- Email: [email protected]
On the Path from Proteomics to Function: GABAAR Trafficking Takes a Turn
Neuron
Previews On the Path from Proteomics to Function: GABAAR Trafficking Takes a Turn Yoav Noam1 and Susumu Tomita1,* 1Department of Cellular and Molecular Physiology, Department of Neuroscience, CNNR program, Yale University School of Medicine, New Haven, CT 06520, USA *Correspondence: [email protected] https://doi.org/10.1016/j.neuron.2018.01.038
There are significant challenges in identifying receptor-specific functional interactors in vivo. In this issue of Neuron, Ge et al. (2018) identify a novel GABAA receptor (GABAAR)-interacting protein, Clptm1, that regulates forward trafficking of GABAARs and inhibitory transmission. Interactions between neurotransmitter receptors and regulatory proteins control synaptic transmission and plasticity through various pathways. In order to fulfill their function, neurotransmitter receptors first exit the endoplasmic reticulum (ER) and travel to the cell surface. During this process, interactions between the receptor and various binding partners promote and/or regulate receptor assembly and trafficking. Through these interactions, a mature receptor complex is formed, enabling its proper localization and function at the plasma membrane and synapses (Figure 1). Indeed, protein complexes between a neurotransmitter receptor and regulatory, interacting proteins (‘‘interactors’’) emerge as a common theme in receptor biology. For example, excitatory AMPA and kainate-type glutamate receptors create a stable complex with their auxiliary proteins TARPs and NETOs, respectively, and these interactions are required for proper synaptic transmission (Jackson and Nicoll, 2011; Yan and Tomita, 2012). Recently, GABAARs were found to form a stable tripartite complex with GARLH and Neuroligin-2 (Yamasaki et al., 2017), which is required for synaptic localization of GABAARs but not forward trafficking (Davenport et al., 2017; Yamasaki et al., 2017). Not only stable, but also transient interactions help shape the receptor landscape on the neuronal membrane (Figure 1). These transient interactions can take place along the various stages of forward receptor trafficking, including complex assembly, ER exit, trafficking, and exocytosis. Uncovering the specific interactors controlling receptor function is critical to our mechanistic under-
standing of neuronal signaling, yet the biochemical isolation and identification of transient interactors in vivo has proven technically demanding. A major challenge is the fact that transient complexes are (by definition) less abundant and are therefore harder to detect. Consequently, proteomic approaches to reveal transient interactions may lead to large sets of candidates, with dozens of potential interactors. In some cases, rather than relying solely on classical proteomic approaches, ‘‘fishing’’ for specific transient interactors can be achieved by adopting complementary methods such as highthroughput functional assays. Indeed, taking such a combined approach has led in the past to a functional confirmation of ten AMPA-receptor interactors and identified Porcupine as a transient interactor that modulates AMPAR forward trafficking (Erlenhardt et al., 2016; Schwenk et al., 2012). A further complicating factor in studying neurotransmitter receptors is heterogeneity in receptor composition. In the case of GABAAR, the receptor assembles as a hetero-pentamer, containing at least one of six a subunits, one of three b subunits and one of ten non-a/b subunits. Various combinations of these subunits give rise to a high degree of GABAAR molecular diversity in the brain. Therefore, identifying specific molecules that control GABAAR trafficking may become a daunting task if trying to account for the many possible subunit combinations. In this issue of Neuron, overcoming many of the challenges inherent to proteomic-based identification of GABAARs-specific transient interactors, Ge et al. (2018) applied an optimized proteomic approach
to identify Clptm1 as a GABAAR-interacting protein that controls receptor forward trafficking in neurons. To circumvent potential caveats in specificity of antibodies in proteomics, the authors applied a transgenic approach. Using knockin mice that express His-FLAG-YFP-GABAAR g2, the authors purified the receptor complex through a tandem purification technique with nickel-charged affinity resin and an anti-GFP antibody. This has led to the identification of 39 proteins as well as previously identified associated proteins of GABAAR subunits and neuroligin-2. Next, Ge et al. (2018) focused on six proteins for further analysis of their interaction in HEK293 cells and found that three transmembrane proteins (Clptm1, Itm2C, and Glgl1) could interact with GABAARs, but not with glycine receptors. Ge et al. (2018) next assessed the functional role of these three proteins and found that only Clptm1 altered GABAARs-mediated currents. This was demonstrated by a substantial reduction in GABA-evoked currents, with no apparent effect on glycine receptor activity. Overexpression of a Myc-tagged Clptm1 resulted in substantial accumulation of Clptm1 and GABAAR in the ER and reduced surface expression of GABAARs, suggesting a role of Clptm1 in intracellular retention. Perhaps most remarkably, knocking down Clptm1 increased GABA-evoked currents in primary cultured neurons, and overexpression and knockdown of clptm1 in vivo reduced and increased miniature inhibitory postsynaptic current (mIPSC) amplitudes, respectively, without altering excitatory miniature excitatory postsynaptic currents (mEPSCs). This set
Neuron 97, February 7, 2018 ª 2018 Elsevier Inc. 479
Neuron
Previews
of experiments establishes An additional outstanding Cltpm1 as an intracellular question concerns the physmolecule for controlling iological roles that Clptm1 GABAAR forward trafficking, serves by accumulating at the ER. acting likely via ER retention. GABAARs GABAARs at the ER may funcIntriguingly, the bi-direction as a reservoir for surface tional effects of Clptm1 expression. In such a sceknockdown and overexpresnario, Clptm1 or its associated sion on mIPSCs resemble proteins could serve as a dythe process of homeostatic namic sensor of neuronal acsynaptic scaling. In primary tivity by releasing GABAARs neuronal culture preparafrom the ER upon demand. tions, homeostatic synaptic Indeed, knockdown or overscaling can be defined as a expression of Clptm1 altered compensatory response in the number of GABAARs which silencing GABAergic at the cell surface, mimicking transmission leads to an inthe effects of homeostatic crease in synaptic GABAAR activity, while silencing oversynaptic scaling in vitro. all neuronal firing reduces Future endeavors should GABAAR activity. Ge et al. reveal whether Clptm1(2018) demonstrated that induced retention of bidirectional manipulation of GABAARs plays a physiological role in the dynamic conGABAARs by Clptm1 knockdown and overexpression trol of inhibitory transmission can either accentuate or in vivo. An alternative (though occlude homeostatic scaling. not mutually exclusive) physiThis raises the possibility that ological role of Clptm1 might rather than playing a static be to delay GABAAR exit from the ER in order to allow proper role, Clptm1 may participate Figure 1. Stable and Transient Interactors Accompany and Control assembly with other stable in the dynamic adjustment Neurotransmitter Receptors During the process of forward trafficking, receptors form complexes with both interactors. Mature GABAARs of GABAARs number at the transient and stable interactors that either limit or facilitate their activity. synapse. form a tri-partite complex Transient interactions can support receptor maturation and transport from ER Overall, the study of Ge with GARLH and Neuroligin2 to plasma membrane, whereas stable interactions (such as with auxiliary subunits) can also modulate membrane localization and functional properties. et al. (2018) adds an impor(Yamasaki et al., 2017), but By their nature, functional transient interactors are more challenging to be tant step on our way to underthe underlying mechanisms identified by proteomic methods. standing the cellular machinremain unknown. Interestery that controls inhibitory ingly, Clptm1 was identified transmission. It identifies a negative lar interaction of Clptm1 with the various using a tagged GABAA-g2 subunit, while regulator, Clptm1, which acts to trap subunits of GABAARs. Traditional molec- GARLH requires the same subunit in order GABAARs within intracellular compart- ular approaches to characterize inter- to interact with GABAARs (Martenson et al., ments and thus limits their expression action domains may be challenging in 2017; Yamasaki et al., 2017). Thus, Clptm1 on the neuronal membrane. Receptor- this case. Typically, deletion mutants or may act as a checkpoint for GABAAR specific interactors that restrict surface chimeric proteins between functional complexes upon exiting the ER. Analysis expression highlight the importance of and non-functional homologous proteins of GABAAR complex assembly and localiprecise and tight control of GABAAR are used for mapping interaction do- zation in Clptm1 knockout mice can be number on the plasma membrane. mains. However, applying this approach especially beneficial in revealing such Several important questions remain to study the interaction between two potential roles. Furthermore, complemenopen for future studies. Interestingly, transmembrane proteins is notoriously tary proteomic analysis of Clptm1 (as although Clptm1 was originally identified difficult because of the relatively low done for GABAAR in the current work by using a tagged GABAAR-g2, Ge et al. tolerance of transmembrane proteins to Ge et al.) can provide important information (2018) detected its interaction (in trans- mutations that affect their structure. With on the molecular makeup of GABAAR in fected heterologous cells) with all tested recent advances in cryoelectron micro- complex with Clptm1 and help discover GABAAR subunits (namely g2, a1, a2, scopy, however, solving the structure of new binding partners involved in Clptm1b2, b3). This is surprising, considering the receptor complex at the atomic level induced retention. the relatively low sequence homology be- should provide important insights on the Finally, the proteomic analysis by tween these different subunits. Future interaction between the receptor and its Ge et al. (2018) identified 39 proteins studies can elucidate the precise molecu- binding partners. and extensively studied 6 of them. It
480 Neuron 97, February 7, 2018
Neuron
Previews is common for proteomic studies to generate relatively large lists of potentially interesting targets. Indeed, different proteomic approaches have been successful in identifying additional sets of GABAAR-associated proteins that may serve important roles in the cellular and physiological regulation of these receptors (Heller et al., 2012; Nakamura et al., 2016). Considering the many functions that GABAAR-associated proteins can serve in receptor maturation, trafficking, membrane localization, and biophysical properties, further analysis of individual interactors and their in vivo functions should provide important insights. Currently, sifting through large amounts of candidates to identify the most promising ones remains labor intensive. Establishing high-throughput pipelines to systematically evaluate the functional contribution of all proteomic hits is therefore of high priority to the field and should bring us closer to a complete mechanistic understanding of a receptor’s life cycle in the living
neuron, and the consequences for brain function.
Jackson, A.C., and Nicoll, R.A. (2011). The expanding social network of ionotropic glutamate receptors: TARPs and other transmembrane auxiliary subunits. Neuron 70, 178–199.
ACKNOWLEDGMENTS S.T. is supported by NIH/NIMH MH115705.
Martenson, J.S., Yamasaki, T., Chaudhury, N.H., Albrecht, D., and Tomita, S. (2017). Assembly rules for GABAA receptor complexes in the brain. eLife 6, 6.
REFERENCES Davenport, E.C., Pendolino, V., Kontou, G., McGee, T.P., Sheehan, D.F., Lo´pez-Dome´nech, G., Farrant, M., and Kittler, J.T. (2017). An Essential Role for the Tetraspanin LHFPL4 in the Cell-TypeSpecific Targeting and Clustering of Synaptic GABAA Receptors. Cell Rep. 21, 70–83. Erlenhardt, N., Yu, H., Abiraman, K., Yamasaki, T., Wadiche, J.I., Tomita, S., and Bredt, D.S. (2016). Porcupine Controls Hippocampal AMPAR Levels, Composition, and Synaptic Transmission. Cell Rep. 14, 782–794. Ge, Y., Kang, Y., Cassidy, R.M., Moon, K., Lewis, R., Wong, R.O.L., Foster, L.J., and Craig, A.M. (2018). Clptm1 Limits Forward Trafficking of GABAA Receptors to Scale Inhibitory Synaptic Strength. Neuron 97, this issue, 596–610. Heller, E.A., Zhang, W., Selimi, F., Earnheart, J.C., Slimak, M.A., Santos-Torres, J., Iban˜ez-Tallon, I., Aoki, C., Chait, B.T., and Heintz, N. (2012). The biochemical anatomy of cortical inhibitory synapses. PLoS ONE 7, e39572.
Nakamura, Y., Morrow, D.H., Modgil, A., Huyghe, D., Deeb, T.Z., Lumb, M.J., Davies, P.A., and Moss, S.J. (2016). Proteomic Characterization of Inhibitory Synapses Using a Novel pHluorintagged g-Aminobutyric Acid Receptor, Type A (GABAA), a2 Subunit Knock-in Mouse. J. Biol. Chem. 291, 12394–12407. Schwenk, J., Harmel, N., Brechet, A., Zolles, G., €ller, C.S., Bildl, W., Baehrens, Berkefeld, H., Mu €ber, B., Kulik, A., et al. (2012). High-resoluD., Hu tion proteomics unravel architecture and molecular diversity of native AMPA receptor complexes. Neuron 74, 621–633. Yamasaki, T., Hoyos-Ramirez, E., Martenson, J.S., Morimoto-Tomita, M., and Tomita, S. (2017). GARLH family proteins stabilize GABAA receptors at synapses. Neuron 93, 1138–1152.e6. Yan, D., and Tomita, S. (2012). Defined criteria for auxiliary subunits of glutamate receptors. J. Physiol. 590, 21–31.
When Acetylcholine Unlocks Feedback Inhibition in Cortex Quentin Chevy1 and Adam Kepecs1,* 1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA *Correspondence: [email protected] https://doi.org/10.1016/j.neuron.2018.01.042
Acetylcholine promotes cognitive function through the regulation of cortical circuits. In this issue of Neuron, Urban-Ciecko et al. (2018) demonstrate how this neuromodulator can rapidly boost synapses from pyramidal to somatostatin neurons, unlocking a new computational ability in the cortical microcircuitry. Cholinergic neurons from the basal forebrain provide dense connections to cortex and are thought to support a range of behavioral functions from attention and learning to sensory processing and memory (Eggermann et al., 2014; Letzkus et al., 2011; Mun˜oz and Rudy, 2014). The release of acetylcholine can profoundly transform cortical processing by boosting firing rates, enhancing synaptic plasticity, and reducing network synchrony. These
changes in turn can result in increased reliability of sensory responses, expansion of receptive fields, and reorganization of cortical maps. Although acetylcholine, like other neuromodulators, has been thought to act slowly via volumetric transmission and metabotropic receptors, recent data reveal a second, rapid, phasic mode of communication with point-to-point synapses and ionotropic transmission (Hangya et al., 2015; Mun˜oz
and Rudy, 2014). Nevertheless, the relative extent and functional impact of these different types of communication remain unclear. At the cellular and synaptic levels, acetylcholine can produce a diversity of responses depending, in part, on the specific acetylcholine receptors present on the cell. Most cortical neurons express either metabotropic muscarinic or ionotropic nicotinic receptors in different
Neuron 97, February 7, 2018 ª 2018 Elsevier Inc. 481
Previews On the Path from Proteomics to Function: GABAAR Trafficking Takes a Turn Yoav Noam1 and Susumu Tomita1,* 1Department of Cellular and Molecular Physiology, Department of Neuroscience, CNNR program, Yale University School of Medicine, New Haven, CT 06520, USA *Correspondence: [email protected] https://doi.org/10.1016/j.neuron.2018.01.038
There are significant challenges in identifying receptor-specific functional interactors in vivo. In this issue of Neuron, Ge et al. (2018) identify a novel GABAA receptor (GABAAR)-interacting protein, Clptm1, that regulates forward trafficking of GABAARs and inhibitory transmission. Interactions between neurotransmitter receptors and regulatory proteins control synaptic transmission and plasticity through various pathways. In order to fulfill their function, neurotransmitter receptors first exit the endoplasmic reticulum (ER) and travel to the cell surface. During this process, interactions between the receptor and various binding partners promote and/or regulate receptor assembly and trafficking. Through these interactions, a mature receptor complex is formed, enabling its proper localization and function at the plasma membrane and synapses (Figure 1). Indeed, protein complexes between a neurotransmitter receptor and regulatory, interacting proteins (‘‘interactors’’) emerge as a common theme in receptor biology. For example, excitatory AMPA and kainate-type glutamate receptors create a stable complex with their auxiliary proteins TARPs and NETOs, respectively, and these interactions are required for proper synaptic transmission (Jackson and Nicoll, 2011; Yan and Tomita, 2012). Recently, GABAARs were found to form a stable tripartite complex with GARLH and Neuroligin-2 (Yamasaki et al., 2017), which is required for synaptic localization of GABAARs but not forward trafficking (Davenport et al., 2017; Yamasaki et al., 2017). Not only stable, but also transient interactions help shape the receptor landscape on the neuronal membrane (Figure 1). These transient interactions can take place along the various stages of forward receptor trafficking, including complex assembly, ER exit, trafficking, and exocytosis. Uncovering the specific interactors controlling receptor function is critical to our mechanistic under-
standing of neuronal signaling, yet the biochemical isolation and identification of transient interactors in vivo has proven technically demanding. A major challenge is the fact that transient complexes are (by definition) less abundant and are therefore harder to detect. Consequently, proteomic approaches to reveal transient interactions may lead to large sets of candidates, with dozens of potential interactors. In some cases, rather than relying solely on classical proteomic approaches, ‘‘fishing’’ for specific transient interactors can be achieved by adopting complementary methods such as highthroughput functional assays. Indeed, taking such a combined approach has led in the past to a functional confirmation of ten AMPA-receptor interactors and identified Porcupine as a transient interactor that modulates AMPAR forward trafficking (Erlenhardt et al., 2016; Schwenk et al., 2012). A further complicating factor in studying neurotransmitter receptors is heterogeneity in receptor composition. In the case of GABAAR, the receptor assembles as a hetero-pentamer, containing at least one of six a subunits, one of three b subunits and one of ten non-a/b subunits. Various combinations of these subunits give rise to a high degree of GABAAR molecular diversity in the brain. Therefore, identifying specific molecules that control GABAAR trafficking may become a daunting task if trying to account for the many possible subunit combinations. In this issue of Neuron, overcoming many of the challenges inherent to proteomic-based identification of GABAARs-specific transient interactors, Ge et al. (2018) applied an optimized proteomic approach
to identify Clptm1 as a GABAAR-interacting protein that controls receptor forward trafficking in neurons. To circumvent potential caveats in specificity of antibodies in proteomics, the authors applied a transgenic approach. Using knockin mice that express His-FLAG-YFP-GABAAR g2, the authors purified the receptor complex through a tandem purification technique with nickel-charged affinity resin and an anti-GFP antibody. This has led to the identification of 39 proteins as well as previously identified associated proteins of GABAAR subunits and neuroligin-2. Next, Ge et al. (2018) focused on six proteins for further analysis of their interaction in HEK293 cells and found that three transmembrane proteins (Clptm1, Itm2C, and Glgl1) could interact with GABAARs, but not with glycine receptors. Ge et al. (2018) next assessed the functional role of these three proteins and found that only Clptm1 altered GABAARs-mediated currents. This was demonstrated by a substantial reduction in GABA-evoked currents, with no apparent effect on glycine receptor activity. Overexpression of a Myc-tagged Clptm1 resulted in substantial accumulation of Clptm1 and GABAAR in the ER and reduced surface expression of GABAARs, suggesting a role of Clptm1 in intracellular retention. Perhaps most remarkably, knocking down Clptm1 increased GABA-evoked currents in primary cultured neurons, and overexpression and knockdown of clptm1 in vivo reduced and increased miniature inhibitory postsynaptic current (mIPSC) amplitudes, respectively, without altering excitatory miniature excitatory postsynaptic currents (mEPSCs). This set
Neuron 97, February 7, 2018 ª 2018 Elsevier Inc. 479
Neuron
Previews
of experiments establishes An additional outstanding Cltpm1 as an intracellular question concerns the physmolecule for controlling iological roles that Clptm1 GABAAR forward trafficking, serves by accumulating at the ER. acting likely via ER retention. GABAARs GABAARs at the ER may funcIntriguingly, the bi-direction as a reservoir for surface tional effects of Clptm1 expression. In such a sceknockdown and overexpresnario, Clptm1 or its associated sion on mIPSCs resemble proteins could serve as a dythe process of homeostatic namic sensor of neuronal acsynaptic scaling. In primary tivity by releasing GABAARs neuronal culture preparafrom the ER upon demand. tions, homeostatic synaptic Indeed, knockdown or overscaling can be defined as a expression of Clptm1 altered compensatory response in the number of GABAARs which silencing GABAergic at the cell surface, mimicking transmission leads to an inthe effects of homeostatic crease in synaptic GABAAR activity, while silencing oversynaptic scaling in vitro. all neuronal firing reduces Future endeavors should GABAAR activity. Ge et al. reveal whether Clptm1(2018) demonstrated that induced retention of bidirectional manipulation of GABAARs plays a physiological role in the dynamic conGABAARs by Clptm1 knockdown and overexpression trol of inhibitory transmission can either accentuate or in vivo. An alternative (though occlude homeostatic scaling. not mutually exclusive) physiThis raises the possibility that ological role of Clptm1 might rather than playing a static be to delay GABAAR exit from the ER in order to allow proper role, Clptm1 may participate Figure 1. Stable and Transient Interactors Accompany and Control assembly with other stable in the dynamic adjustment Neurotransmitter Receptors During the process of forward trafficking, receptors form complexes with both interactors. Mature GABAARs of GABAARs number at the transient and stable interactors that either limit or facilitate their activity. synapse. form a tri-partite complex Transient interactions can support receptor maturation and transport from ER Overall, the study of Ge with GARLH and Neuroligin2 to plasma membrane, whereas stable interactions (such as with auxiliary subunits) can also modulate membrane localization and functional properties. et al. (2018) adds an impor(Yamasaki et al., 2017), but By their nature, functional transient interactors are more challenging to be tant step on our way to underthe underlying mechanisms identified by proteomic methods. standing the cellular machinremain unknown. Interestery that controls inhibitory ingly, Clptm1 was identified transmission. It identifies a negative lar interaction of Clptm1 with the various using a tagged GABAA-g2 subunit, while regulator, Clptm1, which acts to trap subunits of GABAARs. Traditional molec- GARLH requires the same subunit in order GABAARs within intracellular compart- ular approaches to characterize inter- to interact with GABAARs (Martenson et al., ments and thus limits their expression action domains may be challenging in 2017; Yamasaki et al., 2017). Thus, Clptm1 on the neuronal membrane. Receptor- this case. Typically, deletion mutants or may act as a checkpoint for GABAAR specific interactors that restrict surface chimeric proteins between functional complexes upon exiting the ER. Analysis expression highlight the importance of and non-functional homologous proteins of GABAAR complex assembly and localiprecise and tight control of GABAAR are used for mapping interaction do- zation in Clptm1 knockout mice can be number on the plasma membrane. mains. However, applying this approach especially beneficial in revealing such Several important questions remain to study the interaction between two potential roles. Furthermore, complemenopen for future studies. Interestingly, transmembrane proteins is notoriously tary proteomic analysis of Clptm1 (as although Clptm1 was originally identified difficult because of the relatively low done for GABAAR in the current work by using a tagged GABAAR-g2, Ge et al. tolerance of transmembrane proteins to Ge et al.) can provide important information (2018) detected its interaction (in trans- mutations that affect their structure. With on the molecular makeup of GABAAR in fected heterologous cells) with all tested recent advances in cryoelectron micro- complex with Clptm1 and help discover GABAAR subunits (namely g2, a1, a2, scopy, however, solving the structure of new binding partners involved in Clptm1b2, b3). This is surprising, considering the receptor complex at the atomic level induced retention. the relatively low sequence homology be- should provide important insights on the Finally, the proteomic analysis by tween these different subunits. Future interaction between the receptor and its Ge et al. (2018) identified 39 proteins studies can elucidate the precise molecu- binding partners. and extensively studied 6 of them. It
480 Neuron 97, February 7, 2018
Neuron
Previews is common for proteomic studies to generate relatively large lists of potentially interesting targets. Indeed, different proteomic approaches have been successful in identifying additional sets of GABAAR-associated proteins that may serve important roles in the cellular and physiological regulation of these receptors (Heller et al., 2012; Nakamura et al., 2016). Considering the many functions that GABAAR-associated proteins can serve in receptor maturation, trafficking, membrane localization, and biophysical properties, further analysis of individual interactors and their in vivo functions should provide important insights. Currently, sifting through large amounts of candidates to identify the most promising ones remains labor intensive. Establishing high-throughput pipelines to systematically evaluate the functional contribution of all proteomic hits is therefore of high priority to the field and should bring us closer to a complete mechanistic understanding of a receptor’s life cycle in the living
neuron, and the consequences for brain function.
Jackson, A.C., and Nicoll, R.A. (2011). The expanding social network of ionotropic glutamate receptors: TARPs and other transmembrane auxiliary subunits. Neuron 70, 178–199.
ACKNOWLEDGMENTS S.T. is supported by NIH/NIMH MH115705.
Martenson, J.S., Yamasaki, T., Chaudhury, N.H., Albrecht, D., and Tomita, S. (2017). Assembly rules for GABAA receptor complexes in the brain. eLife 6, 6.
REFERENCES Davenport, E.C., Pendolino, V., Kontou, G., McGee, T.P., Sheehan, D.F., Lo´pez-Dome´nech, G., Farrant, M., and Kittler, J.T. (2017). An Essential Role for the Tetraspanin LHFPL4 in the Cell-TypeSpecific Targeting and Clustering of Synaptic GABAA Receptors. Cell Rep. 21, 70–83. Erlenhardt, N., Yu, H., Abiraman, K., Yamasaki, T., Wadiche, J.I., Tomita, S., and Bredt, D.S. (2016). Porcupine Controls Hippocampal AMPAR Levels, Composition, and Synaptic Transmission. Cell Rep. 14, 782–794. Ge, Y., Kang, Y., Cassidy, R.M., Moon, K., Lewis, R., Wong, R.O.L., Foster, L.J., and Craig, A.M. (2018). Clptm1 Limits Forward Trafficking of GABAA Receptors to Scale Inhibitory Synaptic Strength. Neuron 97, this issue, 596–610. Heller, E.A., Zhang, W., Selimi, F., Earnheart, J.C., Slimak, M.A., Santos-Torres, J., Iban˜ez-Tallon, I., Aoki, C., Chait, B.T., and Heintz, N. (2012). The biochemical anatomy of cortical inhibitory synapses. PLoS ONE 7, e39572.
Nakamura, Y., Morrow, D.H., Modgil, A., Huyghe, D., Deeb, T.Z., Lumb, M.J., Davies, P.A., and Moss, S.J. (2016). Proteomic Characterization of Inhibitory Synapses Using a Novel pHluorintagged g-Aminobutyric Acid Receptor, Type A (GABAA), a2 Subunit Knock-in Mouse. J. Biol. Chem. 291, 12394–12407. Schwenk, J., Harmel, N., Brechet, A., Zolles, G., €ller, C.S., Bildl, W., Baehrens, Berkefeld, H., Mu €ber, B., Kulik, A., et al. (2012). High-resoluD., Hu tion proteomics unravel architecture and molecular diversity of native AMPA receptor complexes. Neuron 74, 621–633. Yamasaki, T., Hoyos-Ramirez, E., Martenson, J.S., Morimoto-Tomita, M., and Tomita, S. (2017). GARLH family proteins stabilize GABAA receptors at synapses. Neuron 93, 1138–1152.e6. Yan, D., and Tomita, S. (2012). Defined criteria for auxiliary subunits of glutamate receptors. J. Physiol. 590, 21–31.
When Acetylcholine Unlocks Feedback Inhibition in Cortex Quentin Chevy1 and Adam Kepecs1,* 1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA *Correspondence: [email protected] https://doi.org/10.1016/j.neuron.2018.01.042
Acetylcholine promotes cognitive function through the regulation of cortical circuits. In this issue of Neuron, Urban-Ciecko et al. (2018) demonstrate how this neuromodulator can rapidly boost synapses from pyramidal to somatostatin neurons, unlocking a new computational ability in the cortical microcircuitry. Cholinergic neurons from the basal forebrain provide dense connections to cortex and are thought to support a range of behavioral functions from attention and learning to sensory processing and memory (Eggermann et al., 2014; Letzkus et al., 2011; Mun˜oz and Rudy, 2014). The release of acetylcholine can profoundly transform cortical processing by boosting firing rates, enhancing synaptic plasticity, and reducing network synchrony. These
changes in turn can result in increased reliability of sensory responses, expansion of receptive fields, and reorganization of cortical maps. Although acetylcholine, like other neuromodulators, has been thought to act slowly via volumetric transmission and metabotropic receptors, recent data reveal a second, rapid, phasic mode of communication with point-to-point synapses and ionotropic transmission (Hangya et al., 2015; Mun˜oz
and Rudy, 2014). Nevertheless, the relative extent and functional impact of these different types of communication remain unclear. At the cellular and synaptic levels, acetylcholine can produce a diversity of responses depending, in part, on the specific acetylcholine receptors present on the cell. Most cortical neurons express either metabotropic muscarinic or ionotropic nicotinic receptors in different
Neuron 97, February 7, 2018 ª 2018 Elsevier Inc. 481