Posted 27 October 2006
Important Notice: Schizophrenia Research Forum does not provide medical advice nor promote any product or service. The contents are for informational purposes only and are not intended to substitute for professional medical advice, diagnosis or treatment. Always seek advice from a qualified physician or health care professional about any medical concern, and do not disregard professional medical advice because of anything you may read on this web site. The views of individuals quoted on this site are not necessarily those of the Schizophrenia Research Forum.
We invite your comments on this hypothesis.
See comment by Avi Peled
Bad Brain Vibes: Disturbances of Inhibitory Neural Circuits and Gamma Oscillations in Schizophrenia
By Tsung-Ung W. Woo, Kevin Spencer, and Robert M. McCarley
Tsung-Ung W. Woo
In modern accounts of schizophrenia, researchers have proposed that the disorder arises from a failure to integrate the activity of local and distributed neural circuits (Andreasen, 2000; Benes, 2000; Friston and Frith, 1995). Recently there has been a considerable amount of interest in the role that gamma (γ)-band EEG oscillations might play in the cognitive abnormalities that characterize schizophrenia. γ oscillations may mediate the synchronization of neural circuits for the representation and selection of information (Salinas and Sejnowski, 2001), and thus may be an important mechanism that mediates processes such as perception (Engel et al., 2001), selective attention (Fries et al., 2001), and working memory (Howard et al., 2003; Tallon-Baudry et al., 1998). Consistent with the notion that γ-mediated synchrony may be impaired in schizophrenia, a growing number of studies have reported abnormal γ oscillations associated with sensory stimulation (Brenner et al., 2003; Hong et al., 2004; Kwon et al., 1999; Light et al., 2006), perception (Spencer et al., 2004; Uhlhaas et al., 2006; Wynn et al., 2005), and target-detection tasks (Gallinat et al., 2004; Haig et al., 2000) in subjects with schizophrenia.
It has long been known that treatment with N-methyl-D-aspartate (NMDA) receptor antagonists produces psychosis and cognitive deficits that are reminiscent of the clinical picture of schizophrenia (Javitt and Zukin, 1991; Krystal et al., 1994; Newcomer and Krystal, 2001), and these data led to the NMDA receptor hypofunction model of schizophrenia (Olney and Farber, 1995; Olney et al., 1999) (see SRF Current Hypothesis by Bita Moghaddam). The paradoxical excitotoxic effects observed by Olney and Farber with NMDA antagonists were explained, at least in part, by blockade of the NMDA receptors that are located on γ-aminobutyric acid (GABA)-containing inhibitory neurons, which have been shown to be some 10-fold more sensitive to NMDA receptor antagonists, including psychotomimetics, than the NMDA receptor on pyramidal neurons (Greene et al., 2000; Grunze et al., 1996; Olney and Farber, 1995). We suggest, based on the evidence outlined below, that reduced glutamatergic inputs onto the fast-spiking GABA cells that contain the calcium-binding protein parvalbumin (PV) via NMDA receptors, perhaps especially those that contain the NR2A subunit, may mediate, at least in part, the well-reported downregulation of the 67 kD isoform of the GABA synthesizing enzyme glutamic acid decarboxylase (GAD)67 and PV and the disruption of γ band synchrony in schizophrenia.
Hypofunction of NMDA receptors on GABA neurons, perhaps especially those that contain PV, directly disrupts the synchronization of neural circuits in the γ frequency range by altering inhibitory control of pyramidal cell networks. In addition, γ synchronization may also be indirectly disrupted by excitotoxic injury to pyramidal cells as a result of reduced inhibition and the ensuing dendritic shrinkage and synaptic attrition.
1. NR2A regulates PV and GAD67 expression
In animals, NMDA receptor blockade has been found to reduce the number of PV-immunoreactive neurons in the entorhinal cortex (Cunningham et al., 2006; see SRF related news story); this reduction is accompanied by robust disruption in γ rhythms. Interestingly, these effects may be mediated primarily by the NR2A subunit. Thus, in a recent study, in a primary neuronal culture system, Kinney and colleagues have found that NR2A is particularly enriched in PV-containing GABA cells at both the transcript and protein levels, when compared to pyramidal cells (Kinney et al., 2006). Furthermore, NR2A, but not NR2B selective antagonists, downregulate PV mRNA and protein expression and expression of GAD67 mRNA in PV-containing cells (Kinney et al., 2006). In light of these findings, it is indeed very interesting that, in schizophrenia, GAD67 mRNA expression has been found to be selectively reduced in PV-containing neurons (Hashimoto et al., 2003).
2. Reduced expression of NR2A in GABA neurons in schizophrenia
It has recently been demonstrated that, in both the anterior cingulate (Woo et al., 2004) and dorsolateral prefrontal (PFC; Woo et al., in preparation) cortices, the density of GABA cells, identified with GAD67 labeling, that express the NR2A subunit is significantly decreased in schizophrenia. These findings are consistent with the observations that the expression of the mRNA for the vesicular glutamate transporter vGluT1, which is a marker for cortically originated glutamatergic terminals (Fujiyama et al., 2001; Kaneko and Fujiyama, 2002), was reduced in the PFC in schizophrenia (Eastwood and Harrison, 2005). A remaining question, obviously, is the identity of the GABA cells that exhibit reduced NR2A expression.
3. Excitotoxic injury to pyramidal neurons due to disinhibition
As a result of reduced excitatory drive to GABA neurons, cells that are downstream to these neurons may become disinhibited and thus susceptible to excitotoxic insults (Olney and Farber, 1995). Although cell death is generally not believed to be occurring in schizophrenia (at least not on a large scale), excitotoxic injury to pyramidal cells may be manifested in the form of dendritic and synaptic attrition. This will likely compromise pyramidal cell functions, further contributing to γ synchrony deficits.
Disturbances of γ band synchrony during late adolescence and early adulthood contribute to abnormal maturation of cortical circuits via aberrant synaptic and dendritic pruning. This will then lead to the onset of illness and the subsequent post-onset gray matter loss and functional deterioration that is characteristic of the early course of schizophrenia.
The final stage of the functional maturation of the cerebral cortex is characterized by refinement of synaptic circuits. The neurobiologic mechanisms that regulate the onset and termination of the synaptic refinement process are just beginning to be unraveled; it appears that the maturation of GABA neural circuits, particularly that of the PV-containing neurons, may play a crucial role (Hanover et al., 1999, Hensch, 2005; Huang et al., 1999; Jiang et al., 2005). For example, in the visual cortex, the postnatal maturation of PV expression temporally coincides with the period of experience-dependent refinement of neural circuits (Alcantara and Ferrer, 1994; de Lecea et al., 1995; Gao et al., 2000; Patz et al., 2004). Furthermore, in transgenic mice in which BDNF is developmentally overexpressed, the maturation of PV neuronal circuits is accelerated and, at the same time, the critical period for developmental synaptic plasticity is also precociously terminated (Hanover et al., 1999; Huang et al., 1999).
Among the different regions within the cerebral cortex, the functional maturation of the PFC is quite protracted; the underlying synaptic refinement process is not completed until late adolescence and early adulthood (Bourgeois et al., 1994; Huttenlocher, 1979; Woo et al., 1997), which coincides with the period of time when schizophrenia symptomatology typically begins to emerge. Interestingly, it is also during this period of development when PV neuronal circuits gradually achieve maturation (Anderson et al., 1995; Erickson and Lewis, 2002). Although definitive evidence is not available, in light of these observations, it seems reasonable to postulate that, like in the visual cortex, PV-containing neurons may also play an important role in orchestrating the synaptic refinement process in the PFC.
Synaptic refinement is an activity-dependent process that is governed by the Hebbian principle (Hebb, 1949). When the pre- and postsynaptic elements of a synapse are coincidentally (within a narrow time window) active, the synapse is strengthened; otherwise, the synapse is eliminated. Interestingly, the duration of the time window that is required for activity-dependent strengthening of synapses via coincidence detection closely matches the time scale of γ oscillations (Bi and Poo, 1998; Buzsaki and Draguhn, 2004; Harris, 2005; Harris et al., 2003; Magee and Johnston, 1997; Wespatat et al., 2004; Whittington et al., 1997). In other words, γ oscillations may provide a temporal structure that constrains the activity-dependent synaptic refinement process. Thus, disturbances of PV-containing neurons might lead to aberrant pruning of synapses by disturbing γ oscillations. In addition, glutamatergic axon terminals in the PFC have been shown to undergo a process of elimination during the peri-adolescent period, resulting in a loss of 40-60 percent of axonal boutons (Woo et al., 1997). Perhaps in schizophrenia this axonal elimination process is disordered so that the axons that target the NMDA receptors on PV neurons are preferentially affected. As discussed above, reduced glutamatergic activation of NMDA receptors on PV neurons may lead to γ band oscillation deficits (Cunningham et al., 2006), thus resulting in synaptic loss by disturbing experience-dependent pruning. Finally, as a result of disinhibition, as previously discussed, reduced NMDA activity on PV neurons may cause excitotoxic damage to pyramidal cells; this may result in further loss of dendrites and synapses. Together, these mechanisms may play a role in triggering disease onset and leading to the progressive deterioration during the early phase of the illness.
These hypotheses point to a new direction in our conceptualization of neurobiologically based treatment strategies for schizophrenia. According to these hypotheses, pharmacologic calibration of NMDA neurotransmission via PV-containing GABA neurons, perhaps especially via the NR2A subunit, will correct γ band oscillation deficits of the illness. Furthermore, if implemented early enough, such an approach may actually be able to prevent the onset of illness by normalizing synaptic deficits that, at least in part, result from γ band deficits.
Alcantara S, Ferrer I. Postnatal development of parvalbumin immunoreactivity in the cerebral cortex of the cat.
J Comp Neurol. 1994 Oct 1;348(1):133-49.
Anderson SA, Classey JD, Conde F, Lund JS, Lewis DA. Synchronous development of pyramidal neuron dendritic spines and parvalbumin-immunoreactive chandelier neuron axon terminals in layer III of monkey prefrontal cortex. Neuroscience. 1995 Jul;67(1):7-22. Abstract
Andreasen NC. Schizophrenia: the fundamental questions.
Brain Res Brain Res Rev. 2000 Mar;31(2-3):106-12. Review.
Benes FM. Emerging principles of altered neural circuitry in schizophrenia.
Brain Res Brain Res Rev. 2000 Mar;31(2-3):251-69. Review.
Bi GQ, Poo MM. Synaptic modifications in cultured hippocampal neurons: dependence on spike timing, synaptic strength, and postsynaptic cell type.
J Neurosci. 1998 Dec 15;18(24):10464-72.
Bourgeois JP, Goldman-Rakic PS, Rakic P. Synaptogenesis in the prefrontal cortex of rhesus monkeys.
Cereb Cortex. 1994 Jan-Feb;4(1):78-96.
Brenner CA, Sporns O, Lysaker PH, O'Donnell BF. EEG synchronization to modulated auditory tones in schizophrenia, schizoaffective disorder, and schizotypal personality disorder.
Am J Psychiatry. 2003 Dec;160(12):2238-40.
Buzsaki G, Draguhn A. Neuronal oscillations in cortical networks.
Science. 2004 Jun 25;304(5679):1926-9. Review.
Cunningham MO, Hunt J, Middleton S, LeBeau FE, Gillies MJ, Davies CH, Maycox PR, Whittington MA, Racca C. Region-specific reduction in entorhinal γ oscillations and parvalbumin-immunoreactive neurons in animal models of psychiatric illness.
J Neurosci. 2006 Mar 8;26(10):2767-76. Erratum in: J Neurosci. 2006 May 17;26(20):table of contents. Gillies, Martin G [corrected to Gillies, Martin J].
de Lecea L, del Rio JA, Soriano E. Developmental expression of parvalbumin mRNA in the cerebral cortex and hippocampus of the rat.
Brain Res Mol Brain Res. 1995 Aug;32(1):1-13.
Eastwood SL, Harrison PJ. Decreased expression of vesicular glutamate transporter 1 and complexin II mRNAs in schizophrenia: further evidence for a synaptic pathology affecting glutamate neurons.
Schizophr Res. 2005 Mar 1;73(2-3):159-72.
Engel AK, Fries P, Singer W. Dynamic predictions: oscillations and synchrony in top-down processing.
Nat Rev Neurosci. 2001 Oct;2(10):704-16. Review.
Erickson SL, Lewis DA. Postnatal development of parvalbumin- and GABA transporter-immunoreactive axon terminals in monkey prefrontal cortex.
J Comp Neurol. 2002 Jun 24;448(2):186-202.
Fries P, Reynolds JH, Rorie AE, Desimone R. Modulation of oscillatory neuronal synchronization by selective visual attention.
Science. 2001 Feb 23;291(5508):1560-3.
Friston KJ, Frith CD. Schizophrenia: a disconnection syndrome?
Clin Neurosci. 1995;3(2):89-97. Review.
Fujiyama F, Furuta T, Kaneko T. Immunocytochemical localization of candidates for vesicular glutamate transporters in the rat cerebral cortex.
J Comp Neurol. 2001 Jul 2;435(3):379-87.
Gallinat J, Winterer G, Herrmann CS, Senkowski D. Reduced oscillatory γ-band responses in unmedicated schizophrenic patients indicate impaired frontal network processing. Clin Neurophysiol. 2004 Aug;115(8):1863-74. Abstract
Gao WJ, Wormington AB, Newman DE, Pallas SL. Development of inhibitory circuitry in visual and auditory cortex of postnatal ferrets: immunocytochemical localization of calbindin- and parvalbumin-containing neurons.
J Comp Neurol. 2000 Jun 19;422(1):140-57.
Greene R, Bergeron R, McCarley R, Coyle JT, Grunze H. Short-term and long-term effects of N-methyl-D-aspartate receptor hypofunction.
Arch Gen Psychiatry. 2000 Dec;57(12):1180-1; author reply 1182-3. No abstract available.
Grunze HC, Rainnie DG, Hasselmo ME, Barkai E, Hearn EF, McCarley RW, Greene RW. NMDA-dependent modulation of CA1 local circuit inhibition.
J Neurosci. 1996 Mar 15;16(6):2034-43.
Haig AR, Gordon E, De Pascalis V, Meares RA, Bahramali H, Harris A. γ activity in schizophrenia: evidence of impaired network binding?
Clin Neurophysiol. 2000 Aug;111(8):1461-8.
Hanover JL, Huang ZJ, Tonegawa S, Stryker MP. Brain-derived neurotrophic factor overexpression induces precocious critical period in mouse visual cortex.
J Neurosci. 1999 Nov 15;19(22):RC40.
Harris KD. Neural signatures of cell assembly organization.
Nat Rev Neurosci. 2005 May;6(5):399-407. Review.
Harris KD, Csicsvari J, Hirase H, Dragoi G, Buzsaki G. Organization of cell assemblies in the hippocampus.
Nature. 2003 Jul 31;424(6948):552-6.
Hashimoto T, Volk DW, Eggan SM, Mirnics K, Pierri JN, Sun Z, Sampson AR, Lewis DA. Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia.
J Neurosci. 2003 Jul 16;23(15):6315-26.
Hebb DO (1949). The organization of behavior. New York: John Wiley.
Hensch TK. Critical period plasticity in local cortical circuits.
Nat Rev Neurosci. 2005 Nov;6(11):877-88. Review.
Hong LE, Summerfelt A, McMahon R, Adami H, Francis G, Elliott A, Buchanan RW, Thaker GK. Evoked γ band synchronization and the liability for schizophrenia.
Schizophr Res. 2004 Oct 1;70(2-3):293-302.
Howard MW, Rizzuto DS, Caplan JB, Madsen JR, Lisman J, Aschenbrenner-Scheibe R, Schulze-Bonhage A, Kahana MJ. γ oscillations correlate with working memory load in humans.
Cereb Cortex. 2003 Dec;13(12):1369-74.
Huang ZJ, Kirkwood A, Pizzorusso T, Porciatti V, Morales B, Bear MF, Maffei L, Tonegawa S. BDNF regulates the maturation of inhibition and the critical period of plasticity in mouse visual cortex.
Cell. 1999 Sep 17;98(6):739-55.
Huttenlocher PR. Synaptic density in human frontal cortex - developmental changes and effects of aging.
Brain Res. 1979 Mar 16;163(2):195-205.
Javitt DC, Zukin SR. Recent advances in the phencyclidine model of schizophrenia.
Am J Psychiatry. 1991 Oct;148(10):1301-8. Review.
Jiang B, Huang ZJ, Morales B, Kirkwood A. Maturation of GABAergic transmission and the timing of plasticity in visual cortex.
Brain Res Brain Res Rev. 2005 Dec 1;50(1):126-33. Epub 2005 Jul 15. Review.
Kaneko T, Fujiyama F. Complementary distribution of vesicular glutamate transporters in the central nervous system.
Neurosci Res. 2002 Apr;42(4):243-50. Review.
Kinney JW, Davis CN, Tabarean I, Conti B, Bartfai T, Behrens MM. A specific role for NR2A-containing NMDA receptors in the maintenance of parvalbumin and GAD67 immunoreactivity in cultured interneurons. J Neurosci. 2006 Feb 1;26(5):1604-15. Abstract
Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers MB Jr, Charney DS. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses.
Arch Gen Psychiatry. 1994 Mar;51(3):199-214.
Kwon JS, O'Donnell BF, Wallenstein GV, Greene RW, Hirayasu Y, Nestor PG, Hasselmo ME, Potts GF, Shenton ME, McCarley RW. γ frequency-range abnormalities to auditory stimulation in schizophrenia.
Arch Gen Psychiatry. 1999 Nov;56(11):1001-5.
Light GA, Hsu JL, Hsieh MH, Meyer-Gomes K, Sprock J, Swerdlow NR, Braff DL. γ Band Oscillations Reveal Neural Network Cortical Coherence Dysfunction in Schizophrenia Patients.
Biol Psychiatry. 2006 Aug 4; [Epub ahead of print]
Magee JC, Johnston D. A synaptically controlled, associative signal for Hebbian plasticity in hippocampal neurons.
Science. 1997 Jan 10;275(5297):209-13.
Newcomer JW, Krystal JH. NMDA receptor regulation of memory and behavior in humans.
Hippocampus. 2001;11(5):529-42. Review.
Olney JW, Farber NB. Glutamate receptor dysfunction and schizophrenia.
Arch Gen Psychiatry. 1995 Dec;52(12):998-1007.
Olney JW, Newcomer JW, Farber NB. NMDA receptor hypofunction model of schizophrenia.
J Psychiatr Res. 1999 Nov-Dec;33(6):523-33. Review.
Patz S, Grabert J, Gorba T, Wirth MJ, Wahle P. Parvalbumin expression in visual cortical interneurons depends on neuronal activity and TrkB ligands during an Early period of postnatal development.
Cereb Cortex. 2004 Mar;14(3):342-51.
Salinas E, Sejnowski TJ. Correlated neuronal activity and the flow of neural information.
Nat Rev Neurosci. 2001 Aug;2(8):539-50. Review. No abstract available.
Spencer KM, Nestor PG, Perlmutter R, Niznikiewicz MA, Klump MC, Frumin M, Shenton ME, McCarley RW. Neural synchrony indexes disordered perception and cognition in schizophrenia.
Proc Natl Acad Sci U S A. 2004 Dec 7;101(49):17288-93. Epub 2004 Nov 16.
Tallon-Baudry C, Bertrand O, Peronnet F, Pernier J. Induced γ-band activity during the delay of a visual short-term memory task in humans. J Neurosci. 1998 Jun 1;18(11):4244-54. Abstract
Uhlhaas PJ, Linden DE, Singer W, Haenschel C, Lindner M, Maurer K, Rodriguez E. Dysfunctional long-range coordination of neural activity during Gestalt perception in schizophrenia.
J Neurosci. 2006 Aug 2;26(31):8168-75.
Wespatat V, Tennigkeit F, Singer W. Phase sensitivity of synaptic modifications in oscillating cells of rat visual cortex. J Neurosci. 2004 Oct 13;24(41):9067-75. Abstract
Whittington MA, Traub RD, Faulkner HJ, Stanford IM, Jefferys JG. Recurrent excitatory postsynaptic potentials induced by synchronized fast cortical oscillations.
Proc Natl Acad Sci U S A. 1997 Oct 28;94(22):12198-203.
Woo TU, Pucak ML, Kye CH, Matus CV, Lewis DA. Peripubertal refinement of the intrinsic and associational circuitry in monkey prefrontal cortex.
Neuroscience. 1997 Oct;80(4):1149-58.
Woo TU, Walsh JP, Benes FM. Density of glutamic acid decarboxylase 67 messenger RNA-containing neurons that express the N-methyl-D-aspartate receptor subunit NR2A in the anterior cingulate cortex in schizophrenia and bipolar disorder.
Arch Gen Psychiatry. 2004 Jul;61(7):649-57.
Wynn JK, Light GA, Breitmeyer B, Nuechterlein KH, Green MF. Event-related γ activity in schizophrenia patients during a visual backward-masking task.
Am J Psychiatry. 2005 Dec;162(12):2330-6.
Comment by Avi Peled
This hypothesis is very interesting and in line with the much needed systems approach to understanding mental disorders (see also my website).
Some questions arise: Have gamma band deficits been documented in screening of adolescent populations? Will it be possible to give "NMDA calibrating" medications to those screened for probable future development of schizophrenia, early on before any prominent symptoms erupt? How about later corrective interventions, for example, coupling ampakines such as cx516 with specific targeted cognitive remediation. With ampakines it has been shown (Ingvar et al., 1997) that some cognitive functions can be enhanced. In schizophrenia, one study showed no improvement (Marenco et al., 2002), and another study (Goff et al., 2001) showed some improvement in attention and memory. Ampakines are relevant to Hebbian learning, so it is not surprising that they did not have effect. To create Hebbian learning, the plasticity effects of ampakines should be coupled with relevant cognitive enhancement protocols.
The idea of abnormal maturation of cortical circuits, with aberrant synaptic dendritic pruning, seems very plausible; however, it probably allows for many different patterns of abnormal circuitry. This is probable considering the heterogeneity of clinical manifestations in schizophrenia patients. Should we address also these different pathological aberrant circuits, their identification will not only provide a neuronal basis for schizophrenia, but will provide guidance to which specific corrections should be made using "NMDA calibrating" medications, ampakines, or other plasticity-inducing mediations. Such different patterns of abnormal circuitry have already been described in theory (Peled et al., 2006).