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NMDAR hypofunction attenuates driver inputs in higher order thalamic nuclei: An alternative view
Schizophrenia Research 166 (2015) 341–342
Contents lists available at ScienceDirect
Schizophrenia Research journal homepage: www.elsevier.com/locate/schres
Letter to the Editor NMDAR hypofunction attenuates driver inputs in higher order thalamic nuclei: An alternative view Keywords: NMDA receptor Schizophrenia Thalamus Driver inputs
Dear Editors, Cohen et al. (2015) provide a review of evidence in support of an influential hypothesis linking NMDAR hypofunction in schizophrenia with a dysfunction of GABAergic neurons. The authors further hypothesize that this issue underlies deficits in cortico-thalamo-cortical circuits thereby contributing to positive symptoms and other illness-related deficits. The purpose of this letter is to supplement this hypothesis with an alternative but not mutually exclusive view that, rather than focusing on how NMDAR hypofunction impacts GABAergic neurons, emphasizes that it may directly impair the function of higher order (HO) thalamic nuclei by attenuating driver feedforward excitatory inputs arriving from the cortex (Vukadinovic, 2014). Namely, inputs to the thalamus can be classified into two categories (Sherman, 2012). Driver inputs represent the main information route and a number of features distinguish them from neuromodulatory inputs. For example, driver inputs have larger and more proximal terminals and thick axons; they utilize ionotropic glutamate receptors (such as the NMDAR) and produce larger postsynaptic potentials. Driver inputs to the HO nuclei (e.g., mediodorsal, pulvinar nuclei) arrive from the cortex, and the messages they deliver are then relayed to other cortical areas. As the origin of these inputs is the cortical layer V, whose axons branch and innervate lower motor centers in the CNS, the messages are copies of motor instructions issued to those lower motor centers (see Fig. 1). These copies are thus an integral part of perceptual processes. As driver inputs rely on ionotropic glutamate receptors, NMDAR hypofunction in HO thalamic nuclei may impair sensorimotor integration and thereby lead to disintegration of perceptual and other cognitive processes. This pathomechanism, together with NMDA hypofunction on GABAergic neurons, could perhaps provide a more comprehensive account of the potential role of NMDAR hypofunction in thalamic dysfunction in schizophrenia, and thereby also encourage future research into how thalamic dysfunction may contribute to symptoms and deficits in this illness. For example, it would be interesting to determine what behavioral, cognitive and brain rhythm deficits would emerge with genetic manipulation of the NMDAR in HO thalamic nuclei. Cohen et al. (2015) review cites two studies reporting on findings involving knock-out (KO) mice, in which the NMDAR was ablated from parvalbumin (PV)-positive GABAergic neurons (Korotkova et al., 2010; Carlen et al., 2012). Both studies found that the KO animals
http://dx.doi.org/10.1016/j.schres.2015.03.029 0920-9964/© 2015 Elsevier B.V. All rights reserved.
displayed certain cognitive and brain rhythm abnormalities, but the authors of both studies characterized social behavior of KO animals as otherwise normal. One could argue that behavior of such animals was not adequately studied, as it was not the main focus of either study. However, the contrast to what is observed in rodents administered NMDAR antagonists is striking, which was not discussed in the review by Cohen et al. (2015). Namely, rodents administered NMDAR blockers display hyperlocomotion, reduced sensorimotor gating and reduced social behavior (Jentsch and Roth, 1999). The behavior of mice administered NMDAR antagonists was found to be indistinguishable from behavioral abnormalities displayed by amphetamine-treated mice (Miyamoto et al., 2000). One possibility is that genetic versus acute pharmacologic manipulation of the NMDAR is a fundamentally different approach in studying NMDAR hypofunction in schizophrenia, but the review does not raise this as a possibility explicitly. It is, however, worth noting that a more global reduction in the expression of the NMDAR did result in behavioral abnormalities in KO animals similar to that observed in acute administration of NMDAR antagonists (Mohn et al., 1999). The review also discusses work by Zhang et al. (2009) that suggests that NMDAR hypofunction on PV-containing thalamic reticular nucleus (TRN) neurons underlies emergence of delta oscillations during wakefulness in schizophrenia, which is in turn proposed to disrupt thalamocortical circuits leading to cognitive deficits and positive symptoms. However, one issue that is not discussed in the review by Cohen et al. (2015) is that the presence of delta oscillations in wakefulness is not unique to schizophrenia but can be a feature of a number of pathological states that are not necessarily associated with psychosis (Knyazev, 2012). For example, localized delta activity can emerge in cortical areas overlying white matter and thalamic lesions (Gloor et al., 1977). Despite the fact that Cohen et al. (2015) do not explicitly endorse the view that enhanced delta activity during wakefulness
Fig. 1. Cortico-thalamo-cortical circuits (adapted with permission from Sherman, 2012). Driver inputs to the HO thalamic relays (such as the MD nucleus) arrive from the cortex, and this information is then relayed back to the cortex. More specifically, these driver inputs originate from axonal branches of layer V cortical neurons, which also innervate lower motor centers in the brain stem and the spinal cord. Thus, the HO nuclei, functionally speaking, may be concerned with relaying copies of cortical motor instructions to those lower motor centers. Note that in contrast to transthalamic cortico-cortical links via the HO nuclei, direct cortico-cortical links reside entirely in the cortex.
342
Letter to the Editor
is specific to schizophrenia, their review does not contain a critical discussion of the proposal by Zhang et al. (2009). Conflict of interest None. Acknowledgments None.
References 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. http://dx.doi.org/10.1016/j.schres.2014.12.026. Gloor, P., Ball, G., Schaul, N., 1977. Brain lesions that produce delta waves in the EEG. Neurology 27, 326–333. Jentsch, J.D., Roth, R.H., 1999. The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia. Neuropsychopharmacology 20 (3), 200–225.
Knyazev, G.G., 2012. EEG delta oscillations as a correlate of basic homeostatic and motivational processes. Neurosci. Biobehav. Rev. 36, 677–695. Korotkova, T., Fuchs, E.C., Ponomarenko, A., von Engelhardt, J., Monyer, H., 2010. NMDA receptor ablation on parvalbumin-positive interneurons impairs hippocampal synchrony, spatial representations, and working memory. Neuron 68 (3), 557–569. Miyamoto, S., Leipzig, J.N., Lieberman, J.A., Duncan, G.E., 2000. Effects of ketamine, MK-801, and amphetamine on regional brain 2-deoxyglucose uptake in freely moving mice. Neuropsychopharmacology 22 (4), 400–412. Mohn, A.R., Gainetdinov, R.R., Caron, M.G., Koller, B.H., 1999. Mice with reduced NMDA receptor expression display behaviors related to schizophrenia. Cell 98, 427–436. Sherman, S.M., 2012. Thalamocortical interactions. Curr. Opin. Neurobiol. 22, 575–579. Vukadinovic, Z., 2014. NMDA receptor hypofunction and the thalamus in schizophrenia. Physiol. Behav. 131, 156–159. Zhang, Y., Llinas, R.R., Lisman, J.E., 2009. Inhibition of NMDARs in the nucleus reticularis of the thalamus produces delta frequency bursting. Front. Neural. Circ. 3, 20.
Zoran Vukadinovic Colorado Permanente Medical Group, Denver, CO Tel.: +1 914 574 1286. E-mail address: [email protected]. 12 February 2015
Contents lists available at ScienceDirect
Schizophrenia Research journal homepage: www.elsevier.com/locate/schres
Letter to the Editor NMDAR hypofunction attenuates driver inputs in higher order thalamic nuclei: An alternative view Keywords: NMDA receptor Schizophrenia Thalamus Driver inputs
Dear Editors, Cohen et al. (2015) provide a review of evidence in support of an influential hypothesis linking NMDAR hypofunction in schizophrenia with a dysfunction of GABAergic neurons. The authors further hypothesize that this issue underlies deficits in cortico-thalamo-cortical circuits thereby contributing to positive symptoms and other illness-related deficits. The purpose of this letter is to supplement this hypothesis with an alternative but not mutually exclusive view that, rather than focusing on how NMDAR hypofunction impacts GABAergic neurons, emphasizes that it may directly impair the function of higher order (HO) thalamic nuclei by attenuating driver feedforward excitatory inputs arriving from the cortex (Vukadinovic, 2014). Namely, inputs to the thalamus can be classified into two categories (Sherman, 2012). Driver inputs represent the main information route and a number of features distinguish them from neuromodulatory inputs. For example, driver inputs have larger and more proximal terminals and thick axons; they utilize ionotropic glutamate receptors (such as the NMDAR) and produce larger postsynaptic potentials. Driver inputs to the HO nuclei (e.g., mediodorsal, pulvinar nuclei) arrive from the cortex, and the messages they deliver are then relayed to other cortical areas. As the origin of these inputs is the cortical layer V, whose axons branch and innervate lower motor centers in the CNS, the messages are copies of motor instructions issued to those lower motor centers (see Fig. 1). These copies are thus an integral part of perceptual processes. As driver inputs rely on ionotropic glutamate receptors, NMDAR hypofunction in HO thalamic nuclei may impair sensorimotor integration and thereby lead to disintegration of perceptual and other cognitive processes. This pathomechanism, together with NMDA hypofunction on GABAergic neurons, could perhaps provide a more comprehensive account of the potential role of NMDAR hypofunction in thalamic dysfunction in schizophrenia, and thereby also encourage future research into how thalamic dysfunction may contribute to symptoms and deficits in this illness. For example, it would be interesting to determine what behavioral, cognitive and brain rhythm deficits would emerge with genetic manipulation of the NMDAR in HO thalamic nuclei. Cohen et al. (2015) review cites two studies reporting on findings involving knock-out (KO) mice, in which the NMDAR was ablated from parvalbumin (PV)-positive GABAergic neurons (Korotkova et al., 2010; Carlen et al., 2012). Both studies found that the KO animals
http://dx.doi.org/10.1016/j.schres.2015.03.029 0920-9964/© 2015 Elsevier B.V. All rights reserved.
displayed certain cognitive and brain rhythm abnormalities, but the authors of both studies characterized social behavior of KO animals as otherwise normal. One could argue that behavior of such animals was not adequately studied, as it was not the main focus of either study. However, the contrast to what is observed in rodents administered NMDAR antagonists is striking, which was not discussed in the review by Cohen et al. (2015). Namely, rodents administered NMDAR blockers display hyperlocomotion, reduced sensorimotor gating and reduced social behavior (Jentsch and Roth, 1999). The behavior of mice administered NMDAR antagonists was found to be indistinguishable from behavioral abnormalities displayed by amphetamine-treated mice (Miyamoto et al., 2000). One possibility is that genetic versus acute pharmacologic manipulation of the NMDAR is a fundamentally different approach in studying NMDAR hypofunction in schizophrenia, but the review does not raise this as a possibility explicitly. It is, however, worth noting that a more global reduction in the expression of the NMDAR did result in behavioral abnormalities in KO animals similar to that observed in acute administration of NMDAR antagonists (Mohn et al., 1999). The review also discusses work by Zhang et al. (2009) that suggests that NMDAR hypofunction on PV-containing thalamic reticular nucleus (TRN) neurons underlies emergence of delta oscillations during wakefulness in schizophrenia, which is in turn proposed to disrupt thalamocortical circuits leading to cognitive deficits and positive symptoms. However, one issue that is not discussed in the review by Cohen et al. (2015) is that the presence of delta oscillations in wakefulness is not unique to schizophrenia but can be a feature of a number of pathological states that are not necessarily associated with psychosis (Knyazev, 2012). For example, localized delta activity can emerge in cortical areas overlying white matter and thalamic lesions (Gloor et al., 1977). Despite the fact that Cohen et al. (2015) do not explicitly endorse the view that enhanced delta activity during wakefulness
Fig. 1. Cortico-thalamo-cortical circuits (adapted with permission from Sherman, 2012). Driver inputs to the HO thalamic relays (such as the MD nucleus) arrive from the cortex, and this information is then relayed back to the cortex. More specifically, these driver inputs originate from axonal branches of layer V cortical neurons, which also innervate lower motor centers in the brain stem and the spinal cord. Thus, the HO nuclei, functionally speaking, may be concerned with relaying copies of cortical motor instructions to those lower motor centers. Note that in contrast to transthalamic cortico-cortical links via the HO nuclei, direct cortico-cortical links reside entirely in the cortex.
342
Letter to the Editor
is specific to schizophrenia, their review does not contain a critical discussion of the proposal by Zhang et al. (2009). Conflict of interest None. Acknowledgments None.
References 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. http://dx.doi.org/10.1016/j.schres.2014.12.026. Gloor, P., Ball, G., Schaul, N., 1977. Brain lesions that produce delta waves in the EEG. Neurology 27, 326–333. Jentsch, J.D., Roth, R.H., 1999. The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia. Neuropsychopharmacology 20 (3), 200–225.
Knyazev, G.G., 2012. EEG delta oscillations as a correlate of basic homeostatic and motivational processes. Neurosci. Biobehav. Rev. 36, 677–695. Korotkova, T., Fuchs, E.C., Ponomarenko, A., von Engelhardt, J., Monyer, H., 2010. NMDA receptor ablation on parvalbumin-positive interneurons impairs hippocampal synchrony, spatial representations, and working memory. Neuron 68 (3), 557–569. Miyamoto, S., Leipzig, J.N., Lieberman, J.A., Duncan, G.E., 2000. Effects of ketamine, MK-801, and amphetamine on regional brain 2-deoxyglucose uptake in freely moving mice. Neuropsychopharmacology 22 (4), 400–412. Mohn, A.R., Gainetdinov, R.R., Caron, M.G., Koller, B.H., 1999. Mice with reduced NMDA receptor expression display behaviors related to schizophrenia. Cell 98, 427–436. Sherman, S.M., 2012. Thalamocortical interactions. Curr. Opin. Neurobiol. 22, 575–579. Vukadinovic, Z., 2014. NMDA receptor hypofunction and the thalamus in schizophrenia. Physiol. Behav. 131, 156–159. Zhang, Y., Llinas, R.R., Lisman, J.E., 2009. Inhibition of NMDARs in the nucleus reticularis of the thalamus produces delta frequency bursting. Front. Neural. Circ. 3, 20.
Zoran Vukadinovic Colorado Permanente Medical Group, Denver, CO Tel.: +1 914 574 1286. E-mail address: [email protected]. 12 February 2015