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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.
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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).