- Email: [email protected]
CHD2: One Gene, Many Roles
Neuron
Previews for driving PHP over long timescales. Furthermore, unlike the other components of the PGRP pathway, Tak1 is necessary for normal functioning of the synapse, even in the absence of explicit queues that drive PHP. In the absence of Tak1, synaptic vesicles, specifically those that a primed near release sites at the plasma membrane, become depleted. Thus, it appears that this MAP kinase family member can normally tune the primed vesicle state. These studies bring up several interesting questions. Looming largest among these is what ligands trigger the PGRP to activate PHP? Bacterial peptidoglycans are PAMP ligands for PGRP, and it is possible that PHP is triggered by bacterial pathogens. In this regard, PGRP expressed by optopaminergic neurons in Drosophila modulates their activity in regulating egg laying in response to bacterial peptidoglycans (Kurz et al., 2017). Perhaps more likely is that PHP is regulated by DAMP-like ligands released from muscle cells at an NMJ that bind to PGRP to mediate PHP. These ligands could be released due to changes in the density of post-synaptic transmitter receptors or the size of the muscle fiber. The Davis group previously showed a ge-
netic interaction between PGRP-LC and endostatin (Harris et al., 2015), a proteolytic cleavage product of a collagen VIII that likely resides in the synaptic cleft, in driving PHP. Although PHP is generally examined in the context of genetic, disease-driven, or pharmacological impairment of postsynaptic function, the findings suggest that presynaptic function may always be tuned by muscle-derived signals that gets amplified under certain conditions. Although loss of PGRP function does not appear to impact basal transmission (Harris et al., 2015), loss of the downstream target Tak1 does. Identifying the targets of Tak1 will likely shed important light on synaptic regulation, as it implies that the phosphorylation state of some key protein(s) controls the size of the docked and releasable synaptic vesicle pool. Similarly, it will be important to discover how Tak1 function itself is regulated and whether upstream signals other than PGRP might drive its function.
Cannon, W.B. (1929). Organization for physiological homeostasis. Physiol. Rev. 9, 399–431. Cull-Candy, S.G., Miledi, R., Trautmann, A., and Uchitel, O.D. (1980). On the release of transmitter at normal, myasthenia gravis and myasthenic syndrome affected human end-plates. J. Physiol. 299, 621–638. €ller, M. (2015). Homeostatic Davis, G.W., and Mu control of presynaptic neurotransmitter release. Annu. Rev. Physiol. 77, 251–270. Harris, N., Braiser, D.J., Dickman, D.K., Fetter, R.D., Tong, A., and Davis, G.W. (2015). The innate immune receptor PGRP-LC controls presynaptic homeostatic plasticity. Neuron 88, 1157–1164. Harris, N., Fetter, R.D., Brasier, D.J., Tong, A., and Davis, G.W. (2018). Molecular interface of neuronal innate immunity, synaptic vesicle stabilization, and presynaptic homeostatic plasticity. Neuron 100, this issue, 1163–1179. Kurz, C.L., Charroux, B., Chaduli, D., Viallat-Lieutaud, A., and Royet, J. (2017). Peptidoglycan sensing by octopaminergic neurons modulates Drosophila oviposition. eLife 6, 6.
REFERENCES
Lemaitre, B., Nicolas, E., Michaut, L., Reichhart, J.M., and Hoffmann, J.A. (1996). The dorsoventral €tzle/Toll/cactus conregulatory gene cassette spa trols the potent antifungal response in Drosophila adults. Cell 86, 973–983.
Beutler, B. (2000). Endotoxin, toll-like receptor 4, and the afferent limb of innate immunity. Curr. Opin. Microbiol. 3, 23–28.
Turrigiano, G.G. (2008). The self-tuning neuron: synaptic scaling of excitatory synapses. Cell 135, 422–435.
CHD2: One Gene, Many Roles Vanesa Nieto-Estevez1 and Jenny Hsieh1,* 1Department of Biology, The University of Texas at San Antonio, San Antonio, TX 78249, USA *Correspondence: [email protected] https://doi.org/10.1016/j.neuron.2018.11.036
Mutations in the chromodomain helicase DNA-binding 2 (CHD2) gene have been found in patients with a range of neurodevelopmental disorders. In this issue of Neuron, Kim et al. (2018) showed that Chd2 haploinsufficiency compromises cortical development, synaptic function, and memory in mice. CHD2 belongs to a family of ATP-dependent chromatin remodeling proteins critical for the assembly and regulation of chromatin (Lamar and Carvill, 2018). Mutations in members of this family have been associated with neurodevelopmental disorders, such as autism spectrum disorder, intellectual disability, and epilepsy (Carvill et al., 2013; Allen et al.,
2013). Mutations found in the CHD2 gene include partial or complete deletion of the gene as well as point mutations. All the mutations described are de novo and one mutant allele is enough to cause disease (Carvill et al., 2013; Allen et al., 2013; Suls et al., 2013). Despite this correlation between CHD2 mutations and neurological diseases, very little is
1014 Neuron 100, December 5, 2018 ª 2018 Published by Elsevier Inc.
known about the role of this gene in brain development. Studies in mice have shown that homozygous deletions of Chd2 produce a general growth delay and perinatal lethality, while heterozygous deletions affect neonatal viability and non-neoplastic lesions in most primary organs (Marfella et al., 2006). More recently, it has been
Neuron
Previews described that Chd2 knocknificant increase in miniadown promotes a premature ture excitatory postsynneuronal differentiation during aptic current amplitudes embryonic mouse cortical and a decrease in miniature development due to a decrease inhibitory postsynaptic curin Pax6+ neural progenitor cells rent frequency. In addition, and an increase in Tbr2+ interelectroencephalogram remediate progenitor cells (Shen cordings in the somatoet al., 2015). On the other sensory neocortex rehand, Chd2-knockdown zebravealed an increase in the fish larvae exhibited seizurealpha, delta, theta, and like behavior with epileptiform gamma frequency ranges discharges (Suls et al., 2013). in Chd2+/ mice. Nevertheless, they did not find any Additionally, CHD2 knockout overt convulsive seizures in human embryonic stem in 7 days of continuous cell-derived interneurons promonitoring in mice from motes a decrease in the numboth genotypes. These ber of neurons as well as a data showed that Chd2 afreduction in the neurite length fects both glutamatergic (Meganathan et al., 2017). and GABAergic synaptic These data together suggest transmission in the adult Chd2 is critical for cortical Figure 1. Chd2 Haploinsufficiency Affects Neuronal Differentiation, hippocampus as well as development. However, more Synaptic Properties, and Memory Deficits The figure shows the main phenotypes found in Chd2+/ mice in the embryonic cortical rhythmogenesis. studies are needed to fully and adult brain. Finally, they analyzed understand its role during whether Chd2 haploinsuffineuronal differentiation and how mutations lead to neurodevelop- RNA sequencing of tissue from neocortex ciency alters hippocampal-depended and medial GE of embryonic day (E)13.5 memory tasks using object location and mental disorders. To better understand the role of Chd2, embryos as well as adult mouse hippo- recognition memory paradigms. The auKim et al. generated a Chd2 haploinsuffi- campus. This showed differential gene thors showed Chd2+/ mice spent similar cient mouse line (Kim et al., 2018), which expression in genes associated with ner- time exploring both objects when one mimicked Chd2 loss in only one allele. vous system development, neuron differ- new object was added to the cage or First, the authors showed Chd2 expres- entiation, and neurogenesis in embryos. when one object was moved to a different sion through the adult mouse brain, in Similar categories were observed in adult location. Interestingly, similar memory deNeuN+ neurons, GABAergic interneurons, hippocampus, with additional annota- fects were found in conditional Chd2+/ and oligodendrocytes, as well as in the tions such as synapse organization, mice where Chd2 was altered only in embryonic brain in the cortical plate, ven- neuronal activity and synaptic plasticity, GABAergic progenitor cells (Nkx2.1+ tricular zone (VZ), and subventricular zone transcriptional regulation and behavior, cells). Moreover, when medial GE cells (SVZ), and in the ganglionic eminence forebrain neurogenesis, RNA silencers, were injected, which expressed markers (GE). Then, they analyzed the effect of global regulators of the epigenome, cell of interneurons after 45 days post-transChd2 haploinsufficiency in the brain cy- adhesion molecules, and ion channels. plantation, spatial memory deficits toarchitecture, but they did not find any Despite the presence of prominent improved in Chd2+/ mice. Altogether, laminar disorganization or differential phenotypic changes in GABAergic neu- these data showed that Chd2 affects thickness in the somatosensory cortex rons, they observed many differentially hippocampal memory due to loss of or in the hippocampus. However, they expressed genes involved in glutamater- GABAergic interneurons. As summarized in Figure 1, the results found a decrease in GABAergic interneu- gic synaptic function. Genes associated rons in the somatosensory cortex postna- with epilepsy and autism spectrum disor- presented by Kim and colleagues show tally and in adult Chd2+/ mice. During ders and other neurological disorders that Chd2 is critical for embryonic and embryonic development, they found a were also found. These results showed adult neuronal differentiation, synaptic decrease in proliferative cells in the VZ/ partial Chd2 loss affects the expression properties, and memory, which partially SVZ as well as in Nkx2.1+ progenitor cells of a broad array of genes. explain the symptoms of CHD2 patients. Next, whether Chd2 haploinsufficiency Although there is a broad range of in the medial GE. They also found a reduction in the density of GABAergic neurons affects electrophysiological properties mutations affecting CHD2 in human, in the cortex. These data showed that using patch-clamp recordings in CA1 hip- Chd2+/ mice mimic a type of mutation that produces a small, truncated protein. Chd2 is critical during neuronal differenti- pocampal slices was studied. Chd2+/ mouse pyramidal neurons showed an That could explain why the authors did ation both in embryonic and adult brain. To identify the molecular changes un- increase in action potential firing, a not see some of the phenotypes derlying these defects, they performed decrease in spike adaptation, and a sig- observed in patients such as chronic
Neuron 100, December 5, 2018 1015
Neuron
Previews seizures. Nevertheless, the authors clearly demonstrated that Chd2 is critical for GABAergic interneuron differentiation and a loss of these neurons leads to memory deficits. They also showed evidence that Chd2 may play a role in glutamatergic neuron differentiation and, in addition to the broad expression of Chd2 in the adult mouse brain, demonstrate that further analyses are needed to fully understand the role of Chd2 in specific neuronal subtypes. Moreover, additional experiments are needed to understand the molecular role of Chd2. Despite the gene expression changes in Chd2+/ mice, it is unknown if these are direct targets and whether Chd2 binds chromatin/DNA to directly control gene expression. Furthermore, mouse models may not completely simulate human brain development (Rakic, 2009), e.g., specific subtypes of interneurons may have different origins in the mouse and human brain, and human brain has a larger expansion of cortical surface compared to mouse, among others. For this reason, studies of human tissues or in vitro analyses of patient-derived neurons or 3D organoids represent powerful complementary approaches to
fully comprehend the etiology of CHD2 patients. While there is still a long way to go, this study provides valuable information on understanding the role of Chd2 in the brain, which will be critical in the development of future therapeutics for Chd2-associated neurodevelopmental disorders. ACKNOWLEDGMENTS Work in the laboratory is supported by R01NS093992 and R01NS089770 from the NIH. V.N.-E. is supported by a grant from the LennoxGastaut Syndrome Foundation. J.H. is supported by the Semmes Foundation, Inc. and the Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation. REFERENCES Allen, A.S., Berkovic, S.F., Cossette, P., Delanty, N., Dlugos, D., Eichler, E.E., Epstein, M.P., Glauser, T., Goldstein, D.B., Han, Y., et al.; Epi4K Consortium; Epilepsy Phenome/Genome Project (2013). De novo mutations in epileptic encephalopathies. Nature 501, 217–221. Carvill, G.L., Heavin, S.B., Yendle, S.C., McMahon, J.M., O’Roak, B.J., Cook, J., Khan, A., Dorschner, M.O., Weaver, M., Calvert, S., et al. (2013). Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nat. Genet. 45, 825–830. Kim, Y.J., Khoshkhoo, S., Frankowski, J.C., Zhu, B., Abbasi, S., Lee, S., Wu, Y.E., and Hunt, R.F.
(2018). Chd2 is necessary for neural circuit development and long-term memory. Neuron 100, this issue, 1180–1193. Lamar, K.J., and Carvill, G.L. (2018). Chromatin remodeling proteins in epilepsy: lessons from CHD2associated epilepsy. Front. Mol. Neurosci. 11, 208. Marfella, C.G., Ohkawa, Y., Coles, A.H., Garlick, D.S., Jones, S.N., and Imbalzano, A.N. (2006). Mutation of the SNF2 family member Chd2 affects mouse development and survival. J. Cell. Physiol. 209, 162–171. Meganathan, K., Lewis, E.M.A., Gontarz, P., Liu, S., Stanley, E.G., Elefanty, A.G., Huettner, J.E., Zhang, B., and Kroll, K.L. (2017). Regulatory networks specifying cortical interneurons from human embryonic stem cells reveal roles for CHD2 in interneuron development. Proc. Natl. Acad. Sci. USA 114, E11180–E11189. Rakic, P. (2009). Evolution of the neocortex: a perspective from developmental biology. Nat. Rev. Neurosci. 10, 724–735. Shen, T., Ji, F., Yuan, Z., and Jiao, J. (2015). CHD2 is required for embryonic neurogenesis in the developing cerebral cortex. Stem Cells 33, 1794–1806. Suls, A., Jaehn, J.A., Kecske´s, A., Weber, Y., Weckhuysen, S., Craiu, D.C., Siekierska, A., Dje´mie´, T., Afrikanova, T., Gormley, P., et al.; EuroEPINOMICS RES Consortium (2013). De novo loss-of-function mutations in CHD2 cause a fever-sensitive myoclonic epileptic encephalopathy sharing features with Dravet syndrome. Am. J. Hum. Genet. 93, 967–975.
Conducting the Neural Symphony of Memory Replay Wenbo Tang1 and Shantanu P. Jadhav2,* 1Graduate
Program in Neuroscience, Brandeis University, Waltham, MA, 02453, USA Program, Department of Psychology and Volen National Center for Complex Systems, Brandeis University, Waltham, MA, 02453, USA *Correspondence: [email protected] https://doi.org/10.1016/j.neuron.2018.11.037 2Neuroscience
Hippocampal sharp-wave ripple oscillations and sequence replay events are important for memory. RamirezVillegas et al. present a model that dissects cellular mechanisms of SWR generation in the CA3-CA1 circuit, and explains the network features of slow-gamma coordination and sequence replay. The brain’s ability to generate a coherent thought or memory requires synchronous, patterned activation of many neurons across multiple brain regions. Electrical oscillations in the brain with periodically reduced and enhanced excitability are network patterns that can effectively
govern this synchronization of neuronal ensembles or cell assemblies, just like an orchestral conductor drawing upon different instruments as situations demand. Sharp-wave ripple (SWR) oscillations represent the most intense neural symphony in the mammalian brain, which
1016 Neuron 100, December 5, 2018 ª 2018 Elsevier Inc.
is played together by tens of thousands of neurons in the hippocampus over a timescale of 100 ms (see Buzsa´ki, 2015 for a review). SWRs in area CA1 are prominent during awake immobility and sleep, and are composed of high-frequency ‘‘ripple’’ oscillations (150–250 Hz) and a slower
Previews for driving PHP over long timescales. Furthermore, unlike the other components of the PGRP pathway, Tak1 is necessary for normal functioning of the synapse, even in the absence of explicit queues that drive PHP. In the absence of Tak1, synaptic vesicles, specifically those that a primed near release sites at the plasma membrane, become depleted. Thus, it appears that this MAP kinase family member can normally tune the primed vesicle state. These studies bring up several interesting questions. Looming largest among these is what ligands trigger the PGRP to activate PHP? Bacterial peptidoglycans are PAMP ligands for PGRP, and it is possible that PHP is triggered by bacterial pathogens. In this regard, PGRP expressed by optopaminergic neurons in Drosophila modulates their activity in regulating egg laying in response to bacterial peptidoglycans (Kurz et al., 2017). Perhaps more likely is that PHP is regulated by DAMP-like ligands released from muscle cells at an NMJ that bind to PGRP to mediate PHP. These ligands could be released due to changes in the density of post-synaptic transmitter receptors or the size of the muscle fiber. The Davis group previously showed a ge-
netic interaction between PGRP-LC and endostatin (Harris et al., 2015), a proteolytic cleavage product of a collagen VIII that likely resides in the synaptic cleft, in driving PHP. Although PHP is generally examined in the context of genetic, disease-driven, or pharmacological impairment of postsynaptic function, the findings suggest that presynaptic function may always be tuned by muscle-derived signals that gets amplified under certain conditions. Although loss of PGRP function does not appear to impact basal transmission (Harris et al., 2015), loss of the downstream target Tak1 does. Identifying the targets of Tak1 will likely shed important light on synaptic regulation, as it implies that the phosphorylation state of some key protein(s) controls the size of the docked and releasable synaptic vesicle pool. Similarly, it will be important to discover how Tak1 function itself is regulated and whether upstream signals other than PGRP might drive its function.
Cannon, W.B. (1929). Organization for physiological homeostasis. Physiol. Rev. 9, 399–431. Cull-Candy, S.G., Miledi, R., Trautmann, A., and Uchitel, O.D. (1980). On the release of transmitter at normal, myasthenia gravis and myasthenic syndrome affected human end-plates. J. Physiol. 299, 621–638. €ller, M. (2015). Homeostatic Davis, G.W., and Mu control of presynaptic neurotransmitter release. Annu. Rev. Physiol. 77, 251–270. Harris, N., Braiser, D.J., Dickman, D.K., Fetter, R.D., Tong, A., and Davis, G.W. (2015). The innate immune receptor PGRP-LC controls presynaptic homeostatic plasticity. Neuron 88, 1157–1164. Harris, N., Fetter, R.D., Brasier, D.J., Tong, A., and Davis, G.W. (2018). Molecular interface of neuronal innate immunity, synaptic vesicle stabilization, and presynaptic homeostatic plasticity. Neuron 100, this issue, 1163–1179. Kurz, C.L., Charroux, B., Chaduli, D., Viallat-Lieutaud, A., and Royet, J. (2017). Peptidoglycan sensing by octopaminergic neurons modulates Drosophila oviposition. eLife 6, 6.
REFERENCES
Lemaitre, B., Nicolas, E., Michaut, L., Reichhart, J.M., and Hoffmann, J.A. (1996). The dorsoventral €tzle/Toll/cactus conregulatory gene cassette spa trols the potent antifungal response in Drosophila adults. Cell 86, 973–983.
Beutler, B. (2000). Endotoxin, toll-like receptor 4, and the afferent limb of innate immunity. Curr. Opin. Microbiol. 3, 23–28.
Turrigiano, G.G. (2008). The self-tuning neuron: synaptic scaling of excitatory synapses. Cell 135, 422–435.
CHD2: One Gene, Many Roles Vanesa Nieto-Estevez1 and Jenny Hsieh1,* 1Department of Biology, The University of Texas at San Antonio, San Antonio, TX 78249, USA *Correspondence: [email protected] https://doi.org/10.1016/j.neuron.2018.11.036
Mutations in the chromodomain helicase DNA-binding 2 (CHD2) gene have been found in patients with a range of neurodevelopmental disorders. In this issue of Neuron, Kim et al. (2018) showed that Chd2 haploinsufficiency compromises cortical development, synaptic function, and memory in mice. CHD2 belongs to a family of ATP-dependent chromatin remodeling proteins critical for the assembly and regulation of chromatin (Lamar and Carvill, 2018). Mutations in members of this family have been associated with neurodevelopmental disorders, such as autism spectrum disorder, intellectual disability, and epilepsy (Carvill et al., 2013; Allen et al.,
2013). Mutations found in the CHD2 gene include partial or complete deletion of the gene as well as point mutations. All the mutations described are de novo and one mutant allele is enough to cause disease (Carvill et al., 2013; Allen et al., 2013; Suls et al., 2013). Despite this correlation between CHD2 mutations and neurological diseases, very little is
1014 Neuron 100, December 5, 2018 ª 2018 Published by Elsevier Inc.
known about the role of this gene in brain development. Studies in mice have shown that homozygous deletions of Chd2 produce a general growth delay and perinatal lethality, while heterozygous deletions affect neonatal viability and non-neoplastic lesions in most primary organs (Marfella et al., 2006). More recently, it has been
Neuron
Previews described that Chd2 knocknificant increase in miniadown promotes a premature ture excitatory postsynneuronal differentiation during aptic current amplitudes embryonic mouse cortical and a decrease in miniature development due to a decrease inhibitory postsynaptic curin Pax6+ neural progenitor cells rent frequency. In addition, and an increase in Tbr2+ interelectroencephalogram remediate progenitor cells (Shen cordings in the somatoet al., 2015). On the other sensory neocortex rehand, Chd2-knockdown zebravealed an increase in the fish larvae exhibited seizurealpha, delta, theta, and like behavior with epileptiform gamma frequency ranges discharges (Suls et al., 2013). in Chd2+/ mice. Nevertheless, they did not find any Additionally, CHD2 knockout overt convulsive seizures in human embryonic stem in 7 days of continuous cell-derived interneurons promonitoring in mice from motes a decrease in the numboth genotypes. These ber of neurons as well as a data showed that Chd2 afreduction in the neurite length fects both glutamatergic (Meganathan et al., 2017). and GABAergic synaptic These data together suggest transmission in the adult Chd2 is critical for cortical Figure 1. Chd2 Haploinsufficiency Affects Neuronal Differentiation, hippocampus as well as development. However, more Synaptic Properties, and Memory Deficits The figure shows the main phenotypes found in Chd2+/ mice in the embryonic cortical rhythmogenesis. studies are needed to fully and adult brain. Finally, they analyzed understand its role during whether Chd2 haploinsuffineuronal differentiation and how mutations lead to neurodevelop- RNA sequencing of tissue from neocortex ciency alters hippocampal-depended and medial GE of embryonic day (E)13.5 memory tasks using object location and mental disorders. To better understand the role of Chd2, embryos as well as adult mouse hippo- recognition memory paradigms. The auKim et al. generated a Chd2 haploinsuffi- campus. This showed differential gene thors showed Chd2+/ mice spent similar cient mouse line (Kim et al., 2018), which expression in genes associated with ner- time exploring both objects when one mimicked Chd2 loss in only one allele. vous system development, neuron differ- new object was added to the cage or First, the authors showed Chd2 expres- entiation, and neurogenesis in embryos. when one object was moved to a different sion through the adult mouse brain, in Similar categories were observed in adult location. Interestingly, similar memory deNeuN+ neurons, GABAergic interneurons, hippocampus, with additional annota- fects were found in conditional Chd2+/ and oligodendrocytes, as well as in the tions such as synapse organization, mice where Chd2 was altered only in embryonic brain in the cortical plate, ven- neuronal activity and synaptic plasticity, GABAergic progenitor cells (Nkx2.1+ tricular zone (VZ), and subventricular zone transcriptional regulation and behavior, cells). Moreover, when medial GE cells (SVZ), and in the ganglionic eminence forebrain neurogenesis, RNA silencers, were injected, which expressed markers (GE). Then, they analyzed the effect of global regulators of the epigenome, cell of interneurons after 45 days post-transChd2 haploinsufficiency in the brain cy- adhesion molecules, and ion channels. plantation, spatial memory deficits toarchitecture, but they did not find any Despite the presence of prominent improved in Chd2+/ mice. Altogether, laminar disorganization or differential phenotypic changes in GABAergic neu- these data showed that Chd2 affects thickness in the somatosensory cortex rons, they observed many differentially hippocampal memory due to loss of or in the hippocampus. However, they expressed genes involved in glutamater- GABAergic interneurons. As summarized in Figure 1, the results found a decrease in GABAergic interneu- gic synaptic function. Genes associated rons in the somatosensory cortex postna- with epilepsy and autism spectrum disor- presented by Kim and colleagues show tally and in adult Chd2+/ mice. During ders and other neurological disorders that Chd2 is critical for embryonic and embryonic development, they found a were also found. These results showed adult neuronal differentiation, synaptic decrease in proliferative cells in the VZ/ partial Chd2 loss affects the expression properties, and memory, which partially SVZ as well as in Nkx2.1+ progenitor cells of a broad array of genes. explain the symptoms of CHD2 patients. Next, whether Chd2 haploinsufficiency Although there is a broad range of in the medial GE. They also found a reduction in the density of GABAergic neurons affects electrophysiological properties mutations affecting CHD2 in human, in the cortex. These data showed that using patch-clamp recordings in CA1 hip- Chd2+/ mice mimic a type of mutation that produces a small, truncated protein. Chd2 is critical during neuronal differenti- pocampal slices was studied. Chd2+/ mouse pyramidal neurons showed an That could explain why the authors did ation both in embryonic and adult brain. To identify the molecular changes un- increase in action potential firing, a not see some of the phenotypes derlying these defects, they performed decrease in spike adaptation, and a sig- observed in patients such as chronic
Neuron 100, December 5, 2018 1015
Neuron
Previews seizures. Nevertheless, the authors clearly demonstrated that Chd2 is critical for GABAergic interneuron differentiation and a loss of these neurons leads to memory deficits. They also showed evidence that Chd2 may play a role in glutamatergic neuron differentiation and, in addition to the broad expression of Chd2 in the adult mouse brain, demonstrate that further analyses are needed to fully understand the role of Chd2 in specific neuronal subtypes. Moreover, additional experiments are needed to understand the molecular role of Chd2. Despite the gene expression changes in Chd2+/ mice, it is unknown if these are direct targets and whether Chd2 binds chromatin/DNA to directly control gene expression. Furthermore, mouse models may not completely simulate human brain development (Rakic, 2009), e.g., specific subtypes of interneurons may have different origins in the mouse and human brain, and human brain has a larger expansion of cortical surface compared to mouse, among others. For this reason, studies of human tissues or in vitro analyses of patient-derived neurons or 3D organoids represent powerful complementary approaches to
fully comprehend the etiology of CHD2 patients. While there is still a long way to go, this study provides valuable information on understanding the role of Chd2 in the brain, which will be critical in the development of future therapeutics for Chd2-associated neurodevelopmental disorders. ACKNOWLEDGMENTS Work in the laboratory is supported by R01NS093992 and R01NS089770 from the NIH. V.N.-E. is supported by a grant from the LennoxGastaut Syndrome Foundation. J.H. is supported by the Semmes Foundation, Inc. and the Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation. REFERENCES Allen, A.S., Berkovic, S.F., Cossette, P., Delanty, N., Dlugos, D., Eichler, E.E., Epstein, M.P., Glauser, T., Goldstein, D.B., Han, Y., et al.; Epi4K Consortium; Epilepsy Phenome/Genome Project (2013). De novo mutations in epileptic encephalopathies. Nature 501, 217–221. Carvill, G.L., Heavin, S.B., Yendle, S.C., McMahon, J.M., O’Roak, B.J., Cook, J., Khan, A., Dorschner, M.O., Weaver, M., Calvert, S., et al. (2013). Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nat. Genet. 45, 825–830. Kim, Y.J., Khoshkhoo, S., Frankowski, J.C., Zhu, B., Abbasi, S., Lee, S., Wu, Y.E., and Hunt, R.F.
(2018). Chd2 is necessary for neural circuit development and long-term memory. Neuron 100, this issue, 1180–1193. Lamar, K.J., and Carvill, G.L. (2018). Chromatin remodeling proteins in epilepsy: lessons from CHD2associated epilepsy. Front. Mol. Neurosci. 11, 208. Marfella, C.G., Ohkawa, Y., Coles, A.H., Garlick, D.S., Jones, S.N., and Imbalzano, A.N. (2006). Mutation of the SNF2 family member Chd2 affects mouse development and survival. J. Cell. Physiol. 209, 162–171. Meganathan, K., Lewis, E.M.A., Gontarz, P., Liu, S., Stanley, E.G., Elefanty, A.G., Huettner, J.E., Zhang, B., and Kroll, K.L. (2017). Regulatory networks specifying cortical interneurons from human embryonic stem cells reveal roles for CHD2 in interneuron development. Proc. Natl. Acad. Sci. USA 114, E11180–E11189. Rakic, P. (2009). Evolution of the neocortex: a perspective from developmental biology. Nat. Rev. Neurosci. 10, 724–735. Shen, T., Ji, F., Yuan, Z., and Jiao, J. (2015). CHD2 is required for embryonic neurogenesis in the developing cerebral cortex. Stem Cells 33, 1794–1806. Suls, A., Jaehn, J.A., Kecske´s, A., Weber, Y., Weckhuysen, S., Craiu, D.C., Siekierska, A., Dje´mie´, T., Afrikanova, T., Gormley, P., et al.; EuroEPINOMICS RES Consortium (2013). De novo loss-of-function mutations in CHD2 cause a fever-sensitive myoclonic epileptic encephalopathy sharing features with Dravet syndrome. Am. J. Hum. Genet. 93, 967–975.
Conducting the Neural Symphony of Memory Replay Wenbo Tang1 and Shantanu P. Jadhav2,* 1Graduate
Program in Neuroscience, Brandeis University, Waltham, MA, 02453, USA Program, Department of Psychology and Volen National Center for Complex Systems, Brandeis University, Waltham, MA, 02453, USA *Correspondence: [email protected] https://doi.org/10.1016/j.neuron.2018.11.037 2Neuroscience
Hippocampal sharp-wave ripple oscillations and sequence replay events are important for memory. RamirezVillegas et al. present a model that dissects cellular mechanisms of SWR generation in the CA3-CA1 circuit, and explains the network features of slow-gamma coordination and sequence replay. The brain’s ability to generate a coherent thought or memory requires synchronous, patterned activation of many neurons across multiple brain regions. Electrical oscillations in the brain with periodically reduced and enhanced excitability are network patterns that can effectively
govern this synchronization of neuronal ensembles or cell assemblies, just like an orchestral conductor drawing upon different instruments as situations demand. Sharp-wave ripple (SWR) oscillations represent the most intense neural symphony in the mammalian brain, which
1016 Neuron 100, December 5, 2018 ª 2018 Elsevier Inc.
is played together by tens of thousands of neurons in the hippocampus over a timescale of 100 ms (see Buzsa´ki, 2015 for a review). SWRs in area CA1 are prominent during awake immobility and sleep, and are composed of high-frequency ‘‘ripple’’ oscillations (150–250 Hz) and a slower