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Reluctant Vesicles Coaxed into the Limelight
Preview 523
distributed in a defined, albeit broader, band that is colocalized with AChR (Brandon et al., 2003; Lin et al., 2005; Misgeld et al., 2002). This is unexpected because denervation of adult muscles leads to overexpression of AChRs in entire muscle fibers (Schaeffer et al., 2001). These results could suggest that nerves may release an ACh-independent signal to suppress AChR expression in nonsynaptic areas. Alternatively, AChR gene expression in adult animals may be regulated by a mechanism more sensitive to activity or electric patterns generated by adult AChRs. Nevertheless, AChR expression and clusters are both regulated by positive and negative signals from the nerve. Negative signals are propagated in the muscle to shut down operation in distance, whereas positive factors reverse the inhibitory effect in the synaptic region (Figure 1). The beautiful coordination between nerves and muscles ensures concentration of AChRs at nowhere but synapses. In sum, the data presented by Lin et al., together with their earlier studies and those by Sanes and colleagues (Brandon et al., 2003; Misgeld et al., 2002), firmly establish a role of AChR in receptor clustering. It allows us to discuss a model that may be generally applicable to other synapses. Neuronal activity regulates the number of neurotransmitter receptors at synapses including AMPA receptors, NMDA receptors, and GABA receptors. Cdk5 is expressed abundantly in the brain and is implicated in neuron migration, neurotransmission, and neuronal cell death (Cheng and Ip, 2003; Cruz and Tsai, 2004). The findings of this paper suggest that the model and perhaps some of its molecular details such as Cdk5 may be applicable to synaptogenesis in the brain. Wen C. Xiong and Lin Mei Program of Developmental Neurobiology Institute of Molecular Medicine and Genetics Department of Neurology Medical College of Georgia Augusta, Georgia 30912
Selected Reading Akaaboune, M., Culican, S.M., Turney, S.G., and Lichtman, J.W. (1999). Science 286, 503–507. Brandon, E.P., Lin, W., D'Amour, K.A., Pizzo, D.P., Dominguez, B., Sugiura, Y., Thode, S., Ko, C.P., Thal, L.J., Gage, F.H., and Lee, K.F. (2003). J. Neurosci. 23, 539–549. Cheng, K., and Ip, N.Y. (2003). Neurosignals 12, 180–190. Cruz, J.C., and Tsai, L.H. (2004). Curr. Opin. Neurobiol. 14, 390–394. Finn, A.J., Feng, G., and Pendergast, A.M. (2003). Nat. Neurosci. 6, 717–723. Fischbach, G.D., and Rosen, K.M. (1997). Annu. Rev. Neruosci. 20, 429–458. Fu, A.K., Fu, W.Y., Cheung, J., Tsim, K.W., Ip, F.C., Wang, J.H., and Ip, N.Y. (2001). Nat. Neurosci. 4, 374–381. Lin, W., Burgess, R.W., Dominguez, B., Pfaff, S.L., Sanes, J.R., and Lee, K.F. (2001). Nature 410, 1057–1064. Lin, W., Dominguez, B., Yang, J., Aryal, P., Brandon, E.P., Gage, F.H., and Lee, K.-F. (2005). Neuron 46, this issue, 569–579. Luo, Z., Wang, Q., Zhou, J., Wang, J., Liu, M., He, X., WynshawBoris, A., Xiong, W., Lu, B., and Mei, L. (2002). Neuron 35, 489–505. Misgeld, T., Burgess, R.W., Lewis, R.M., Cunningham, J.M., Lichtman, J.W., and Sanes, J.R. (2002). Neuron 36, 635–648.
Sanes, J.R., and Lichtman, J.W. (1999). Annu. Rev. Neurosci. 22, 389–442. Schaeffer, L., de Kerchove d'Exaerde, A., and Changeux, J.P. (2001). Neuron 31, 15–22. Trinidad, J.C., and Cohen, J.B. (2004). J. Biol. Chem. 279, 31622– 31628. Yang, X., Arber, S., William, C., Li, L., Tanabe, Y., Jessell, T.M., Birchmeier, C., and Burden, S.J. (2001). Neuron 30, 399–410. DOI 10.1016/j.neuron.2005.05.008
Reluctant Vesicles Coaxed into the Limelight Synapses respond to brief, repetitive stimulation with synaptic depression when initial transmitter release probability is high. Vesicle depletion has been a longstanding hypothesis for depression, but results unexplained by the depletion hypothesis have been nagging. In this issue of Neuron, Xu and Wu show that, under some conditions, calcium current inactivation explains stimulus-dependent depression at the calyx of Held. Synaptic facilitation and depression are two of the earliest described forms of synaptic plasticity (Zucker and Regehr, 2002). These forms of synaptic plasticity are still actively studied, both because of their likely importance to information processing (Thomson, 2003) and because their underlying mechanisms have been difficult to pin down (Zucker and Regehr, 2002). This issue of Neuron contains a new chapter in the mechanistic studies of depression (Xu and Wu, 2005). Elegant studies by Xu and Wu at the calyx of Held show that decreased vesicle release probability is caused under many conditions by Ca2+ current inactivation during repetitive stimulation. Early studies at neuromuscular synapses noted that depression was dependent on the output of the synapse; when initial vesicular output is high, depression of subsequent transmission is greater. Although postsynaptic receptor properties (saturation, desensitization) and transmitter or neuromodulator feedback onto presynaptic receptors can partially account for depression at some synapses (Zucker and Regehr, 2002), these mechanisms cannot account for the ubiquity of depression across many different synapse types. Furthermore, even when the contributions of these mechanisms are taken into account, depression is often still evident. Vesicle depletion has represented a more global, favored hypothesis since the earliest studies of synaptic depression. It is well known that a subset of synaptic vesicles residing at the presynaptic terminal is poised and available for release (Rizzoli and Betz, 2005). The depletion of these accessible vesicles during repetitive stimulation is thought to account for a
Neuron 524
major portion of depression at many synapses (Zucker and Regehr, 2002). Nevertheless, many observations have accumulated over the years that do not fit with the idea that vesicle depletion explains presynaptic depression. For instance, vesicle depletion predicts that, in quantal analysis of synaptic depression, the binomial parameter N should change with depression. Classic studies of depression at the neuromuscular junction found that not only N, but also p, the probability of vesicle release, changed during depressing stimulus trains. Many studies have also observed that the steady-state level of transmitter output during action potential trains is not close enough to zero for the depletion model to apply. Other work has shown that the amount of depression does not scale appropriately with the amount of initial transmitter release, as would be expected from the depletion model (Zucker and Regehr, 2002). Finally, some studies have shown that “depleting” trains of presynaptic action potentials can cross-deplete with other depleting secretagogues (e.g., sucrose application, sustained depolarization) (Rosenmund and Stevens, 1996). However, under some conditions, trains of action potentials that cause strong EPSC depression do not cross-deplete available vesicles (Moulder and Mennerick, 2005; Schneggenburger et al., 1999; Wu and Borst, 1999). The paper by Xu and Wu provides an appealing mechanistic solution to the puzzle of the relative contributions of depletion and release probability to stimulus-dependent synaptic depression. Altering Ca2+ influx into the presynaptic terminal has been a favorite way of altering release probability experimentally for more than 50 years. Now it appears that this mechanism is also exploited by nature to downregulate transmission during action potential trains. In the present study, the authors measure Ca2+ currents in the calyx presynaptic terminal during spike-like depolarizations while simultaneously monitoring transmitter release. The high-voltage activated Ca2+ channels that drive transmitter release do not inactivate rapidly, and therefore inactivation may not be a prime suspect for changing release probability during the brief, repetitive depolarizations provided by action potentials. Furthermore, facilitation of Ca2+ current can occur under some repetitive stimulus conditions (Catterall, 2000). Nevertheless, Xu and Wu find that sufficient Ca2+ current inactivation occurs during action potential trains over 0.2–100 Hz to explain much of the depression of transmitter release during these trains. Because of the nonlinear dependence of transmitter release on Ca2+ concentration, a small amount of channel inactivation and resulting Ca2+ influx can lead to a large depression of transmitter release. The authors also use time-resolved capacitance measurements from the presynaptic terminal to assay directly the number of available vesicles after action potential trains at varied frequency. The results clearly show that depletion is minimal until frequency trains reach w100 Hz. Xu and Wu propose that Ca2+ channel inactivation may have been missed in previous studies because, with these very high-frequency trains, depletion accounts for the bulk of depression. Previous studies have shown, however, that Ca2+ channel inactivation can also contribute to depression during trains
at R100 Hz if those trains persist on the order of seconds (Forsythe et al., 1998) The authors show that the mechanism of inactivation of Ca2+ channels is Ca2+ dependent. P/Q-type Ca2+ channels are prominently affected, and the authors’ results are consistent with previous work showing that the mechanism of Ca2+-dependent inactivation involves calmodulin (Catterall, 2000). The involvement of Ca2+-dependent inactivation in depression is appealing because this could explain why reducing transmitter release (usually achieved by reducing Ca2+ influx) also reduces synaptic depression. Under a version of the Ca2+ current inactivation hypothesis, it is not the decreased depletion of vesicles that is important when transmitter release is reduced, but rather the reduced Ca2+-dependent depression of Ca2+ influx. Therefore, it may be a bit surprising that, in Xu and Wu’s study, inactivation of Ca2+ current was relatively insensitive to depression of Ca2+ influx. Accordingly, it is a little unclear how previous observations of release dependence of depression can be accounted for by this mechanism. Also unclear is how the present mechanism accounts for previous results at the calyx suggesting that a factor related to pool replenishment accounts for reduced release probability during very high-frequency trains (Wu and Borst, 1999). It seems possible that other mechanisms of reduced release probability may still be lingering and may represent the next chapter in our understanding of synaptic depression. Because large synapses like the calyx of Held may have a particularly large pool of available vesicles (Rizzoli and Betz, 2005), it is possible that, at smaller synapses with smaller vesicle pools, depletion is more prominent. On the other hand, we and others have recently suggested that small hippocampal glutamate, but not GABA, synapses also have a depletion-independent form of synaptic depression (Brody and Yue, 2000; Moulder and Mennerick, 2005). It will be interesting to test the ubiquity of Ca2+ current inactivation as a mechanism of release-independent synaptic depression. It seems likely that, as we gain better understanding over the factors controlling vesicle availability and release probability, we will find that synapses use multiple ways of controlling short-term efficacy. Krista L. Moulder1 and Steven Mennerick1,2 1 Department of Psychiatry 2 Department of Anatomy and Neurobiology Washington University School of Medicine St. Louis, Missouri 63110
Selected Reading Brody, D.L., and Yue, D.T. (2000). J. Neurosci. 20, 2480–2494. Catterall, W.A. (2000). Annu. Rev. Cell Dev. Biol. 16, 521–555. Forsythe, I.D., Tsujimoto, T., Barnes-Davies, M., Cuttle, M.F., and Takahashi, T. (1998). Neuron 20, 797–807. Moulder, K.L., and Mennerick, S. (2005). J. Neurosci. 25, 3842– 3850. Rizzoli, S.O., and Betz, W.J. (2005). Nat. Rev. Neurosci. 6, 57–69. Rosenmund, C., and Stevens, C.F. (1996). Neuron 16, 1197–1207.
Preview 525
Schneggenburger, R., Meyer, A.C., and Neher, E. (1999). Neuron 23, 399–409. Thomson, A.M. (2003). J. Comput. Neurosci. 15, 159–202. Wu, L.G., and Borst, J.G. (1999). Neuron 23, 821–832. Xu, J., and Wu, L.-G. (2005). Neuron 46, this issue, 633–645. Zucker, R.S., and Regehr, W.G. (2002). Annu. Rev. Physiol. 64, 355–405. DOI 10.1016/j.neuron.2005.05.003
distributed in a defined, albeit broader, band that is colocalized with AChR (Brandon et al., 2003; Lin et al., 2005; Misgeld et al., 2002). This is unexpected because denervation of adult muscles leads to overexpression of AChRs in entire muscle fibers (Schaeffer et al., 2001). These results could suggest that nerves may release an ACh-independent signal to suppress AChR expression in nonsynaptic areas. Alternatively, AChR gene expression in adult animals may be regulated by a mechanism more sensitive to activity or electric patterns generated by adult AChRs. Nevertheless, AChR expression and clusters are both regulated by positive and negative signals from the nerve. Negative signals are propagated in the muscle to shut down operation in distance, whereas positive factors reverse the inhibitory effect in the synaptic region (Figure 1). The beautiful coordination between nerves and muscles ensures concentration of AChRs at nowhere but synapses. In sum, the data presented by Lin et al., together with their earlier studies and those by Sanes and colleagues (Brandon et al., 2003; Misgeld et al., 2002), firmly establish a role of AChR in receptor clustering. It allows us to discuss a model that may be generally applicable to other synapses. Neuronal activity regulates the number of neurotransmitter receptors at synapses including AMPA receptors, NMDA receptors, and GABA receptors. Cdk5 is expressed abundantly in the brain and is implicated in neuron migration, neurotransmission, and neuronal cell death (Cheng and Ip, 2003; Cruz and Tsai, 2004). The findings of this paper suggest that the model and perhaps some of its molecular details such as Cdk5 may be applicable to synaptogenesis in the brain. Wen C. Xiong and Lin Mei Program of Developmental Neurobiology Institute of Molecular Medicine and Genetics Department of Neurology Medical College of Georgia Augusta, Georgia 30912
Selected Reading Akaaboune, M., Culican, S.M., Turney, S.G., and Lichtman, J.W. (1999). Science 286, 503–507. Brandon, E.P., Lin, W., D'Amour, K.A., Pizzo, D.P., Dominguez, B., Sugiura, Y., Thode, S., Ko, C.P., Thal, L.J., Gage, F.H., and Lee, K.F. (2003). J. Neurosci. 23, 539–549. Cheng, K., and Ip, N.Y. (2003). Neurosignals 12, 180–190. Cruz, J.C., and Tsai, L.H. (2004). Curr. Opin. Neurobiol. 14, 390–394. Finn, A.J., Feng, G., and Pendergast, A.M. (2003). Nat. Neurosci. 6, 717–723. Fischbach, G.D., and Rosen, K.M. (1997). Annu. Rev. Neruosci. 20, 429–458. Fu, A.K., Fu, W.Y., Cheung, J., Tsim, K.W., Ip, F.C., Wang, J.H., and Ip, N.Y. (2001). Nat. Neurosci. 4, 374–381. Lin, W., Burgess, R.W., Dominguez, B., Pfaff, S.L., Sanes, J.R., and Lee, K.F. (2001). Nature 410, 1057–1064. Lin, W., Dominguez, B., Yang, J., Aryal, P., Brandon, E.P., Gage, F.H., and Lee, K.-F. (2005). Neuron 46, this issue, 569–579. Luo, Z., Wang, Q., Zhou, J., Wang, J., Liu, M., He, X., WynshawBoris, A., Xiong, W., Lu, B., and Mei, L. (2002). Neuron 35, 489–505. Misgeld, T., Burgess, R.W., Lewis, R.M., Cunningham, J.M., Lichtman, J.W., and Sanes, J.R. (2002). Neuron 36, 635–648.
Sanes, J.R., and Lichtman, J.W. (1999). Annu. Rev. Neurosci. 22, 389–442. Schaeffer, L., de Kerchove d'Exaerde, A., and Changeux, J.P. (2001). Neuron 31, 15–22. Trinidad, J.C., and Cohen, J.B. (2004). J. Biol. Chem. 279, 31622– 31628. Yang, X., Arber, S., William, C., Li, L., Tanabe, Y., Jessell, T.M., Birchmeier, C., and Burden, S.J. (2001). Neuron 30, 399–410. DOI 10.1016/j.neuron.2005.05.008
Reluctant Vesicles Coaxed into the Limelight Synapses respond to brief, repetitive stimulation with synaptic depression when initial transmitter release probability is high. Vesicle depletion has been a longstanding hypothesis for depression, but results unexplained by the depletion hypothesis have been nagging. In this issue of Neuron, Xu and Wu show that, under some conditions, calcium current inactivation explains stimulus-dependent depression at the calyx of Held. Synaptic facilitation and depression are two of the earliest described forms of synaptic plasticity (Zucker and Regehr, 2002). These forms of synaptic plasticity are still actively studied, both because of their likely importance to information processing (Thomson, 2003) and because their underlying mechanisms have been difficult to pin down (Zucker and Regehr, 2002). This issue of Neuron contains a new chapter in the mechanistic studies of depression (Xu and Wu, 2005). Elegant studies by Xu and Wu at the calyx of Held show that decreased vesicle release probability is caused under many conditions by Ca2+ current inactivation during repetitive stimulation. Early studies at neuromuscular synapses noted that depression was dependent on the output of the synapse; when initial vesicular output is high, depression of subsequent transmission is greater. Although postsynaptic receptor properties (saturation, desensitization) and transmitter or neuromodulator feedback onto presynaptic receptors can partially account for depression at some synapses (Zucker and Regehr, 2002), these mechanisms cannot account for the ubiquity of depression across many different synapse types. Furthermore, even when the contributions of these mechanisms are taken into account, depression is often still evident. Vesicle depletion has represented a more global, favored hypothesis since the earliest studies of synaptic depression. It is well known that a subset of synaptic vesicles residing at the presynaptic terminal is poised and available for release (Rizzoli and Betz, 2005). The depletion of these accessible vesicles during repetitive stimulation is thought to account for a
Neuron 524
major portion of depression at many synapses (Zucker and Regehr, 2002). Nevertheless, many observations have accumulated over the years that do not fit with the idea that vesicle depletion explains presynaptic depression. For instance, vesicle depletion predicts that, in quantal analysis of synaptic depression, the binomial parameter N should change with depression. Classic studies of depression at the neuromuscular junction found that not only N, but also p, the probability of vesicle release, changed during depressing stimulus trains. Many studies have also observed that the steady-state level of transmitter output during action potential trains is not close enough to zero for the depletion model to apply. Other work has shown that the amount of depression does not scale appropriately with the amount of initial transmitter release, as would be expected from the depletion model (Zucker and Regehr, 2002). Finally, some studies have shown that “depleting” trains of presynaptic action potentials can cross-deplete with other depleting secretagogues (e.g., sucrose application, sustained depolarization) (Rosenmund and Stevens, 1996). However, under some conditions, trains of action potentials that cause strong EPSC depression do not cross-deplete available vesicles (Moulder and Mennerick, 2005; Schneggenburger et al., 1999; Wu and Borst, 1999). The paper by Xu and Wu provides an appealing mechanistic solution to the puzzle of the relative contributions of depletion and release probability to stimulus-dependent synaptic depression. Altering Ca2+ influx into the presynaptic terminal has been a favorite way of altering release probability experimentally for more than 50 years. Now it appears that this mechanism is also exploited by nature to downregulate transmission during action potential trains. In the present study, the authors measure Ca2+ currents in the calyx presynaptic terminal during spike-like depolarizations while simultaneously monitoring transmitter release. The high-voltage activated Ca2+ channels that drive transmitter release do not inactivate rapidly, and therefore inactivation may not be a prime suspect for changing release probability during the brief, repetitive depolarizations provided by action potentials. Furthermore, facilitation of Ca2+ current can occur under some repetitive stimulus conditions (Catterall, 2000). Nevertheless, Xu and Wu find that sufficient Ca2+ current inactivation occurs during action potential trains over 0.2–100 Hz to explain much of the depression of transmitter release during these trains. Because of the nonlinear dependence of transmitter release on Ca2+ concentration, a small amount of channel inactivation and resulting Ca2+ influx can lead to a large depression of transmitter release. The authors also use time-resolved capacitance measurements from the presynaptic terminal to assay directly the number of available vesicles after action potential trains at varied frequency. The results clearly show that depletion is minimal until frequency trains reach w100 Hz. Xu and Wu propose that Ca2+ channel inactivation may have been missed in previous studies because, with these very high-frequency trains, depletion accounts for the bulk of depression. Previous studies have shown, however, that Ca2+ channel inactivation can also contribute to depression during trains
at R100 Hz if those trains persist on the order of seconds (Forsythe et al., 1998) The authors show that the mechanism of inactivation of Ca2+ channels is Ca2+ dependent. P/Q-type Ca2+ channels are prominently affected, and the authors’ results are consistent with previous work showing that the mechanism of Ca2+-dependent inactivation involves calmodulin (Catterall, 2000). The involvement of Ca2+-dependent inactivation in depression is appealing because this could explain why reducing transmitter release (usually achieved by reducing Ca2+ influx) also reduces synaptic depression. Under a version of the Ca2+ current inactivation hypothesis, it is not the decreased depletion of vesicles that is important when transmitter release is reduced, but rather the reduced Ca2+-dependent depression of Ca2+ influx. Therefore, it may be a bit surprising that, in Xu and Wu’s study, inactivation of Ca2+ current was relatively insensitive to depression of Ca2+ influx. Accordingly, it is a little unclear how previous observations of release dependence of depression can be accounted for by this mechanism. Also unclear is how the present mechanism accounts for previous results at the calyx suggesting that a factor related to pool replenishment accounts for reduced release probability during very high-frequency trains (Wu and Borst, 1999). It seems possible that other mechanisms of reduced release probability may still be lingering and may represent the next chapter in our understanding of synaptic depression. Because large synapses like the calyx of Held may have a particularly large pool of available vesicles (Rizzoli and Betz, 2005), it is possible that, at smaller synapses with smaller vesicle pools, depletion is more prominent. On the other hand, we and others have recently suggested that small hippocampal glutamate, but not GABA, synapses also have a depletion-independent form of synaptic depression (Brody and Yue, 2000; Moulder and Mennerick, 2005). It will be interesting to test the ubiquity of Ca2+ current inactivation as a mechanism of release-independent synaptic depression. It seems likely that, as we gain better understanding over the factors controlling vesicle availability and release probability, we will find that synapses use multiple ways of controlling short-term efficacy. Krista L. Moulder1 and Steven Mennerick1,2 1 Department of Psychiatry 2 Department of Anatomy and Neurobiology Washington University School of Medicine St. Louis, Missouri 63110
Selected Reading Brody, D.L., and Yue, D.T. (2000). J. Neurosci. 20, 2480–2494. Catterall, W.A. (2000). Annu. Rev. Cell Dev. Biol. 16, 521–555. Forsythe, I.D., Tsujimoto, T., Barnes-Davies, M., Cuttle, M.F., and Takahashi, T. (1998). Neuron 20, 797–807. Moulder, K.L., and Mennerick, S. (2005). J. Neurosci. 25, 3842– 3850. Rizzoli, S.O., and Betz, W.J. (2005). Nat. Rev. Neurosci. 6, 57–69. Rosenmund, C., and Stevens, C.F. (1996). Neuron 16, 1197–1207.
Preview 525
Schneggenburger, R., Meyer, A.C., and Neher, E. (1999). Neuron 23, 399–409. Thomson, A.M. (2003). J. Comput. Neurosci. 15, 159–202. Wu, L.G., and Borst, J.G. (1999). Neuron 23, 821–832. Xu, J., and Wu, L.-G. (2005). Neuron 46, this issue, 633–645. Zucker, R.S., and Regehr, W.G. (2002). Annu. Rev. Physiol. 64, 355–405. DOI 10.1016/j.neuron.2005.05.003