- Email: [email protected]
The blu Blur: Mutation of a Vesicular Glutamate Transporter Reduces the Resolution of Zebrafish Vision
Neuron
Previews it is now clear that signaling events, such as Erk and PI3K activation, are induced from distinct cellular compartments with different latencies. Events that impinge on receptor trafficking and degradation are therefore key junction points for understanding the physiological consequences of receptor activation. TrkA endocytosis and transport has been well studied, and the concept of a signaling endosome that functions as a retrograde platform that supports TrkA survival signaling is established in the field. Ubiquitination of cell-surface receptors has recently emerged as a key regulatory event important for internalization, signaling, and receptor degradation. Recent studies have not only demonstrated that Trk receptors become ubiquitinated but that this is regulated by p75NTR (Geetha et al., 2005; Makkerh et al., 2005). It therefore seems likely that regulated ubiquitination of p75NTR and TrkA will prove to be an important intersection point that will also
facilitate cross-regulation between these receptors. The work of Wehrman et al. (2007) provides key insights into the structural and kinetic issues concerning p75NTR and Trk interactions. With this structural information, improving technical tools, and an increased focus on the cell-biological events that underlie receptor activation and signaling, the future is bright, and the precise mechanisms that regulate the p75NTR-TrkA regulatory network are certain to emerge.
Geetha, T., Jiang, J., and Wooten, M.W. (2005). Mol. Cell 20, 301–312. He, X.L., and Garcia, K.C. (2004). Science 304, 870–875. Hempstead, B.L., Martin-Zanca, D., Kaplan, D.R., Parada, L.F., and Chao, M.V. (1991). Nature 350, 678–683. Ivanisevic, L., Banerjee, K., and Saragovi, H.U. (2003). Oncogene 22, 5677–5685. Kuruvilla, R., Zweifel, L.S., Glebova, N.O., Lonze, B.E., Valdez, G., Ye, H., and Ginty, D.D. (2004). Cell 118, 243–255. Lachyankar, M.B., Condon, P.J., Daou, M.C., De, A.K., Levine, J.B., Obermeier, A., and Ross, A.H. (2003). J. Neurosci. Res. 71, 157–172.
REFERENCES
Lee, K.-F., Davies, A.M., and Jaenisch, R. (1994). Development 120, 1027–1033.
Barker, P.A., and Shooter, E.M. (1994). Neuron 13, 203–215.
Mahadeo, D., Kaplan, L., Chao, M.V., and Hempstead, B.L. (1994). J. Biol. Chem. 269, 6884–6891.
Bibel, M., Hoppe, E., and Barde, Y.A. (1999). EMBO J. 18, 616–622. Brennan, C., Rivas-Plata, K., and Landis, S.C. (1999). Nat. Neurosci. 2, 699–705. Clary, D.O., and Reichardt, L.F. (1994). Proc. Natl. Acad. Sci. USA 91, 11133–11137. Dechant, G., Tsoulfas, P., Parada, L.F., and Barde, Y.A. (1997). J. Neurosci. 17, 5281–5287.
Makkerh, J.P., Ceni, C., Auld, D.S., Vaillancourt, F., Dorval, G., and Barker, P.A. (2005). EMBO Rep. 6, 936–941. Roux, P.P., and Barker, P.A. (2002). Prog. Neurobiol. 67, 203–233. Wehrman, T., He, X., Raab, B., Dukipatti, A., Blau, H., and Garcia, K.C. (2007). Neuron 53, this issue, 25–38.
The blu Blur: Mutation of a Vesicular Glutamate Transporter Reduces the Resolution of Zebrafish Vision Jay Demas1 and Hollis T. Cline1,* 1
Cold Spring Harbor Lab, Beckman Building, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA *Correspondence: [email protected] DOI 10.1016/j.neuron.2006.12.019
Vesicular transporters mediate the packaging of neurotransmitters into synaptic vesicles and can therefore control the amount of neurotransmitter released into the synaptic cleft. In this issue of Neuron, Smear et al. demonstrate that mutation of a vesicular glutamate transporter (Vglut) found in the retinal ganglion cells (RGCs) of zebrafish alters both the synaptic transmission and connectivity between RGCs and their targets, limiting the transfer of visually evoked activity from RGCs and degrading behaviors that depend on high-acuity vision. Discovered in an anatomical screen for zebrafish retinotectal projection defects, the blumenkohl (or blu) mutant was characterized by enlarged termination zones and defasciculation of
RGC axons in a way reminiscent of the shape of its namesake, the cauliflower (Baier et al., 1996; Neuhauss et al., 1999). Reported in this issue of Neuron, Smear et al. (2007) began their
4 Neuron 53, January 4, 2007 ª2007 Elsevier Inc.
investigation by assaying the mutant’s vision using the optomotor response, an innate behavior where zebrafish swim in the same direction as a drifting grating stimulus presented at the
Neuron
Previews bottom of their tank. An elegant motion-nulling experimental design made use of the optomotor response to compare the perception of two gratings drifting in the opposite directions: a test grating with different spatial and temporal frequencies across trials, and a reference grating with fixed properties. On average, a group of zebrafish will swim in the direction of the grating that is more robustly perceived, or they will not swim at all when the two gratings are perceived equally well. To isolate visual perception from possible motor defects, the contrast of a given test grating was adjusted so that there was no net movement. The lower the contrast required for motion nulling, the more sensitive vision is to that test grating. These experiments revealed that the neural mechanisms for processing high-frequency spatial and temporal components of the visual scene were disproportionately affected by the blu mutation. No doubt spurred by their interesting behavioral results, Smear et al. (2007) mapped the blu mutation to vglut2a, a member of the vesicular glutamate transporter family. The mutation is a putative null because it places a stop codon in-frame that eliminates more than 75% of the amino acid sequence, including a number of transmembrane domains. Although retinal expression of Vglut2a is normally robust, it is confined to the ganglion cell layer, whose only glutamatergic residents are RGCs. Because RGCs form synapses onto targets located (almost) exclusively outside the retina, it is not surprising that the electroretinogram and gross anatomy of the blu retina are indistinguishable from those of wild-type fish (Neuhauss et al., 1999). This led to a fortuitous situation in which the blu mutant retinas have a selective loss of Vglut2a in RGCs, while other Vglut gene expression appears to be unperturbed in the CNS. Smear and colleagues hypothesized that the mutant’s visual deficits are likely to be a consequence of defective synaptic transmission between RGCs and their targets. Smear et al. (2007) chose to investigate retinotectal synaptic physiology,
Figure 1. Changes in the Connectivity of Excitatory Circuitry in the Early Visual System of the blu Mutant The excitatory circuitry in the early visual system consists of photoreceptors (PR), bipolar cells (BC), and retinal ganglion cells (RGC) which project to tectal neurons (shown in blue). RGCs, but not photoreceptors or bipolar cells, express Vglut2a, so the retinotectal synapse is likely to be the first site in the visual stream affected by the blu mutation. At retinotectal synapses, the amount of glutamate packaged in each vesicle is higher in WT (left inset) than in blu (right inset). An expansion of blu RGC axonal territory compensates for their reduced synapses, but increases their convergence onto tectal cells. The spatial extent of the tectal cells’ receptive fields (RF) is largely determined by the distribution of photoreceptors that feed into the tectal cell via bipolar and ganglion cells. Because RGC to tectal cell convergence is higher in the blu mutant, the receptive field is expanded.
an odd selection at first glance since the optomotor response does not require the retinotectal projection (Roeser and Baier, 2003). However, the abnormal morphology of the blu retinotectal projection was the phenotype that originally brought the mutant into the limelight (Baier et al., 1996; Neuhauss et al., 1999). Furthermore, the tectum is the most experimentally accessible retinorecipient structure, making it the best choice for these challenging in vivo patch-clamp experiments. Both visual stimulation and direct electrical stimulation of RGCs evoked excitatory postsynaptic currents (EPSCs) in tectal cells that were within the range seen in WT, and the electrically evoked EPSCs were blocked by AMPA receptor antagonists. So blu RGCs clearly continue to secrete glutamate in response to ac-
tion potentials. How then are blu RGC synaptic vesicles filled in Vglut2a’s absence? Vglut1a is a likely answer, as it is the only other Vglut expressed, albeit weakly, by WT and blu RGCs. Importantly, the expression of Vglut1a is not upregulated in blu RGCs, suggesting that Vglut1a is not likely to completely compensate for the loss of Vglut2a. To probe synaptic transmission in more detail, Smear and colleagues recorded spontaneous miniature excitatory synaptic currents (mEPSCs). The mean mEPSC amplitude was lower in blu than in WT, consistent with less transmitter being loaded into the blu synaptic vesicles. Because mEPSCs record spontaneous release from all glutamatergic inputs and not just RGCs, and because their amplitude is affected by both pre- and postsynaptic components, the mEPSC data do not permit an unambiguous conclusion about the transmitter content of RGC synaptic vesicles. Smear et al. strengthened this conclusion by showing that exposure to g-DGG, a low-affinity competitive AMPA receptor antagonist, eliminates a larger fraction of the electrically evoked response in blu neurons than in WT neurons. Because g-DGG competes with endogenous transmitter more effectively at blu synapses, the concentration of glutamate must be lower in the mutant retinotectal synaptic cleft, providing strong evidence that the vesicles contain less glutamate (Figure 1). Possibly to compensate for this weakening of individual synapses, mEPSC frequency is elevated in the mutant. Similar homeostatic compensation has been seen at the Drosophila NMJ, where increasing quantal size by Vglut overexpression led to decreased quantal content to maintain the amplitude of end junction potentials (Daniels et al., 2004). Individual blu RGC arbors covered more of the tectum and branched more often than WT RGCs. Given that branch number correlates with synapse number in RGC axons (Ruthazer et al., 2006), the increased mEPSC frequency in blu probably reflects an addition of RGC release sites. Unless the expansion of RGC
Neuron 53, January 4, 2007 ª2007 Elsevier Inc. 5
Neuron
Previews axons is very well matched by an expansion of tectal cell dendritic arbors, the convergence from RGCs onto tectal cells should be greater in the mutant than in WT. This is indeed the case, since blu tectal cell receptive fields are expanded relative to those in WT, indicating that they sample a larger part of the visual scene because they are postsynaptic to more RGCs (see Figure 1). A homeostatic increase in the RGC release sites is not sufficient to explain the receptive field expansion. Why don’t the blu axons simply form more synaptic contacts with a few select tectal targets, thereby preserving convergence and retinotopy? Activity-dependent axonal retractions (Ruthazer et al., 2006) are thought to reduce convergence during retinotectal development (Tao and Poo, 2005). Are these retractions hindered in blu, or is pruning simply overwhelmed by the exuberant addition of synapses, causing a developmental delay in the contraction of receptive fields? Smear et al. focused on young zebrafish (8 days postfertilization or less), so it will be important to see if receptive fields in blu remain expanded relative to WT ones in older fish. Nevertheless, the blu fish allow Smear et al. to determine the impact of tectal receptive field expansion on the mutant’s vision. By comparing the activity of multiple overlapping tectal cells, it is certainly possible to extract
details of the visual scene on a spatial scale finer than that of the tectal cell receptive fields (Meister, 1996); however, it is more likely that the degraded resolving power of tectal cells simply propagates to their targets. To test the resolving power of the tectum, Smear and colleagues assayed the ability of WT and blu larvae to hunt large and small species of paramecium, an extremely salient behavior that depends not only on vision but also on the tectum (Gahtan et al., 2005). They found that blu fish were comparable to WT when tracking down large prey, but significantly less effective at capturing, or even orienting toward, the small prey. Because blu and WT fish orient their swims to the larger paramecia with comparable frequency and are roughly equally successful at capturing even the smaller paramecia after orienting toward them, the mutants are not deficient at capturing prey following their detection. The blu mutants eat fewer small paramecia simply because they cannot see them as well. This paper is remarkable because the authors started with a phenotype based on a forward genetic screen for connectivity defects and have mapped out a plausible path from a genetic lesion to a molecular defect at a particular synapse to physiological abnormalities at that synapse to wiring errors in the local circuitry to degraded circuit performance and
6 Neuron 53, January 4, 2007 ª2007 Elsevier Inc.
finally behavioral deficits. This comprehensive approach helps establish a higher standard in vertebrate model systems for relating changes in synaptic physiology to changes in behavior, and in particular stands as a textbook example of how genetic screens can illuminate complex mechanisms, including homeostatic mechanisms, that cooperate to yield adaptive behaviors. REFERENCES Baier, H., Klostermann, S., Trowe, T., Karlstrom, R.O., Nusslein-Volhard, C., and Bonhoeffer, F. (1996). Development 123, 415–425. Daniels, R.W., Collins, C.A., Gelfand, M.V., Dant, J., Brooks, E.S., Krantz, D.E., and DiAntonio, A. (2004). J. Neurosci. 24, 10466– 10474. Gahtan, E., Tanger, P., and Baier, H. (2005). J. Neurosci. 25, 9294–9303. Meister, M. (1996). Proc. Natl. Acad. Sci. USA 93, 609–614. Neuhauss, S.C., Biehlmaier, O., Seeliger, M.W., Das, T., Kohler, K., Harris, W.A., and Baier, H. (1999). J. Neurosci. 19, 8603–8615. Roeser, T., and Baier, H. (2003). J. Neurosci. 23, 3726–3734. Ruthazer, E.S., Li, J., and Cline, H.T. (2006). J. Neurosci. 26, 3594–3603. Smear, M.C., Tao, H.W., Staub, W., Orger, M.B., Gosse, N.J., Liu, Y., Takahshi, K., Poo, M.M., and Baier, H. (2007). Neuron 53, this issue, 65–77. Tao, H.W., and Poo, M.M. (2005). Neuron 45, 829–836.
Previews it is now clear that signaling events, such as Erk and PI3K activation, are induced from distinct cellular compartments with different latencies. Events that impinge on receptor trafficking and degradation are therefore key junction points for understanding the physiological consequences of receptor activation. TrkA endocytosis and transport has been well studied, and the concept of a signaling endosome that functions as a retrograde platform that supports TrkA survival signaling is established in the field. Ubiquitination of cell-surface receptors has recently emerged as a key regulatory event important for internalization, signaling, and receptor degradation. Recent studies have not only demonstrated that Trk receptors become ubiquitinated but that this is regulated by p75NTR (Geetha et al., 2005; Makkerh et al., 2005). It therefore seems likely that regulated ubiquitination of p75NTR and TrkA will prove to be an important intersection point that will also
facilitate cross-regulation between these receptors. The work of Wehrman et al. (2007) provides key insights into the structural and kinetic issues concerning p75NTR and Trk interactions. With this structural information, improving technical tools, and an increased focus on the cell-biological events that underlie receptor activation and signaling, the future is bright, and the precise mechanisms that regulate the p75NTR-TrkA regulatory network are certain to emerge.
Geetha, T., Jiang, J., and Wooten, M.W. (2005). Mol. Cell 20, 301–312. He, X.L., and Garcia, K.C. (2004). Science 304, 870–875. Hempstead, B.L., Martin-Zanca, D., Kaplan, D.R., Parada, L.F., and Chao, M.V. (1991). Nature 350, 678–683. Ivanisevic, L., Banerjee, K., and Saragovi, H.U. (2003). Oncogene 22, 5677–5685. Kuruvilla, R., Zweifel, L.S., Glebova, N.O., Lonze, B.E., Valdez, G., Ye, H., and Ginty, D.D. (2004). Cell 118, 243–255. Lachyankar, M.B., Condon, P.J., Daou, M.C., De, A.K., Levine, J.B., Obermeier, A., and Ross, A.H. (2003). J. Neurosci. Res. 71, 157–172.
REFERENCES
Lee, K.-F., Davies, A.M., and Jaenisch, R. (1994). Development 120, 1027–1033.
Barker, P.A., and Shooter, E.M. (1994). Neuron 13, 203–215.
Mahadeo, D., Kaplan, L., Chao, M.V., and Hempstead, B.L. (1994). J. Biol. Chem. 269, 6884–6891.
Bibel, M., Hoppe, E., and Barde, Y.A. (1999). EMBO J. 18, 616–622. Brennan, C., Rivas-Plata, K., and Landis, S.C. (1999). Nat. Neurosci. 2, 699–705. Clary, D.O., and Reichardt, L.F. (1994). Proc. Natl. Acad. Sci. USA 91, 11133–11137. Dechant, G., Tsoulfas, P., Parada, L.F., and Barde, Y.A. (1997). J. Neurosci. 17, 5281–5287.
Makkerh, J.P., Ceni, C., Auld, D.S., Vaillancourt, F., Dorval, G., and Barker, P.A. (2005). EMBO Rep. 6, 936–941. Roux, P.P., and Barker, P.A. (2002). Prog. Neurobiol. 67, 203–233. Wehrman, T., He, X., Raab, B., Dukipatti, A., Blau, H., and Garcia, K.C. (2007). Neuron 53, this issue, 25–38.
The blu Blur: Mutation of a Vesicular Glutamate Transporter Reduces the Resolution of Zebrafish Vision Jay Demas1 and Hollis T. Cline1,* 1
Cold Spring Harbor Lab, Beckman Building, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA *Correspondence: [email protected] DOI 10.1016/j.neuron.2006.12.019
Vesicular transporters mediate the packaging of neurotransmitters into synaptic vesicles and can therefore control the amount of neurotransmitter released into the synaptic cleft. In this issue of Neuron, Smear et al. demonstrate that mutation of a vesicular glutamate transporter (Vglut) found in the retinal ganglion cells (RGCs) of zebrafish alters both the synaptic transmission and connectivity between RGCs and their targets, limiting the transfer of visually evoked activity from RGCs and degrading behaviors that depend on high-acuity vision. Discovered in an anatomical screen for zebrafish retinotectal projection defects, the blumenkohl (or blu) mutant was characterized by enlarged termination zones and defasciculation of
RGC axons in a way reminiscent of the shape of its namesake, the cauliflower (Baier et al., 1996; Neuhauss et al., 1999). Reported in this issue of Neuron, Smear et al. (2007) began their
4 Neuron 53, January 4, 2007 ª2007 Elsevier Inc.
investigation by assaying the mutant’s vision using the optomotor response, an innate behavior where zebrafish swim in the same direction as a drifting grating stimulus presented at the
Neuron
Previews bottom of their tank. An elegant motion-nulling experimental design made use of the optomotor response to compare the perception of two gratings drifting in the opposite directions: a test grating with different spatial and temporal frequencies across trials, and a reference grating with fixed properties. On average, a group of zebrafish will swim in the direction of the grating that is more robustly perceived, or they will not swim at all when the two gratings are perceived equally well. To isolate visual perception from possible motor defects, the contrast of a given test grating was adjusted so that there was no net movement. The lower the contrast required for motion nulling, the more sensitive vision is to that test grating. These experiments revealed that the neural mechanisms for processing high-frequency spatial and temporal components of the visual scene were disproportionately affected by the blu mutation. No doubt spurred by their interesting behavioral results, Smear et al. (2007) mapped the blu mutation to vglut2a, a member of the vesicular glutamate transporter family. The mutation is a putative null because it places a stop codon in-frame that eliminates more than 75% of the amino acid sequence, including a number of transmembrane domains. Although retinal expression of Vglut2a is normally robust, it is confined to the ganglion cell layer, whose only glutamatergic residents are RGCs. Because RGCs form synapses onto targets located (almost) exclusively outside the retina, it is not surprising that the electroretinogram and gross anatomy of the blu retina are indistinguishable from those of wild-type fish (Neuhauss et al., 1999). This led to a fortuitous situation in which the blu mutant retinas have a selective loss of Vglut2a in RGCs, while other Vglut gene expression appears to be unperturbed in the CNS. Smear and colleagues hypothesized that the mutant’s visual deficits are likely to be a consequence of defective synaptic transmission between RGCs and their targets. Smear et al. (2007) chose to investigate retinotectal synaptic physiology,
Figure 1. Changes in the Connectivity of Excitatory Circuitry in the Early Visual System of the blu Mutant The excitatory circuitry in the early visual system consists of photoreceptors (PR), bipolar cells (BC), and retinal ganglion cells (RGC) which project to tectal neurons (shown in blue). RGCs, but not photoreceptors or bipolar cells, express Vglut2a, so the retinotectal synapse is likely to be the first site in the visual stream affected by the blu mutation. At retinotectal synapses, the amount of glutamate packaged in each vesicle is higher in WT (left inset) than in blu (right inset). An expansion of blu RGC axonal territory compensates for their reduced synapses, but increases their convergence onto tectal cells. The spatial extent of the tectal cells’ receptive fields (RF) is largely determined by the distribution of photoreceptors that feed into the tectal cell via bipolar and ganglion cells. Because RGC to tectal cell convergence is higher in the blu mutant, the receptive field is expanded.
an odd selection at first glance since the optomotor response does not require the retinotectal projection (Roeser and Baier, 2003). However, the abnormal morphology of the blu retinotectal projection was the phenotype that originally brought the mutant into the limelight (Baier et al., 1996; Neuhauss et al., 1999). Furthermore, the tectum is the most experimentally accessible retinorecipient structure, making it the best choice for these challenging in vivo patch-clamp experiments. Both visual stimulation and direct electrical stimulation of RGCs evoked excitatory postsynaptic currents (EPSCs) in tectal cells that were within the range seen in WT, and the electrically evoked EPSCs were blocked by AMPA receptor antagonists. So blu RGCs clearly continue to secrete glutamate in response to ac-
tion potentials. How then are blu RGC synaptic vesicles filled in Vglut2a’s absence? Vglut1a is a likely answer, as it is the only other Vglut expressed, albeit weakly, by WT and blu RGCs. Importantly, the expression of Vglut1a is not upregulated in blu RGCs, suggesting that Vglut1a is not likely to completely compensate for the loss of Vglut2a. To probe synaptic transmission in more detail, Smear and colleagues recorded spontaneous miniature excitatory synaptic currents (mEPSCs). The mean mEPSC amplitude was lower in blu than in WT, consistent with less transmitter being loaded into the blu synaptic vesicles. Because mEPSCs record spontaneous release from all glutamatergic inputs and not just RGCs, and because their amplitude is affected by both pre- and postsynaptic components, the mEPSC data do not permit an unambiguous conclusion about the transmitter content of RGC synaptic vesicles. Smear et al. strengthened this conclusion by showing that exposure to g-DGG, a low-affinity competitive AMPA receptor antagonist, eliminates a larger fraction of the electrically evoked response in blu neurons than in WT neurons. Because g-DGG competes with endogenous transmitter more effectively at blu synapses, the concentration of glutamate must be lower in the mutant retinotectal synaptic cleft, providing strong evidence that the vesicles contain less glutamate (Figure 1). Possibly to compensate for this weakening of individual synapses, mEPSC frequency is elevated in the mutant. Similar homeostatic compensation has been seen at the Drosophila NMJ, where increasing quantal size by Vglut overexpression led to decreased quantal content to maintain the amplitude of end junction potentials (Daniels et al., 2004). Individual blu RGC arbors covered more of the tectum and branched more often than WT RGCs. Given that branch number correlates with synapse number in RGC axons (Ruthazer et al., 2006), the increased mEPSC frequency in blu probably reflects an addition of RGC release sites. Unless the expansion of RGC
Neuron 53, January 4, 2007 ª2007 Elsevier Inc. 5
Neuron
Previews axons is very well matched by an expansion of tectal cell dendritic arbors, the convergence from RGCs onto tectal cells should be greater in the mutant than in WT. This is indeed the case, since blu tectal cell receptive fields are expanded relative to those in WT, indicating that they sample a larger part of the visual scene because they are postsynaptic to more RGCs (see Figure 1). A homeostatic increase in the RGC release sites is not sufficient to explain the receptive field expansion. Why don’t the blu axons simply form more synaptic contacts with a few select tectal targets, thereby preserving convergence and retinotopy? Activity-dependent axonal retractions (Ruthazer et al., 2006) are thought to reduce convergence during retinotectal development (Tao and Poo, 2005). Are these retractions hindered in blu, or is pruning simply overwhelmed by the exuberant addition of synapses, causing a developmental delay in the contraction of receptive fields? Smear et al. focused on young zebrafish (8 days postfertilization or less), so it will be important to see if receptive fields in blu remain expanded relative to WT ones in older fish. Nevertheless, the blu fish allow Smear et al. to determine the impact of tectal receptive field expansion on the mutant’s vision. By comparing the activity of multiple overlapping tectal cells, it is certainly possible to extract
details of the visual scene on a spatial scale finer than that of the tectal cell receptive fields (Meister, 1996); however, it is more likely that the degraded resolving power of tectal cells simply propagates to their targets. To test the resolving power of the tectum, Smear and colleagues assayed the ability of WT and blu larvae to hunt large and small species of paramecium, an extremely salient behavior that depends not only on vision but also on the tectum (Gahtan et al., 2005). They found that blu fish were comparable to WT when tracking down large prey, but significantly less effective at capturing, or even orienting toward, the small prey. Because blu and WT fish orient their swims to the larger paramecia with comparable frequency and are roughly equally successful at capturing even the smaller paramecia after orienting toward them, the mutants are not deficient at capturing prey following their detection. The blu mutants eat fewer small paramecia simply because they cannot see them as well. This paper is remarkable because the authors started with a phenotype based on a forward genetic screen for connectivity defects and have mapped out a plausible path from a genetic lesion to a molecular defect at a particular synapse to physiological abnormalities at that synapse to wiring errors in the local circuitry to degraded circuit performance and
6 Neuron 53, January 4, 2007 ª2007 Elsevier Inc.
finally behavioral deficits. This comprehensive approach helps establish a higher standard in vertebrate model systems for relating changes in synaptic physiology to changes in behavior, and in particular stands as a textbook example of how genetic screens can illuminate complex mechanisms, including homeostatic mechanisms, that cooperate to yield adaptive behaviors. REFERENCES Baier, H., Klostermann, S., Trowe, T., Karlstrom, R.O., Nusslein-Volhard, C., and Bonhoeffer, F. (1996). Development 123, 415–425. Daniels, R.W., Collins, C.A., Gelfand, M.V., Dant, J., Brooks, E.S., Krantz, D.E., and DiAntonio, A. (2004). J. Neurosci. 24, 10466– 10474. Gahtan, E., Tanger, P., and Baier, H. (2005). J. Neurosci. 25, 9294–9303. Meister, M. (1996). Proc. Natl. Acad. Sci. USA 93, 609–614. Neuhauss, S.C., Biehlmaier, O., Seeliger, M.W., Das, T., Kohler, K., Harris, W.A., and Baier, H. (1999). J. Neurosci. 19, 8603–8615. Roeser, T., and Baier, H. (2003). J. Neurosci. 23, 3726–3734. Ruthazer, E.S., Li, J., and Cline, H.T. (2006). J. Neurosci. 26, 3594–3603. Smear, M.C., Tao, H.W., Staub, W., Orger, M.B., Gosse, N.J., Liu, Y., Takahshi, K., Poo, M.M., and Baier, H. (2007). Neuron 53, this issue, 65–77. Tao, H.W., and Poo, M.M. (2005). Neuron 45, 829–836.