and L2 to L4 larvae (L2–L4), with an animal length of 350 microns being the cutoff between the two groups (Hirsh et al. 1976). We observed a threefold increase in whole cell capacitance as the animal age increased [Fig. 1A; F(1,11) = 15.773, P < 0.01; see METHODS]. However, the amplitude of steady-state membrane currents evoked by a family of voltage pulses remained constant [Fig. 1B; F(1,11) = 0.85, P > 0.05]. Thus there was an overall decrease in current density with age. This is surprising because other types of C. elegans neurons exhibit an increase in both capacitance and current amplitude as the animal grows (Goodman et al. 1998).
Although steady-state current amplitude remained constant over larval development, the time course of outward current changed. Figure 1C shows average currents generated by voltage steps from –154 to +86 mV in L1 and L2–L4 animals. In general, we observed a change from an outward current that activates slowly during depolarization (Fig. 1C1, arrow) to an outward current that activates more rapidly and decays slightly over the time course of the depolarization (Fig. 1C2, arrow). The change in time course of the outward current seems to result from the appearance of an early component in the outward current in L2–L4 animals (Fig. 1D). We henceforth refer to this current as the fast-activating component of the outward current.
The change in outward current was quantified in two ways. First, the ratio of early-to-late current (see METHODS) was displayed for the L1 and L2–L4 larvae for the outward current generated by a voltage step from –74 to +86 mV (Fig. 1E). Note that a ratio >1 indicates the appearance of the fast-activating component of the outward current. This ratio increased as the animals grew [F(1,11) = 11.177, P < 0.01]. A similar increase was observed when ratios from a range of voltage steps were pooled [voltage steps to +26, +46, +66, and +86 mV; F(1,11) = 7.601, P < 0.05], demonstrating that this increase was not an artifact of using a particular voltage step. Second, because there was considerable individual variability in early-to-late current ratios in WT and mutant animals (see following text), we also compared the within-group frequency of cells displaying an early-to-late current ratio >1. A ratio >1 was evident in over 80% of the cells from L2–L4 animals, but evident in only 20% of cells from L1 animals (Fig. 1F). Thus the appearance of the fast-activating component of the outward current was a common feature of maturation in AIY neurons.
Development of electrical properties is altered in ttx-3 mutants
We next examined how the development of capacitance and voltage-dependent currents was affected in ttx-3(ks5) mutants. In contrast to WT animals, AIY capacitance did not increase in ttx-3 mutants [Fig. 2A; F(1,16) = 0.894, P > 0.05]. Moreover, the capacitance observed in L1 ttx-3 mutants (0.49 ± 0.09 pF) was similar to that of L2–L4 WT animals [0.68 ± 0.11; F(2,21) = 1.09, P > 0.05]. This result suggests that capacitance matures precociously in ttx-3 mutants and, further, that ttx-3 may function to reduce or retard maturation of AIY capacitance.
As in WT animals, no change in steady-state current amplitude could be detected during larval development in ttx-3 mutants [Fig. 2B; F(1,16) = 0.474; P > 0.05]. We therefore pooled the data from L1 and L2–L4 ttx-3 animals and compared the pooled data with that of WT animals. No significant difference could be detected [F(4,64) = 2.17, P > 0.05]. Therefore ttx-3 mutants do not differ from WT in terms of steady-state current amplitude and its maturation.
We next analyzed age-dependent changes in the time course of outward current in the mutants. Figure 2C shows average currents for both L1 and L2–L4 animals. One important difference from WT is apparent in outward currents in ttx-3: in L1 animals, early outward current is dominated by the fast-activating component, rather than by the slowly activating currents observed in WT L1 (Fig. 2C1, compare with Fig. 1C1). Thus outward current time course matures precociously in ttx-3 mutants. These differences are further quantified in Fig. 2, D and E for the current elicited by a voltage pulse to +86 mV. Figure 2D shows the ratio of early-to-late current for L1 and L2–L4 animals. Whereas WT animals displayed a progressive increase of the early-to-late current ratio as the animals grew (Fig. 1E), in ttx-3 mutants this ratio remained constant [Fig. 2D; F(1,16) = 1.35; P > 0.05]. Moreover, a ratio >1 was evident in 88% of cells in L1 animals and 100% of cells in L2–L4 animals (Fig. 2E). Therefore AIY displayed the fast-activating component in outward currents irrespective of developmental stage in ttx-3 mutants, suggesting ttx-3 functions to prevent or retard the maturation of this current.
wrk-1 expression is regulated by ttx-3 and alters the development of AIY properties
We next sought to understand the mechanism of action of ttx-3 by analyzing the effect of mutations in candidate downstream genes. We focused on the wrk-1 gene, a GPI-anchored member of the immunoglobulin superfamily with three Ig and one FnIII domain (Hutter et al. 2000), for two main reasons: 1) wrk-1 is expressed in AIY (Aurelio et al. 2002), and is thus a potential target of ttx-3; and 2) members of the IgSF have been shown to regulate potassium currents in other preparations (Rasband 2004; Traka et al. 2003).
To determine whether wrk-1 is indeed a target of ttx-3, we examined the expression of wrk-1 in WT and ttx-3 mutants. Expression of wrk-1 was detected using a wrk-1prom gfp reporter (Fig. 3A; see METHODS). In WT animals, wrk-1 was expressed in several neurons in the C. elegans nerve ring (Fig. 3A). In the same animals, AIY was specifically labeled using a ttx-3prom DsRed2 reporter (Fig. 3B). The two reporters co-localized, confirming that wrk-1 is expressed in AIY (Fig. 3C). We found that wrk-1 was expressed in AIY in 100% of WT animals (Fig. 3D). In contrast, using the same reporter genes in a ttx-3 mutant background, we found that the frequency of expression of wrk-1 was greatly reduced (Fig. 3D). We conclude that wrk-1 expression is regulated by ttx-3 in AIY.
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Using wrk-1(tm1099) as a representative case, we next asked whether we could convert the more mature form of the outward current into its immature form by pharmacological blockade. Given a positive result in such an experiment, the simplest model would be that maturation of the outward current involves expression of one additional type of ion channel. We therefore measured outward currents in AIY in the presence and absence of the potassium channel blocker 4-aminopyridine (4-AP). This drug was chosen because the fast-activating component in AIY is also a transient current, and 4-AP is known to block transient potassium currents in other C. elegans cells (Jospin et al. 2002). We found that 3 mM 4-AP partially blocked both the fast and slow components of the outward current (Fig. 6A). Both components were blocked to the same extent [Fig. 6B; F(1,16) = 0.425, P > 0.05]. Thus we could not convert the more mature form of the current into its immature form using 4-AP. This result supports the hypothesis that maturation of outward currents is more complex than expression of a single additional type of ion channel. However, the simple model could still be the case if 4-AP partially blocks both the new component and the original component of the outward current. Thus this experiment remains inconclusive.
To test whether the alteration of the developmental timing observed in wrk-1 mutants was a nonspecific effect of mutating ttx-3 target genes, we analyzed the effect of complete removal of ser-2, a putative tyramine receptor gene that is expressed in AIY and is regulated by ttx-3 (Tsalik et al. 2003). In ser-2 null mutants, AIY displayed an entirely WT sequence of maturation that included 1) an increase in capacitance with age [Fig. 7A; F(1,10) = 6.05, P < 0.05]; 2) a WT steady-state current amplitude that did not change during development [Fig. 7B; F(1,10) = 4.613, P > 0.05], and that was similar to that of WT animals [F(4,64) = 2.17, P > 0.05]; and 3) the presence of the fast-activating component in the outward current in L2–L4 animals, but not L1 animals (Fig. 7C). This absence is further reflected in the ratio of early-to-late current [Fig. 7D; F(1,9) = 5.78, P < 0.05] and the percentage of cells exhibiting an early-to-late current ratio >1 (Fig. 7E). Moreover, the values of these different parameters were similar to those of WT animals. Therefore the developmental defects observed in wrk-1 mutants are not the result of a nonspecific effect of mutating ttx-3 target genes.
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DISCUSSION |
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The electrical properties of wild-type AIY neurons exhibit a clear pattern of developmental maturation. The immature state is characterized by relatively low capacitance and slowly activating outward currents. The more mature state is characterized by relatively high capacitance and the addition of a fast-activating component to the outward current.
The capacitance increase could be explained in two main ways: 1) by an increase in membrane resistance, leading to better space-clamp, and thus a more accurate measurement of capacitance; or 2) by growth of the cell. We favor the second explanation because AIY is likely to be isopotential at all developmental stages, given that larger C. elegans neurons are isopotential in adult worms (Goodman et al. 1998). However, our results do not rule out other potential factors, such as developmental increases in the conductance of gap junctions between AIY and other neurons (White et al. 1986). Premature appearance of such gap junctions could explain the increased capacitance observed at the first larval stage (L1) in ttx-3 mutants. The additional outward current component could be explained by modification of an existing current or addition of a new one. The changes in capacitance and membrane current that we observed could alter membrane excitability in ways that modify the integrative properties of AIY neurons.
Interestingly, not all aspects of AIY electrophysiology exhibit a process of maturation, in that steady-state outward current amplitude remained constant over the developmental period studied. Under the assumption that increased capacitance reflects cell growth, the constancy of current amplitude implies that the number of channels carrying this current remains approximately constant as the cell grows, leading to a decrease in current density. This stands in contrast to the development of the ASE chemosensory neurons in C. elegans, in which steady-state outward current amplitude increases but current density remains constant (Goodman et al. 1998). It remains to be seen which trend is more common in C. elegans.
Mutant analysis of the electrophysiological maturation of AIY
Mutations in the genes ttx-3 and wrk-1 result in precocious maturation of AIY electrical properties. In ttx-3 mutants, capacitance and outward current already display a more mature phenotype by the L1 stage. In wrk-1 mutants, capacitance develops normally, but outward current displays a more mature phenotype by the L1 stage, as in ttx-3 mutants. The fact that these effects were produced by LOF alleles indicates that both genes normally act to retard the electrophysiological maturation of AIY, implying that the more mature state is the default state.
Our genetic analysis indicates that AIY contains distinct pathways for regulating cell growth and ionic currents. This follows from the fact that wrk-1 mutants exhibit normal development of capacitance, but precocious development of outward current. Thus wrk-1 appears to be part of the pathway for regulating outward current, but not part of the pathway for regulating capacitance. In contrast, ttx-3 appears to be part of both pathways because development of capacitance and outward current are precocious in ttx-3 mutants. In addition, we found that ttx-3 is required for normal levels of wrk-1 expression. Taken together, our results are consistent with a model in which ttx-3 acts in the outward current pathway by positively regulating wrk-1.
The mechanism by which wrk-1 retards the development of outward currents remains to be elucidated. IgSF proteins have been shown to alter the localization of K+ channels in the node of Ranvier (Rasband 2004; Traka et al. 2003) and are able to trigger second-messenger cascades in neurons (Walsh and Doherty 1997). Both mechanisms could be related to alteration of the outward current we observed.
Limitations
The number of the developmental changes in AIY electrical properties, as well the extent to which their maturation is altered in the mutants, may have been underestimated in this study in three main ways. First, ttx-3(ks5) is a hypomorphic rather than a null allele (Altun-Gultekin et al. 2001) and, although hypomorphic and null alleles of ttx-3 mutants are indistinguishable from one another by almost all known criteria, we note that in theory, a null allele could have produced a stronger electrophysiological phenotype. Although null alleles of ttx-3 are available, AIY neurons cannot be identified in these strains after dissection because these animals do not express the ttx-3prom gfp reporter construct (Altun-Gultekin et al. 2001). Second, because we analyzed net whole cell currents, which were dominated by outward currents, we might have missed changes in the amplitude or time course of inward currents. For example, Ca2+ currents, which were not resolved under the conditions of this study, might also be developmentally regulated. Third, it is possible that we missed changes in currents that activate on a slower timescale than the one studied here (Weinshenker et al. 1999). Nevertheless, this report establishes the AIY interneuron as an effective system in which to investigate the genetic control of the development of electrical properties of neurons.
Whereas we could implicate wrk-1 in the electrophysiological maturation of the AIY interneurons, using two independently isolated wrk-1 alleles, we note that we have not formally demonstrated that wrk-1 indeed acts in the AIY interneurons, e.g., by rescuing the gene cell specifically. There is, however, no indication that wrk-1 is expressed in neurons that are either synaptically connected to AIY or whose axons are in close physical proximity to AIY. Thus the most parsimonious explanation of our findings is that wrk-1 acts cell-autonomously in AIY.
For technical reasons (see METHODS), no adult animals were included in this study. Therefore we cannot rule out further maturation of membrane currents in AIY past the L4 stage, nor can we rule out a role for ttx-3 and wrk-1 past the L4 stage.
Future work
Adult ttx-3 mutants exhibit several behavioral deficits (Mori and Ohshima 1995; Remy and Hobert 2005; Tsalik and Hobert 2003). The fact that ttx-3 acts in the AIY neurons to cause these behavioral defects strongly implicates this neuron class in these deficits. Such deficits could arise from alterations in intrinsic electrical properties or from alterations in synaptic function, including synaptic connectivity. The fact that the changes in intrinsic properties in ttx-3 mutants are minor seems to argue for changes in synaptic function as the main cause of behavioral deficits. However, as noted, we may have missed certain alterations in intrinsic properties.
The functional consequences of the maturation of outward currents remain unclear because little is known about the behavior of C. elegans larvae and how it changes as the animals grow (Chiba and Rankin 1990). Further work is therefore required to characterize the emergence of AIY-mediated behaviors during larval development of C. elegans. This would establish AIY as a model to study how genetic alterations in electrophysiological properties translate into behavioral defects.
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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: S. Lockery, 1254 University of Oregon, Eugene, OR 97403 (E-mail:shawn{at}lox.uoregon.edu)
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ABSTRACT
INTRODUCTION
