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progenitors in the intermediate zone and SVZ. Through knockdown of Eml1 synthesis using short hairpin RNA, Kielar et al.11 also show that Eml1 deficiency alone is able to cause disorganized migration and that reintroduction of wild-type Eml1 rescues this defect. These data indicate that lack of Eml1 is necessary and sufficient for the cortical heterotopia in HeCo mice and that loss of function leads to misplacement of upper-layer progenitors and cortical disorganization. The results of this study reveal that the mutation of a single gene, encoding the Eml1 protein, can cause subcortical heterotopias in mice and is responsible for some fraction of cases of giant subcortical heterotopia. These defects, unlike classic DCX- or LIS1-associated lissencephalies, are not the result of a primary
neuronal migration defect, but are rather a result of the disruption of Eml1’s role in the maintenance and organization of progenitors in the ventricular zone. All indications are that ectopic progenitors are the primary cause of the cortical heterotopias in this syndrome, and it seems likely that this will be the first of a new set of similar disorders that are identified as resulting from disruption of cortical development in humans because of scaffolding defects that secondarily impair neuronal migration. Previous studies have hinted at the possibility that cytoskeletal disruption by manipulating RhoA GTPase function in the radial glial scaffolding can secondarily cause cortical heterotopias in experimental animals14, and Kielar et al.11 bring these previous suspicions to fruition by identifying the cause of this human syndrome.
COMPETING FINANCIAL INTERESTS The authors declare no competing financial interests. Geschwind, D.H. & Rakic, P. Neuron 80, 633–647 (2013). Chenn, A. & Walsh, C.A. Science 297, 365–369 (2002). Siegenthaler, J.A. et al. Cell 139, 597–609 (2009). Asami, M. et al. Development 138, 5067–5078 (2011). 5. Konno, D. et al. Nat. Cell Biol. 10, 93–101 (2008). 6. Javaherian, A. & Kriegstein, A. Cereb. Cortex 19 (suppl. 1), i70–i77 (2009). 7. Noctor, S.C., Martinez-Cerdeno, V. & Kriegstein, A.R. J. Comp. Neurol. 508, 28–44 (2008). 8. Molnár, Z. & Clowry, G. Prog. Brain Res. 195, 45–70 (2012). 9. Moon, H.M. & Wynshaw-Boris, A. Wiley Interdiscip. Rev. Dev. Biol. 2, 229–245 (2013). 10. Barkovich, A.J., Kuzniecky, R.I., Jackson, G.D., Guerrini, R. & Dobyns, W.B. Neurology 65, 1873–1887 (2005). 11. Kielar, M. et al. Nat. Neurosci. 17, 923–933 (2014). 12. Croquelois, A. et al. Cereb. Cortex 19, 563–575 (2009). 13. Novegno, F. et al. Epilepsy Res. 87, 88–94 (2009). 14. Cappello, S. et al. Neuron 73, 911–924 (2012). 1. 2. 3. 4.
Unlocking the constraints on memory formation Dina P Matheos & Marcelo A Wood A leading therapeutic molecule for multiple sclerosis, FTY720, is shown to mimic a key component of sphingolipid signaling, resulting in specific manipulation of histone deacetylases and the extinction of memory. It is well known that genomic DNA undergoes a nearly incomprehensible level of compaction so that all of our genetic information fits into a tiny nucleus. This compaction, carried out by specialized chromatin modification and chromatin remodeling complexes, solves a storage problem, but in turn creates a DNA access problem. How, then, is access achieved to turn on and off specific genes required for long-term memory? One mechanism involves the same chromatin-modifying enzymes that package genomic DNA: histone deacetylases (HDACs). Endogenous regulators of HDACs remain elusive. However, a relatively recent discovery demonstrated that sphingosine-1-phosphate (S1P) is an endogenous HDAC inhibitor1. Hait et al.2 report in this issue of Nature Neuroscience that a synthetic analog of sphingosine, fingolimod (referred to here as FTY720), is recognized by intracellular machinery in a similar fashion to S1P, including the inhibition of HDACs. This opens a line of investigation into the signaling mechanisms that regulate HDAC activity, as well as a potential avenue for therapeutic development of cognitive enhancers. Fingolimod (Gilenya) is US Food and Drug Administration approved for the treatment of Dina P. Matheos and Marcelo A. Wood are in the Department of Neurobiology and Behavior, Center for the Neurobiology of Learning and Memory, University of California Irvine, Irvine, California, USA. e-mail: [email protected] or [email protected]
relapsing-remitting multiple sclerosis (RRMS; see ref. 3 for a review). In earlier studies examining the action of FTY720, researchers found that the phosphorylated form of FTY720 (FTY720-P) was structurally similar to sphingosine and was likewise a substrate of sphingosine kinase 2 (SphK2)4,5. As a mimetic of S1P, FTY720 acts initially as an agonist of the S1P receptors on the cell membrane, which are then internalized, thereby inhibiting S1P receptor function. For its treatment of RRMS, FTY720 acts by binding of S1P receptors at the plasma membrane. This binding inhibits egress of a certain subset of T cells from lymph nodes, thereby reducing the destructive inflammatory response in the CNS associated with RRMS3. However, S1P has an intriguing second mode of action that is independent of binding to S1P receptors on the cell membrane. S1P is an endogenous inhibitor of HDACs, and this inhibition occurs through an interaction with HDACs in the nucleus1. This finding represents a paradigm shift in thinking about the function of sphingolipid signaling because the nuclear actions of S1P are independent of its cell surface receptor signaling mechanisms. Considering the structural similarity between S1P and FTY720, it might be possible for FTY720 to hijack the pathways involving SphK2, ultimately leading to the regulation of HDACs and even memory (Fig. 1). This is the focus of the study by Hait et al.2. The authors first asked whether FTY720 would function similarly to S1P in neurons.
nature neuroscience volume 17 | number 7 | july 2014
They demonstrated that FTY720 is taken up by neurons and phosphorylated by SphK2 (the main isoform of this kinase found in the CNS), and that this phosphorylation event leads to retention in the nucleus. Furthermore, in hippocampal neurons treated with FTY720, accumulation of nuclear FTY720-P resulted in the decrease of endogenous nuclear S1P, suggesting direct competition between the similar molecules. Functionally, FTY720-P led to the increase of the same histone acetylation marks that S1P affects in vivo. The phosphorylation of FTY720 was blocked by short interfering RNA against SphK2, suggesting that SphK2 is indeed the kinase directly phosphorylating FTY720. To show that the increases in acetylation by FTY720-P are independent of potential interaction between FTY720-P and S1P receptors on the cell surface, Hait et al.2 treated purified nuclei with FTY720. This led to increased histone acetylation. Thus, FTY720 is sufficient to drive histone acetylation in purified nuclei. The authors also demonstrated that FTY720-P added to intact cells had no effect on acetylation. Together, these and additional results suggest that FTY720 is phosphorylated in the nucleus by SphK2 and that nuclear FTY720-P regulates specific histone acetylation. How does FTY720-P lead to the increase in histone acetylation? Modeling the docking of FTY720-P to the catalytic domain of HDAC2 using the crystal structure of HDAC2 suggests that FTY720-P has interactions in the catalytic 895
news and views
ATP SphK2 FTY720
FTY720-P
HDAC
Cytoplasm Nucleus
Ac
Ac
npg
© 2014 Nature America, Inc. All rights reserved.
Ac
Ac
Gene silencing
Gene expression
Blocks memory
Facilitates memory
Figure 1 A nuclear role for FTY720-P. Nuclear phosphorylation of FTY720 (FTY720-P) by SphK2 allows binding in the catalytic domain of class I HDACs, thereby inhibiting them. This causes an increase in certain histone acetylation marks (Ac) that can change the DNA environment and lead to an increase in transcription required for long-term memory processes, including extinction.
domain similar to those of the HDAC inhibitor SAHA (Fig. 1). Indeed, in an experiment using purified recombinant HDACs, FTY720-P was found to block HDACs 1, 2, 3 and 8, but not 7. There are slight differences between the predicted binding of FTY720-P and that of SAHA, which may account for the observation that SAHA affects HDAC7, but FTY720-P does not. In any case, the data provide a compelling case for FTY720-P functioning as a bona fide HDAC inhibitor. One note of caution is with regard to the interpretation of the mode of action. If a molecule binds a catalytic domain, then it is thought to disrupt the enzymatic function. However, and especially with regard to HDACs, it is entirely possible that FTY720-P disrupts protein-protein interactions (see ref. 6 for an example involving HDAC3 and HDAC4), which could lead to similar downstream effects of increased histone acetylation. Another key question addressed by the authors was whether FTY720 could affect synaptic plasticity and memory processes. An extensive literature has demonstrated that either pharmacological or genetic manipulation of specific HDACs affects synaptic plasticity and memory processes7–9. The histone acetylation changes caused by FTY720-P are associated with epigenetic regulation of learning and memory. Thus, the authors examined whether FTY720 would function like other known HDAC inhibitors with regard to synaptic plasticity and memory. The main problem was how to dissociate potential effects of FTY720 on memory from its known effect on lymphocyte trafficking. To address this problem, the authors used severe 896
combined immunodeficiency (SCID) mice, which lack T or B lymphocytes. Mice treated with a clinically relevant dose of FTY720 showed an accumulation of FTY720-P in hippocampal neurons, along with a corresponding decrease in S1P and an increase in histone acetylation. The authors used two different hippocampus-dependent tasks, contextual fear conditioning and the Morris water maze (MWM). In both the MWM and the fear conditioning tasks, animals treated with FTY720 behaved similarly to littermates treated with saline, indicating that FTY720 does not affect acquisition of memory. This is an intriguing result, as there have been mixed results in the literature regarding the ability of HDAC inhibitors, when delivered systemically, to enhance acquisition of contextual fear memories and enhance learning during the acquisition phase of the MWM. These are inherently stressful models in which to study memory, and it is difficult to observe enhancements, most likely because of the elevated stress. It will be interesting to determine whether FTY720 modulates memory formation for subthreshold learning events or nonstressful memory formation. Regardless, the authors did observe an effect on the extinction of contextual fear. In the fear conditioning and extinction protocol used by the authors, vehicle-treated mice extinguished well, but the extinction learning did not persist, as demonstrated by increased freezing behavior a day after extinction. In contrast, FTY720treated mice achieved similar extinction levels by the end of the extinction training, and they
exhibited significantly lower freezing than the vehicle-treated mice on the test day following extinction learning. These findings suggest that FTY720 facilitated the transition of subthreshold extinction training into a robust form of extinction memory (see also ref. 10). The mechanism may involve SphK2, as Sphk2–/– homozygous knockout mice completely failed to extinguish and FTY720 was unable to rescue extinction learning in these knockout mice. Understanding which HDACs may be involved in FTY720-dependent modulation of extinction remains an open question. HDACs have a complicated role in extinction, as general HDAC inhibitors, such as sodium butyrate, valproate and trichostatin A, have been shown to enhance extinction of contextual and cued fear10,11. Individual HDACs, including HDAC3 (ref. 12) and HDAC2 (ref. 13), have also been shown to affect extinction. In contrast, HDAC1 appears to have an opposite role. Inhibition of HDAC1 blocks extinction and overexpression of wild-type HDAC1 facilitates extinction14. Thus, how exactly FTY720-P may be regulating extinction remains a complex question, as FTY720-P can affect HDAC1, 2, 3 and 8. In summary, the study by Hait et al.2 opens an exciting new door to the development of cognitive enhancers that modulate epigenetic machinery during memory consolidation. The findings also provide additional support for the newly discovered role of S1P, and FTY720, in nuclear functions that is independent of their previously characterized activities at the cell surface and their interactions with S1P receptors. This research represents the tip of the iceberg and future work will undoubtedly continue to expand our knowledge of how sphingolipid metabolism and signaling, and pharmacological manipulation of that signaling, function to modulate neuronal activity during synaptic plasticity, learning and memory. COMPETING FINANCIAL INTERESTS The authors declare no competing financial interests. 1. Hait, N.C. et al. Science 325, 1254–1257 (2009). 2. Hait, N.C. et al. Nat. Neurosci. 17, 971–980 (2014). 3. Brinkmann, V. et al. Nat. Rev. Drug Discov. 9, 883–897 (2010). 4. Brinkmann, V. et al. J. Biol. Chem. 277, 21453– 21457 (2002). 5. Zemann, B. et al. Blood 15, 1454–1458 (2006). 6. McQuown, S.C. et al. J. Neurosci. 31, 764–774 (2011). 7. Peixoto, L. & Abel, T. Neuropsychopharmacology 38, 62–76 (2013). 8. Day, J.J. & Sweatt, J.D. Neuron 70, 813–829 (2011). 9. Lattal, K.M. & Wood, M.A. Nat. Neurosci. 16, 124–129 (2013). 10. Lattal, K.M., Barrett, R.M. & Wood, M.A. Behav. Neurosci. 121, 1125–1131 (2007). 11. Bredy, T.W. et al. Learn. Mem. 14, 268–276 (2007). 12. Malvaez, M. et al. Proc. Natl. Acad. Sci. USA 110, 2647–2652 (2013). 13. Morris, M.J. et al. J. Neurosci. 33, 6401–6411. 14. Bahari-Javan, S. et al. J. Neurosci. 32, 5062–5073 (2012).
volume 17 | number 7 | july 2014 nature neuroscience
npg
© 2014 Nature America, Inc. All rights reserved.
progenitors in the intermediate zone and SVZ. Through knockdown of Eml1 synthesis using short hairpin RNA, Kielar et al.11 also show that Eml1 deficiency alone is able to cause disorganized migration and that reintroduction of wild-type Eml1 rescues this defect. These data indicate that lack of Eml1 is necessary and sufficient for the cortical heterotopia in HeCo mice and that loss of function leads to misplacement of upper-layer progenitors and cortical disorganization. The results of this study reveal that the mutation of a single gene, encoding the Eml1 protein, can cause subcortical heterotopias in mice and is responsible for some fraction of cases of giant subcortical heterotopia. These defects, unlike classic DCX- or LIS1-associated lissencephalies, are not the result of a primary
neuronal migration defect, but are rather a result of the disruption of Eml1’s role in the maintenance and organization of progenitors in the ventricular zone. All indications are that ectopic progenitors are the primary cause of the cortical heterotopias in this syndrome, and it seems likely that this will be the first of a new set of similar disorders that are identified as resulting from disruption of cortical development in humans because of scaffolding defects that secondarily impair neuronal migration. Previous studies have hinted at the possibility that cytoskeletal disruption by manipulating RhoA GTPase function in the radial glial scaffolding can secondarily cause cortical heterotopias in experimental animals14, and Kielar et al.11 bring these previous suspicions to fruition by identifying the cause of this human syndrome.
COMPETING FINANCIAL INTERESTS The authors declare no competing financial interests. Geschwind, D.H. & Rakic, P. Neuron 80, 633–647 (2013). Chenn, A. & Walsh, C.A. Science 297, 365–369 (2002). Siegenthaler, J.A. et al. Cell 139, 597–609 (2009). Asami, M. et al. Development 138, 5067–5078 (2011). 5. Konno, D. et al. Nat. Cell Biol. 10, 93–101 (2008). 6. Javaherian, A. & Kriegstein, A. Cereb. Cortex 19 (suppl. 1), i70–i77 (2009). 7. Noctor, S.C., Martinez-Cerdeno, V. & Kriegstein, A.R. J. Comp. Neurol. 508, 28–44 (2008). 8. Molnár, Z. & Clowry, G. Prog. Brain Res. 195, 45–70 (2012). 9. Moon, H.M. & Wynshaw-Boris, A. Wiley Interdiscip. Rev. Dev. Biol. 2, 229–245 (2013). 10. Barkovich, A.J., Kuzniecky, R.I., Jackson, G.D., Guerrini, R. & Dobyns, W.B. Neurology 65, 1873–1887 (2005). 11. Kielar, M. et al. Nat. Neurosci. 17, 923–933 (2014). 12. Croquelois, A. et al. Cereb. Cortex 19, 563–575 (2009). 13. Novegno, F. et al. Epilepsy Res. 87, 88–94 (2009). 14. Cappello, S. et al. Neuron 73, 911–924 (2012). 1. 2. 3. 4.
Unlocking the constraints on memory formation Dina P Matheos & Marcelo A Wood A leading therapeutic molecule for multiple sclerosis, FTY720, is shown to mimic a key component of sphingolipid signaling, resulting in specific manipulation of histone deacetylases and the extinction of memory. It is well known that genomic DNA undergoes a nearly incomprehensible level of compaction so that all of our genetic information fits into a tiny nucleus. This compaction, carried out by specialized chromatin modification and chromatin remodeling complexes, solves a storage problem, but in turn creates a DNA access problem. How, then, is access achieved to turn on and off specific genes required for long-term memory? One mechanism involves the same chromatin-modifying enzymes that package genomic DNA: histone deacetylases (HDACs). Endogenous regulators of HDACs remain elusive. However, a relatively recent discovery demonstrated that sphingosine-1-phosphate (S1P) is an endogenous HDAC inhibitor1. Hait et al.2 report in this issue of Nature Neuroscience that a synthetic analog of sphingosine, fingolimod (referred to here as FTY720), is recognized by intracellular machinery in a similar fashion to S1P, including the inhibition of HDACs. This opens a line of investigation into the signaling mechanisms that regulate HDAC activity, as well as a potential avenue for therapeutic development of cognitive enhancers. Fingolimod (Gilenya) is US Food and Drug Administration approved for the treatment of Dina P. Matheos and Marcelo A. Wood are in the Department of Neurobiology and Behavior, Center for the Neurobiology of Learning and Memory, University of California Irvine, Irvine, California, USA. e-mail: [email protected] or [email protected]
relapsing-remitting multiple sclerosis (RRMS; see ref. 3 for a review). In earlier studies examining the action of FTY720, researchers found that the phosphorylated form of FTY720 (FTY720-P) was structurally similar to sphingosine and was likewise a substrate of sphingosine kinase 2 (SphK2)4,5. As a mimetic of S1P, FTY720 acts initially as an agonist of the S1P receptors on the cell membrane, which are then internalized, thereby inhibiting S1P receptor function. For its treatment of RRMS, FTY720 acts by binding of S1P receptors at the plasma membrane. This binding inhibits egress of a certain subset of T cells from lymph nodes, thereby reducing the destructive inflammatory response in the CNS associated with RRMS3. However, S1P has an intriguing second mode of action that is independent of binding to S1P receptors on the cell membrane. S1P is an endogenous inhibitor of HDACs, and this inhibition occurs through an interaction with HDACs in the nucleus1. This finding represents a paradigm shift in thinking about the function of sphingolipid signaling because the nuclear actions of S1P are independent of its cell surface receptor signaling mechanisms. Considering the structural similarity between S1P and FTY720, it might be possible for FTY720 to hijack the pathways involving SphK2, ultimately leading to the regulation of HDACs and even memory (Fig. 1). This is the focus of the study by Hait et al.2. The authors first asked whether FTY720 would function similarly to S1P in neurons.
nature neuroscience volume 17 | number 7 | july 2014
They demonstrated that FTY720 is taken up by neurons and phosphorylated by SphK2 (the main isoform of this kinase found in the CNS), and that this phosphorylation event leads to retention in the nucleus. Furthermore, in hippocampal neurons treated with FTY720, accumulation of nuclear FTY720-P resulted in the decrease of endogenous nuclear S1P, suggesting direct competition between the similar molecules. Functionally, FTY720-P led to the increase of the same histone acetylation marks that S1P affects in vivo. The phosphorylation of FTY720 was blocked by short interfering RNA against SphK2, suggesting that SphK2 is indeed the kinase directly phosphorylating FTY720. To show that the increases in acetylation by FTY720-P are independent of potential interaction between FTY720-P and S1P receptors on the cell surface, Hait et al.2 treated purified nuclei with FTY720. This led to increased histone acetylation. Thus, FTY720 is sufficient to drive histone acetylation in purified nuclei. The authors also demonstrated that FTY720-P added to intact cells had no effect on acetylation. Together, these and additional results suggest that FTY720 is phosphorylated in the nucleus by SphK2 and that nuclear FTY720-P regulates specific histone acetylation. How does FTY720-P lead to the increase in histone acetylation? Modeling the docking of FTY720-P to the catalytic domain of HDAC2 using the crystal structure of HDAC2 suggests that FTY720-P has interactions in the catalytic 895
news and views
ATP SphK2 FTY720
FTY720-P
HDAC
Cytoplasm Nucleus
Ac
Ac
npg
© 2014 Nature America, Inc. All rights reserved.
Ac
Ac
Gene silencing
Gene expression
Blocks memory
Facilitates memory
Figure 1 A nuclear role for FTY720-P. Nuclear phosphorylation of FTY720 (FTY720-P) by SphK2 allows binding in the catalytic domain of class I HDACs, thereby inhibiting them. This causes an increase in certain histone acetylation marks (Ac) that can change the DNA environment and lead to an increase in transcription required for long-term memory processes, including extinction.
domain similar to those of the HDAC inhibitor SAHA (Fig. 1). Indeed, in an experiment using purified recombinant HDACs, FTY720-P was found to block HDACs 1, 2, 3 and 8, but not 7. There are slight differences between the predicted binding of FTY720-P and that of SAHA, which may account for the observation that SAHA affects HDAC7, but FTY720-P does not. In any case, the data provide a compelling case for FTY720-P functioning as a bona fide HDAC inhibitor. One note of caution is with regard to the interpretation of the mode of action. If a molecule binds a catalytic domain, then it is thought to disrupt the enzymatic function. However, and especially with regard to HDACs, it is entirely possible that FTY720-P disrupts protein-protein interactions (see ref. 6 for an example involving HDAC3 and HDAC4), which could lead to similar downstream effects of increased histone acetylation. Another key question addressed by the authors was whether FTY720 could affect synaptic plasticity and memory processes. An extensive literature has demonstrated that either pharmacological or genetic manipulation of specific HDACs affects synaptic plasticity and memory processes7–9. The histone acetylation changes caused by FTY720-P are associated with epigenetic regulation of learning and memory. Thus, the authors examined whether FTY720 would function like other known HDAC inhibitors with regard to synaptic plasticity and memory. The main problem was how to dissociate potential effects of FTY720 on memory from its known effect on lymphocyte trafficking. To address this problem, the authors used severe 896
combined immunodeficiency (SCID) mice, which lack T or B lymphocytes. Mice treated with a clinically relevant dose of FTY720 showed an accumulation of FTY720-P in hippocampal neurons, along with a corresponding decrease in S1P and an increase in histone acetylation. The authors used two different hippocampus-dependent tasks, contextual fear conditioning and the Morris water maze (MWM). In both the MWM and the fear conditioning tasks, animals treated with FTY720 behaved similarly to littermates treated with saline, indicating that FTY720 does not affect acquisition of memory. This is an intriguing result, as there have been mixed results in the literature regarding the ability of HDAC inhibitors, when delivered systemically, to enhance acquisition of contextual fear memories and enhance learning during the acquisition phase of the MWM. These are inherently stressful models in which to study memory, and it is difficult to observe enhancements, most likely because of the elevated stress. It will be interesting to determine whether FTY720 modulates memory formation for subthreshold learning events or nonstressful memory formation. Regardless, the authors did observe an effect on the extinction of contextual fear. In the fear conditioning and extinction protocol used by the authors, vehicle-treated mice extinguished well, but the extinction learning did not persist, as demonstrated by increased freezing behavior a day after extinction. In contrast, FTY720treated mice achieved similar extinction levels by the end of the extinction training, and they
exhibited significantly lower freezing than the vehicle-treated mice on the test day following extinction learning. These findings suggest that FTY720 facilitated the transition of subthreshold extinction training into a robust form of extinction memory (see also ref. 10). The mechanism may involve SphK2, as Sphk2–/– homozygous knockout mice completely failed to extinguish and FTY720 was unable to rescue extinction learning in these knockout mice. Understanding which HDACs may be involved in FTY720-dependent modulation of extinction remains an open question. HDACs have a complicated role in extinction, as general HDAC inhibitors, such as sodium butyrate, valproate and trichostatin A, have been shown to enhance extinction of contextual and cued fear10,11. Individual HDACs, including HDAC3 (ref. 12) and HDAC2 (ref. 13), have also been shown to affect extinction. In contrast, HDAC1 appears to have an opposite role. Inhibition of HDAC1 blocks extinction and overexpression of wild-type HDAC1 facilitates extinction14. Thus, how exactly FTY720-P may be regulating extinction remains a complex question, as FTY720-P can affect HDAC1, 2, 3 and 8. In summary, the study by Hait et al.2 opens an exciting new door to the development of cognitive enhancers that modulate epigenetic machinery during memory consolidation. The findings also provide additional support for the newly discovered role of S1P, and FTY720, in nuclear functions that is independent of their previously characterized activities at the cell surface and their interactions with S1P receptors. This research represents the tip of the iceberg and future work will undoubtedly continue to expand our knowledge of how sphingolipid metabolism and signaling, and pharmacological manipulation of that signaling, function to modulate neuronal activity during synaptic plasticity, learning and memory. COMPETING FINANCIAL INTERESTS The authors declare no competing financial interests. 1. Hait, N.C. et al. Science 325, 1254–1257 (2009). 2. Hait, N.C. et al. Nat. Neurosci. 17, 971–980 (2014). 3. Brinkmann, V. et al. Nat. Rev. Drug Discov. 9, 883–897 (2010). 4. Brinkmann, V. et al. J. Biol. Chem. 277, 21453– 21457 (2002). 5. Zemann, B. et al. Blood 15, 1454–1458 (2006). 6. McQuown, S.C. et al. J. Neurosci. 31, 764–774 (2011). 7. Peixoto, L. & Abel, T. Neuropsychopharmacology 38, 62–76 (2013). 8. Day, J.J. & Sweatt, J.D. Neuron 70, 813–829 (2011). 9. Lattal, K.M. & Wood, M.A. Nat. Neurosci. 16, 124–129 (2013). 10. Lattal, K.M., Barrett, R.M. & Wood, M.A. Behav. Neurosci. 121, 1125–1131 (2007). 11. Bredy, T.W. et al. Learn. Mem. 14, 268–276 (2007). 12. Malvaez, M. et al. Proc. Natl. Acad. Sci. USA 110, 2647–2652 (2013). 13. Morris, M.J. et al. J. Neurosci. 33, 6401–6411. 14. Bahari-Javan, S. et al. J. Neurosci. 32, 5062–5073 (2012).
volume 17 | number 7 | july 2014 nature neuroscience
