Schizophrenia Research 166 (2015) 343–344
Contents lists available at ScienceDirect
Schizophrenia Research journal homepage: www.elsevier.com/locate/schres
Letter to the Editor Response to: NMDA hypofunction attenuates driver inputs in higher order thalamic nuclei: An alternative view
In response to the review by Cohen et al. (2015), Vukadinovic points out the inherent incompleteness of the ‘NMDA receptor hypofunction on GABAergic neurons’ model as an explanation for schizophrenia. Additionally, he posits that NMDA hypofunction on relay cells of higher order thalamic nuclei may provide an ‘alternative, but not mutually exclusive’ explanation for this disorder. In this response, we aim to clarify some of the limitations this letter highlights, discuss existing efforts to overcome them, and emphasize the critical role of experimental evidence in refining our understanding of pathophysiological mechanisms in psychiatric disorders. Studies are showing that schizophrenia as a diagnostic and statistical manual (DSM)-defined entity, is unlikely to map onto a single brain disorder with a uniform pathophysiology (Arnedo et al., 2015). The mismatch between psychiatric diagnosis and neurobiology extends well beyond schizophrenia, and has led to launching the Research Domain Criteria (RDoC) project by the National Institute of Mental Health (NIMH) (Insel et al., 2010). This project is meant to organize our descriptions of mental illnesses within a neurobiological circuit-based framework with the hope of creating precision medicine for psychiatry. This would mean that future clinicians would be able to supplement their clinical interview with diagnostic tests aimed at uncovering dysfunctional brain circuits and subsequently leverage treatments geared towards reversing such abnormalities. Parallel efforts in psychiatric genetics are also meant to introduce a robust organizational scheme. As such, DSM disease boundaries will likely be revised, and the notion of schizophrenia recognized by Kreplin and formalized by Schneider will likely be impractical for circuit-based diagnostics and therapeutics of psychotic spectrum disorders. With this in mind, Cohen et al. wrote an invited review to discuss Nmethyl D-Aspartate (NMDA)-related perturbations in schizophrenia within the context of a special issue focused on γ-aminobutyric acid (GABA)-ergic dysfunction. By design, this review highlighted the existing experimental evidence supporting the link between NMDA and GABA in schizophrenia. It left out many studies that show NMDA hypofunction across brain regions and cell types that could explain some aspects of psychotic illnesses. For example, eliminating NMDA receptors specifically in dopaminergic neurons results in learning phenotypes that may be related to chronic psychosis (Zweifel et al., 2009). Because this is not a GABAergic manipulation, it provides experimental support for NMDA hypofunction extending beyond what Cohen et al. highlighted. Vukadinovic's thesis of NMDA hypofunction on higher order thalamic neurons being a contributor to cortical dysconnectivity is certainly an interesting idea. However, it lacks both clarity and experimental support. It is unclear how exactly NMDA receptor currents factor into
http://dx.doi.org/10.1016/j.schres.2015.04.020 0920-9964/© 2015 Elsevier B.V. All rights reserved.
cortical drive of higher order thalamic neurons; whether it is deployed under certain behavioral states or how it engages in specific computations. From an experimental perspective, the basic physiological properties of the higher order cortico-thalamic synapse have not been systematically studied, so a data-driven prediction of what NMDA antagonism is supposed to do is difficult to make. In fact, one study that examined higher order somatosensory thalamic neuronal drive by cortical input in vivo did not show a role for NMDA receptors (Groh et al., 2014). Figures 3 and 4 of that paper show that, under ketamine anesthesia, primary somatosensory cortex evokes robust excitatory postsynaptic potentials (EPSPs) in posteromedial thalamic neurons. This finding argues against a requirement for NMDA receptors in higher order thalamic drive, undermining Vukadinovic's thesis from a strict datadriven perspective. Clearly, in the drug-free brain and under different behavioral conditions NMDA requirement may change, but none of these issues are articulated or discussed in Vukadinovic's papers. In contrast to higher order thalamus, several studies have examined synaptic properties of cortical (Carlen et al., 2012) and thalamic reticular (Zhang et al., 2012) GABAergic neurons, allowing for data-driven hypotheses to be postulated regarding the impact of NMDA hypofunction on their cellular and associated circuit properties. Cohen et al. highlighted a study of NMDA receptor currents in thalamic reticular nucleus (TRN) neurons (Zhang et al., 2012). The critical finding of that paper is in Figure 1A where the application of 50 μM APV results in a tonic hyperpolarization of a TRN neuron (Group average in Figure 1B). This finding suggests that tonic activation of NMDA receptors contributes to a more depolarized resting membrane potential among TRN neurons, and thereby, one conclusion may be that TRN excitability is NMDA receptor-dependent. The finding that APV application results in oscillatory bursting of TRN neurons at the delta frequency (Figure 3) is intriguing, but whether this observation in an acute brain slice occurs in the intact brain and contributes to delta observed at the level of the surface electroencephalogram (EEG) is an open question. In fact, a study that employed phenylcyclidine injection of rats in vivo, showed the predicted reduction in TRN neuronal firing rates, but not enhanced delta (Troyano-Rodriguez et al., 2014). Again, the issue of anesthesia complicates the interpretation of that particular finding, but clearly both slice and in vivo studies show an important role of NMDA in TRN excitability. The notion of TRN involvement in psychotic illness extends beyond the aforementioned papers. For example, several studies have shown reduction in spindle oscillations in schizophrenia patients. These 7–15 Hz oscillations are thought to be dependent on TRN neurons (Halassa et al., 2011), strengthening the link between TRN dysfunction and psychotic illnesses. One should keep in mind, however, that reduced spindles have also been observed in autism spectrum disorders, and therefore may be reflective of impaired thalamo-cortical function across disorders unified by an RDoC organizational scheme. As Vukadinovic rightly points out, waking delta may also reflect similar dysfunction across disorders. Regardless, the idea that the TRN can operate like a switchboard, changing sensory and limbic gain according to behavioral demand is likely to be most relevant to understanding how its dysfunction contributes to
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disease states. This idea is supported by basic (Halassa et al., 2014), and translational (Ahrens et al., 2015) rodent models, as well as human neuroimaging (Viviano and Schneider, 2015). Vukadinovic's ideas related to the role of NMDA receptors in higher order thalamic relay cells in cortico-cortical coordination require experimental testing. As he suggested, experiments that utilize genetic ablation of NMDA receptors selectively in these neurons could be a reasonable first step. Driver Cre mice with expression patterns in these areas are available (http://www.gensat.org/index.html), and can be used for this very purpose. Clarification of the theoretical framework guiding the behavioral and electrophysiological characterization of these animals is important. This clarification will allow for hypothesisdriven research that will be useful regardless of whether NMDA receptors in higher order thalamus turn out to be relevant to psychotic illnesses or not. To summarize, we agree with Vukadinovic's implicit message that NMDA hypofunction on GABAergic neurons is not the whole story in schizophrenia. How can it be? Schizophrenia is not one thing, and likely reflects several pathophysiological mechanisms. Given this complexity, is there hope of ever understanding these illnesses and ultimately reversing them? We are betting on the answer being yes. Through careful experimental design, analysis and interpretation, the scientific community is systematically confirming certain models of pathophysiology and falsifying others. Through coordinated efforts between human and animal studies, we now have the unique opportunity of understanding the circuit basis of many serious mental illnesses, which together will define psychiatry in the 21st century. Contributors Samuel Cohen and Michael Halassa. Conflict of interest We have no conflict of interest to declare. Acknowledgment We thank D.C. Goff for thoughtful comments on the manuscript. MMH is supported by grants from the NIH, Brain and Behavior Research Foundation, Simons Foundation, Alfred P. Sloan Foundation and Feldstein Medical Foundation.
References Ahrens, S., Jaramillo, S., Yu, K., Ghosh, S., Hwang, G.R., Paik, R., Lai, C., He, M., Huang, Z.J., Li, B., 2015. ErbB4 regulation of a thalamic reticular nucleus circuit for sensory selection. Nat. Neurosci. 18 (1), 104–111. Arnedo, J., Svrakic, D.M., Del Val, C., Romero-Zaliz, R., Hernandez-Cuervo, H., Molecular Genetics of Schizophrenia, C., Fanous, A.H., Pato, M.T., Pato, C.N., de Erausquin, G.A.,
Cloninger, C.R., Zwir, I., 2015. Uncovering the hidden risk architecture of the schizophrenias: confirmation in three independent genome-wide association studies. Am. J. Psychiatry 172 (2), 139–153. Carlen, M., Meletis, K., Siegle, J.H., Cardin, J.A., Futai, K., Vierling-Claassen, D., Ruhlmann, C., Jones, S.R., Deisseroth, K., Sheng, M., Moore, C.I., Tsai, L.H., 2012. A critical role for NMDA receptors in parvalbumin interneurons for gamma rhythm induction and behavior. Mol. Psychiatry 17 (5), 537–548. Cohen, S.M., Tsien, R.W., Goff, D.C., Halassa, M.M., 2015. The impact of NMDA receptor hypofunction on GABAergic neurons in the pathophysiology of schizophrenia. Schizophr. Res. (pii: S0920-9954). Groh, A., Bokor, H., Mease, R.A., Plattner, V.M., Hangya, B., Stroh, A., Deschenes, M., Acsady, L., 2014. Convergence of cortical and sensory driver inputs on single thalamocortical cells. Cereb. Cortex 24 (12), 3167–3179. Halassa, M.M., Siegle, J.H., Ritt, J.T., Ting, J.T., Feng, G., Moore, C.I., 2011. Selective optical drive of thalamic reticular nucleus generates thalamic bursts and cortical spindles. Nat. Neurosci. 14 (9), 1118–1120. Halassa, M.M., Chen, Z., Wimmer, R.D., Brunetti, P.M., Zhao, S., Zikopoulos, B., Wang, F., Brown, E.N., Wilson, M.A., 2014. State-dependent architecture of thalamic reticular subnetworks. Cell 158 (4), 808–821. Insel, T., Cuthbert, B., Garvey, M., Heinssen, R., Pine, D.S., Quinn, K., Sanislow, C., Wang, P., 2010. Research domain criteria (RDoC): toward a new classification framework for research on mental disorders. Am. J. Psychiatry 167 (7), 748–751. Troyano-Rodriguez, E., Llado-Pelfort, L., Santana, N., Teruel-Marti, V., Celada, P., Artigas, F., 2014. Phencyclidine inhibits the activity of thalamic reticular gamma-aminobutyric acidergic neurons in rat brain. Biol. Psychiatry 76 (12), 937–945. Viviano, J.D., Schneider, K.A., 2015. Interhemispheric interactions of the human thalamic reticular nucleus. J. Neurosci. 35 (5), 2026–2032. Zhang, Y., Buonanno, A., Vertes, R.P., Hoover, W.B., Lisman, J.E., 2012. NR2C in the thalamic reticular nucleus; effects of the NR2C knockout. PLoS One 7 (7), e41908. Zweifel, L.S., Parker, J.G., Lobb, C.J., Rainwater, A., Wall, V.Z., Fadok, J.P., Darvas, M., Kim, M.J., Mizumori, S.J., Paladini, C.A., Phillips, P.E., Palmiter, R.D., 2009. Disruption of NMDAR-dependent burst firing by dopamine neurons provides selective assessment of phasic dopamine-dependent behavior. Proc. Natl. Acad. Sci. U. S. A. 106 (18), 7281–7288.
Samuel M. Cohen NYU Neuroscience Institute and Department of Neuroscience and Physiology, NYU Langone Medical Center, New York, NY 10016, USA Michael M. Halassa NYU Neuroscience Institute and Department of Neuroscience and Physiology, NYU Langone Medical Center, New York, NY 10016, USA Department of Psychiatry, NYU Langone Medical Center, New York, NY 10016, USA Corresponding author at: NYU Neuroscience Institute and Department of Neuroscience and Physiology, NYU Langone Medical Center, New York, NY 10016, USA. E-mail address: [email protected] 15 April 2015
Contents lists available at ScienceDirect
Schizophrenia Research journal homepage: www.elsevier.com/locate/schres
Letter to the Editor Response to: NMDA hypofunction attenuates driver inputs in higher order thalamic nuclei: An alternative view
In response to the review by Cohen et al. (2015), Vukadinovic points out the inherent incompleteness of the ‘NMDA receptor hypofunction on GABAergic neurons’ model as an explanation for schizophrenia. Additionally, he posits that NMDA hypofunction on relay cells of higher order thalamic nuclei may provide an ‘alternative, but not mutually exclusive’ explanation for this disorder. In this response, we aim to clarify some of the limitations this letter highlights, discuss existing efforts to overcome them, and emphasize the critical role of experimental evidence in refining our understanding of pathophysiological mechanisms in psychiatric disorders. Studies are showing that schizophrenia as a diagnostic and statistical manual (DSM)-defined entity, is unlikely to map onto a single brain disorder with a uniform pathophysiology (Arnedo et al., 2015). The mismatch between psychiatric diagnosis and neurobiology extends well beyond schizophrenia, and has led to launching the Research Domain Criteria (RDoC) project by the National Institute of Mental Health (NIMH) (Insel et al., 2010). This project is meant to organize our descriptions of mental illnesses within a neurobiological circuit-based framework with the hope of creating precision medicine for psychiatry. This would mean that future clinicians would be able to supplement their clinical interview with diagnostic tests aimed at uncovering dysfunctional brain circuits and subsequently leverage treatments geared towards reversing such abnormalities. Parallel efforts in psychiatric genetics are also meant to introduce a robust organizational scheme. As such, DSM disease boundaries will likely be revised, and the notion of schizophrenia recognized by Kreplin and formalized by Schneider will likely be impractical for circuit-based diagnostics and therapeutics of psychotic spectrum disorders. With this in mind, Cohen et al. wrote an invited review to discuss Nmethyl D-Aspartate (NMDA)-related perturbations in schizophrenia within the context of a special issue focused on γ-aminobutyric acid (GABA)-ergic dysfunction. By design, this review highlighted the existing experimental evidence supporting the link between NMDA and GABA in schizophrenia. It left out many studies that show NMDA hypofunction across brain regions and cell types that could explain some aspects of psychotic illnesses. For example, eliminating NMDA receptors specifically in dopaminergic neurons results in learning phenotypes that may be related to chronic psychosis (Zweifel et al., 2009). Because this is not a GABAergic manipulation, it provides experimental support for NMDA hypofunction extending beyond what Cohen et al. highlighted. Vukadinovic's thesis of NMDA hypofunction on higher order thalamic neurons being a contributor to cortical dysconnectivity is certainly an interesting idea. However, it lacks both clarity and experimental support. It is unclear how exactly NMDA receptor currents factor into
http://dx.doi.org/10.1016/j.schres.2015.04.020 0920-9964/© 2015 Elsevier B.V. All rights reserved.
cortical drive of higher order thalamic neurons; whether it is deployed under certain behavioral states or how it engages in specific computations. From an experimental perspective, the basic physiological properties of the higher order cortico-thalamic synapse have not been systematically studied, so a data-driven prediction of what NMDA antagonism is supposed to do is difficult to make. In fact, one study that examined higher order somatosensory thalamic neuronal drive by cortical input in vivo did not show a role for NMDA receptors (Groh et al., 2014). Figures 3 and 4 of that paper show that, under ketamine anesthesia, primary somatosensory cortex evokes robust excitatory postsynaptic potentials (EPSPs) in posteromedial thalamic neurons. This finding argues against a requirement for NMDA receptors in higher order thalamic drive, undermining Vukadinovic's thesis from a strict datadriven perspective. Clearly, in the drug-free brain and under different behavioral conditions NMDA requirement may change, but none of these issues are articulated or discussed in Vukadinovic's papers. In contrast to higher order thalamus, several studies have examined synaptic properties of cortical (Carlen et al., 2012) and thalamic reticular (Zhang et al., 2012) GABAergic neurons, allowing for data-driven hypotheses to be postulated regarding the impact of NMDA hypofunction on their cellular and associated circuit properties. Cohen et al. highlighted a study of NMDA receptor currents in thalamic reticular nucleus (TRN) neurons (Zhang et al., 2012). The critical finding of that paper is in Figure 1A where the application of 50 μM APV results in a tonic hyperpolarization of a TRN neuron (Group average in Figure 1B). This finding suggests that tonic activation of NMDA receptors contributes to a more depolarized resting membrane potential among TRN neurons, and thereby, one conclusion may be that TRN excitability is NMDA receptor-dependent. The finding that APV application results in oscillatory bursting of TRN neurons at the delta frequency (Figure 3) is intriguing, but whether this observation in an acute brain slice occurs in the intact brain and contributes to delta observed at the level of the surface electroencephalogram (EEG) is an open question. In fact, a study that employed phenylcyclidine injection of rats in vivo, showed the predicted reduction in TRN neuronal firing rates, but not enhanced delta (Troyano-Rodriguez et al., 2014). Again, the issue of anesthesia complicates the interpretation of that particular finding, but clearly both slice and in vivo studies show an important role of NMDA in TRN excitability. The notion of TRN involvement in psychotic illness extends beyond the aforementioned papers. For example, several studies have shown reduction in spindle oscillations in schizophrenia patients. These 7–15 Hz oscillations are thought to be dependent on TRN neurons (Halassa et al., 2011), strengthening the link between TRN dysfunction and psychotic illnesses. One should keep in mind, however, that reduced spindles have also been observed in autism spectrum disorders, and therefore may be reflective of impaired thalamo-cortical function across disorders unified by an RDoC organizational scheme. As Vukadinovic rightly points out, waking delta may also reflect similar dysfunction across disorders. Regardless, the idea that the TRN can operate like a switchboard, changing sensory and limbic gain according to behavioral demand is likely to be most relevant to understanding how its dysfunction contributes to
344
Letter to the Editor
disease states. This idea is supported by basic (Halassa et al., 2014), and translational (Ahrens et al., 2015) rodent models, as well as human neuroimaging (Viviano and Schneider, 2015). Vukadinovic's ideas related to the role of NMDA receptors in higher order thalamic relay cells in cortico-cortical coordination require experimental testing. As he suggested, experiments that utilize genetic ablation of NMDA receptors selectively in these neurons could be a reasonable first step. Driver Cre mice with expression patterns in these areas are available (http://www.gensat.org/index.html), and can be used for this very purpose. Clarification of the theoretical framework guiding the behavioral and electrophysiological characterization of these animals is important. This clarification will allow for hypothesisdriven research that will be useful regardless of whether NMDA receptors in higher order thalamus turn out to be relevant to psychotic illnesses or not. To summarize, we agree with Vukadinovic's implicit message that NMDA hypofunction on GABAergic neurons is not the whole story in schizophrenia. How can it be? Schizophrenia is not one thing, and likely reflects several pathophysiological mechanisms. Given this complexity, is there hope of ever understanding these illnesses and ultimately reversing them? We are betting on the answer being yes. Through careful experimental design, analysis and interpretation, the scientific community is systematically confirming certain models of pathophysiology and falsifying others. Through coordinated efforts between human and animal studies, we now have the unique opportunity of understanding the circuit basis of many serious mental illnesses, which together will define psychiatry in the 21st century. Contributors Samuel Cohen and Michael Halassa. Conflict of interest We have no conflict of interest to declare. Acknowledgment We thank D.C. Goff for thoughtful comments on the manuscript. MMH is supported by grants from the NIH, Brain and Behavior Research Foundation, Simons Foundation, Alfred P. Sloan Foundation and Feldstein Medical Foundation.
References Ahrens, S., Jaramillo, S., Yu, K., Ghosh, S., Hwang, G.R., Paik, R., Lai, C., He, M., Huang, Z.J., Li, B., 2015. ErbB4 regulation of a thalamic reticular nucleus circuit for sensory selection. Nat. Neurosci. 18 (1), 104–111. Arnedo, J., Svrakic, D.M., Del Val, C., Romero-Zaliz, R., Hernandez-Cuervo, H., Molecular Genetics of Schizophrenia, C., Fanous, A.H., Pato, M.T., Pato, C.N., de Erausquin, G.A.,
Cloninger, C.R., Zwir, I., 2015. Uncovering the hidden risk architecture of the schizophrenias: confirmation in three independent genome-wide association studies. Am. J. Psychiatry 172 (2), 139–153. Carlen, M., Meletis, K., Siegle, J.H., Cardin, J.A., Futai, K., Vierling-Claassen, D., Ruhlmann, C., Jones, S.R., Deisseroth, K., Sheng, M., Moore, C.I., Tsai, L.H., 2012. A critical role for NMDA receptors in parvalbumin interneurons for gamma rhythm induction and behavior. Mol. Psychiatry 17 (5), 537–548. Cohen, S.M., Tsien, R.W., Goff, D.C., Halassa, M.M., 2015. The impact of NMDA receptor hypofunction on GABAergic neurons in the pathophysiology of schizophrenia. Schizophr. Res. (pii: S0920-9954). Groh, A., Bokor, H., Mease, R.A., Plattner, V.M., Hangya, B., Stroh, A., Deschenes, M., Acsady, L., 2014. Convergence of cortical and sensory driver inputs on single thalamocortical cells. Cereb. Cortex 24 (12), 3167–3179. Halassa, M.M., Siegle, J.H., Ritt, J.T., Ting, J.T., Feng, G., Moore, C.I., 2011. Selective optical drive of thalamic reticular nucleus generates thalamic bursts and cortical spindles. Nat. Neurosci. 14 (9), 1118–1120. Halassa, M.M., Chen, Z., Wimmer, R.D., Brunetti, P.M., Zhao, S., Zikopoulos, B., Wang, F., Brown, E.N., Wilson, M.A., 2014. State-dependent architecture of thalamic reticular subnetworks. Cell 158 (4), 808–821. Insel, T., Cuthbert, B., Garvey, M., Heinssen, R., Pine, D.S., Quinn, K., Sanislow, C., Wang, P., 2010. Research domain criteria (RDoC): toward a new classification framework for research on mental disorders. Am. J. Psychiatry 167 (7), 748–751. Troyano-Rodriguez, E., Llado-Pelfort, L., Santana, N., Teruel-Marti, V., Celada, P., Artigas, F., 2014. Phencyclidine inhibits the activity of thalamic reticular gamma-aminobutyric acidergic neurons in rat brain. Biol. Psychiatry 76 (12), 937–945. Viviano, J.D., Schneider, K.A., 2015. Interhemispheric interactions of the human thalamic reticular nucleus. J. Neurosci. 35 (5), 2026–2032. Zhang, Y., Buonanno, A., Vertes, R.P., Hoover, W.B., Lisman, J.E., 2012. NR2C in the thalamic reticular nucleus; effects of the NR2C knockout. PLoS One 7 (7), e41908. Zweifel, L.S., Parker, J.G., Lobb, C.J., Rainwater, A., Wall, V.Z., Fadok, J.P., Darvas, M., Kim, M.J., Mizumori, S.J., Paladini, C.A., Phillips, P.E., Palmiter, R.D., 2009. Disruption of NMDAR-dependent burst firing by dopamine neurons provides selective assessment of phasic dopamine-dependent behavior. Proc. Natl. Acad. Sci. U. S. A. 106 (18), 7281–7288.
Samuel M. Cohen NYU Neuroscience Institute and Department of Neuroscience and Physiology, NYU Langone Medical Center, New York, NY 10016, USA Michael M. Halassa NYU Neuroscience Institute and Department of Neuroscience and Physiology, NYU Langone Medical Center, New York, NY 10016, USA Department of Psychiatry, NYU Langone Medical Center, New York, NY 10016, USA Corresponding author at: NYU Neuroscience Institute and Department of Neuroscience and Physiology, NYU Langone Medical Center, New York, NY 10016, USA. E-mail address: [email protected] 15 April 2015
