Schizophrenia Research Forum - A Catalyst for Creative Thinking

Order in the Cortex: Clozapine Curbs Unruly Networks

13 September 2007. Changes in neuronal activity in the prefrontal cortex (PFC) are thought to give rise to some of the cognitive symptoms of schizophrenia. Successful treatment of these symptoms with antipsychotic medicines predicts better disease management and outcome. Of the drugs available, the atypical antipsychotic clozapine is regarded as the most effective against cognitive symptoms, but how it acts on neurons of the PFC is not understood.

To shed some light on that question, two groups took the tack of recording single neuron activity in living animals treated with NMDA receptor antagonists to induce schizophrenia-like symptoms. The studies, one published by a group led by Pau Celada and Francesco Artigas of the Institut d’Investigacions Biomediques de Barcelona in Spain in PNAS on September 4, and another from Houman Homayoun and Bita Moghaddam of the University of Pittsburgh, Pennsylvania, in Biological Psychiatry last year, come up with similar findings: NMDA antagonists disrupt spontaneous rates and patterns of PFC neuronal spiking, which clozapine restores with a surprising and unique deftness. Compared to the first-generation (typical) medicine haloperidol, clozapine has an ability to fine-tune neuronal activity toward a more normal state, which may help explain its improved clinical efficacy.

In their study, published online October 13, 2006, Homayoun and Moghaddam carried out single neuron recording in awake rats after treatment with clozapine or haloperidol, and the NMDA antagonist MK801, which induces some symptoms of schizophrenia in humans. When they gave clozapine alone, the researchers saw the firing rates of some neurons increase, while other decreased or stayed the same. In all, they saw effects on half the neurons they recorded. Interestingly, clozapine tended to activate neurons with low baseline firing rates, and inhibit those with high baseline rate. This effect was not seen with haloperidol, which caused only transient increases in activity in some neurons, but sustained decreases in others.

MK801 by itself increased activity in 80 percent of recorded neurons, while in animals pretreated with clozapine and then MK801, significantly fewer neurons showed increased activity, and the increases were of lower magnitude. Half of the neurons in the clozapine group showed no change in activity. Haloperidol was much less effective at reducing the number of neurons with high activity, and did not reduce average firing rates at all.

Because the experiments involved awake animals, the researchers could look at behavior, and they found that despite the vastly different effects of the drugs on PFC firing, either antipsychotic reversed the appearance of stereotypical repetitive behaviors induced by MK801. They saw a close correlation between behavioral responses and neuronal firing in individual clozapine-treated animals, but not in those treated with haloperidol. From this, the authors conclude that the behavioral effect of haloperidol is “most probably” mediated at the subcortical level.

“The present data suggest that clozapine modulates PFC neuronal firing on the basis of baseline activity level of different ensembles. This modulatory activity might confer clozapine an ability to fine-tune the PFC function through gating unwanted disturbances in neuronal signal to noise ratio,” Homayoun and Moghaddam write.

The new data from the Spanish group support those results, with the psychotomimetic phencyclidine (PCP) used to induce PFC functional abnormalities in anesthetized rats. In single cell recordings of PFC pyramidal neurons, they found that PCP activated some neurons and inhibited others. First author Lucila Kargieman and colleagues also found a disruption in neuronal synchrony. By measuring local field potentials, they discovered that PCP decreased cortical synchrony in the delta frequency range. In addition, they found that PCP caused induction of c-fos expression in PFC pyramidal neurons, an indicator of increased neuronal activity. Either clozapine or haloperidol treatment reduced the excess neuronal firing and re-established synchrony. Clozapine also inhibited fos induction.

Taken together, the results of both papers suggest that antipsychotic drugs may partly exert their therapeutic effect by normalizing PFC activity, which is required for higher order functions that integrate external information with internal representations to determine behavior. This could occur via blocking dopamine D2 receptors. In the case of clozapine, other receptor targets may help produce its constellation of actions distinct from older drugs like haloperidol. Whatever the cause, the ability of clozapine to modulate neuronal activity both up and down could be one key to its therapeutic actions.—Pat McCaffrey.

Kargieman L, Santana N, Mengod G, Celada P, Artigas F. Antipsychotic drugs reverse the disruption in prefrontal cortex function produced by NMDA receptor blockade with phencyclidine. Proc Natl Acad Sci U S A. 2007 Sep 4; [Epub ahead of print] Abstract Homayoun H, Moghaddam B. Fine-tuning of awake prefrontal cortex neurons by clozapine: comparison with haloperidol and N-desmethylclozapine. Biol Psychiatry. 2007 Mar 1;61(5):679-87. Epub 2006 Oct 13. Abstract

Comments on News and Primary Papers

Primary Papers: Antipsychotic drugs reverse the disruption in prefrontal cortex function produced by NMDA receptor blockade with phencyclidine.

Comment by:  Dan Javitt, SRF Advisor
Submitted 13 September 2007
Posted 13 September 2007

PCP model forges ahead
What is the true cause of schizophrenia? Over the past 50 years, the amphetamine and PCP models have been fighting it out. Amphetamine got out to an early lead, mostly because it was discovered first, and PCP has been playing catch-up ever since. One way to keep score with these models is to track citations in general “high-profile” science journals such as PNAS for (dopamine or D2) vs. (glutamate or NMDA), and schizophrenia.

Since 1967, in MEDLINE, the amphetamine model has a commanding lead, 35 cites to 19. However, since 2004, the two models are exactly equal, with 12 cites each. With this article, glutamate forges out to a commanding lead.

The article by Kargieman and colleagues also points out the importance of delta rhythms as indices of thalamocortical activity. The finding that PCP disrupts delta rhythmicity resonates with the emerging literature on slow-wave sleep reductions in schizophrenia. The finding that clozapine reverses PCP-induced disruption of delta sleep is consistent with improvements in slow-wave sleep that have been reported with several atypical antipsychotics, including risperidone and olanzapine. The challenge is to isolate the mechanism of action of clozapine, and to design more specific and more effective agents.

In Science, amphetamine has a commanding 40 to 7 lead in MEDLINE, but PCP and amphetamine are tied at 1 and 1 since 2004. The game is on.

View all comments by Dan JavittComment by:  J David Jentsch
Submitted 16 September 2007
Posted 17 September 2007

The article by Kargieman and colleagues further specifies the cellular mechanisms underlying the actions of clozapine in a model of pharmacologically induced cortical dysfunction. Separately, clozapine has been demonstrated to be capable of reducing or eliminating the complex behavioral and cognitive impairments elicited by acutely administered NMDA antagonists (Geyer et al., 2001; Idris et al., 2005; Lipina et al., 2005), and these cellular mechanisms shown by Kargieman et al. may represent the level of interaction between clozapine and phencyclidine-like drugs.

What is surprising from so many of these studies is the quality of the reversal of effects produced by clozapine, despite the fact that it (like most other antipsychotic drugs) has limited efficacy both at an individual and population level. Furthermore, there remain many reports in the literature demonstrating that while some cognitive and symptomatic domains in schizophrenia are improved by clozapine, others clearly are not (Goldberg and Weinberger, 1996; Bilder et al., 2002). Why, then, is clozapine so effective in the PCP model? One concern, of course, is that its effects are related to a specific type of pharmacological interaction; one certainly needs to see clozapine's effects in other models that do not involve the acute administration of an NMDA antagonist.

Notably, several groups have been studying the effects of long-term administration of phencyclidine, sometimes followed by washout of the NMDA antagonist, to develop an alternative type of model that may depend upon the neuroadaptations resulting from blockade of NMDA receptors, rather than on the acute pharmacological action itself (Jentsch et al., 1997; Balla et al., 2003; Amitai et al., 2007, and many others). Whilst the specific validity of any one of these approaches is debatable, what appears to be clear is that the ability of clozapine to reverse behavioral or neurochemical deficits is much more tenuous. Is this a weakness of these models, or does it mean they are actually more realistic in their predictions?

Based upon these facts, one is left with a number of questions. First, is a model that predicts that clozapine is completely effective at blocking psychopathology or pathophysiology valid? Second, is the action of clozapine in any one model based upon one kind of manipulation really that provocative? And finally (and perhaps most importantly), is developing models that explain how clozapine works really in our best interest, or is it time to move beyond models that predict marginal gains from existing drugs, in order to look to targets flowing from the new valid genetic mechanisms that appear to hold the keys to the next generation of treatments for schizophrenia?


Amitai N, Semenova S, Markou A. Cognitive-disruptive effects of the psychotomimetic phencyclidine and attenuation by atypical antipsychotic medications in rats. Psychopharmacology (Berl). 2007 Sep;193(4):521-37. Abstract

Balla A, Sershen H, Serra M, Koneru R, Javitt DC. Subchronic continuous phencyclidine administration potentiates amphetamine-induced frontal cortex dopamine release. Neuropsychopharmacology. 2003 Jan;28(1):34-44. Abstract

Bilder RM, Goldman RS, Volavka J, Czobor P, Hoptman M, Sheitman B, Lindenmayer JP, Citrome L, McEvoy J, Kunz M, Chakos M, Cooper TB, Horowitz TL, Lieberman JA. Neurocognitive effects of clozapine, olanzapine, risperidone, and haloperidol in patients with chronic schizophrenia or schizoaffective disorder. Am J Psychiatry. 2002 Jun;159(6):1018-28. Abstract

Geyer MA, Krebs-Thomson K, Braff DL, Swerdlow NR. Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review. Psychopharmacology (Berl). 2001 Jul;156(2-3):117-54. Abstract

Goldberg TE, Weinberger DR. Effects of neuroleptic medications on the cognition of patients with schizophrenia: a review of recent studies. J Clin Psychiatry. 1996;57 Suppl 9:62-5. Abstract

Idris NF, Repeto P, Neill JC, Large CH. Investigation of the effects of lamotrigine and clozapine in improving reversal-learning impairments induced by acute phencyclidine and D-amphetamine in the rat. Psychopharmacology (Berl). 2005 May;179(2):336-48. Abstract

Jentsch JD, Redmond DE Jr, Elsworth JD, Taylor JR, Youngren KD, Roth RH. Enduring cognitive deficits and cortical dopamine dysfunction in monkeys after long-term administration of phencyclidine. Science. 1997 Aug 15;277(5328):953-5. Abstract

Lipina T, Labrie V, Weiner I, Roder J. Modulators of the glycine site on NMDA receptors, D-serine and ALX 5407, display similar beneficial effects to clozapine in mouse models of schizophrenia. Psychopharmacology (Berl). 2005 Apr;179(1):54-67. Abstract

View all comments by J David JentschComment by:  Jeremy Seamans
Submitted 28 September 2007
Posted 28 September 2007

The paper by Kargieman et al. provides an interesting perspective on the effects of PCP on activity in the prefrontal cortex. Dr. Javitt brings up an excellent point in his commentary that the study highlights the importance of PCP in this preparation as a model of slow-wave sleep disturbances in schizophrenia. In anesthetized animals, field potential recordings resemble the up and down states observed in slow-wave sleep. These states are driven by NMDA receptors and, accordingly, NMDA antagonists such as PCP and ketamine should reduce them as reported. The odd thing about NMDA antagonists is that they themselves can be used as anesthetics to produce a state where slow delta oscillations predominate. For instance, robust up and down states or slow oscillations at or below delta are observed when ketamine is used as an anesthetic. Therefore, NMDA antagonists can induce a state where delta activity is prominent, yet if the subject is already in that state, the effect of the drug is to reduce such activity.

So this also may be the case with PCP. There are numerous EEG studies showing that PCP significantly increases activity in the delta band of awake humans or animals (Stockard et al., 1976; Matsuzaki and Dowling, 1985; Mattia et al.,1988; Marquis et al., 1989; Yamamoto, 1997; Sebban et al., 2002), yet reduces power in this band of anesthetized animals. Moreover, schizophrenics appear to have a significant increase in frontal delta oscillations when awake (Wuebben and Winterer, 2001), yet exhibit slow-wave sleep disturbances and lower delta count when asleep (Ganguli et al., 1987). How is that?

It may be a matter of perspective. In the awake state the cortex is highly desynchronized and firing is quite irregular with power in a variety of high-frequency bands and neurons firing at every phase angle of the field potential. With anesthetics, higher frequencies become unsustainable. Using realistic network model simulations, Durstewitz and Gabriel (2007) showed that if you come from a regime which is quite irregular and then reduce NMDA, you get clear delta wave oscillations, but as you keep reducing NMDA, these delta oscillations will become progressively reduced as well. So in the awake state, reductions in NMDA currents should relatively decrease power in many bands yet enhance delta, but if the network is already in delta, as when the subject is anesthetized or asleep, NMDA reduction would decrease power in this band. Therefore, the results of Kargieman et al., when viewed in light of the literature obtained in awake subjects and schizophrenics, confirms a non-trivial and somewhat paradoxical prediction of the NMDA theory of schizophrenia and the PCP model.


Durstewitz D, Gabriel T. Dynamical basis of irregular spiking in NMDA-driven prefrontal cortex neurons. Cereb Cortex. 2007 Apr;17(4):894-908. Epub 2006 Jun 1. Abstract

Ganguli R, Reynolds CF 3rd, Kupfer DJ. Electroencephalographic sleep in young, never-medicated schizophrenics. A comparison with delusional and nondelusional depressives and with healthy controls. Arch Gen Psychiatry. 1987 Jan;44(1):36-44. Abstract

Marquis KL, Paquette NC, Gussio RP, Moreton JE. Comparative electroencephalographic and behavioral effects of phencyclidine, (+)-SKF-10,047 and MK-801 in rats. J Pharmacol Exp Ther. 1989 Dec;251(3):1104-12. Abstract

Matsuzaki M, Dowling KC. Phencyclidine (PCP): effects of acute and chronic administration on EEG activities in the rhesus monkey. Electroencephalogr Clin Neurophysiol. 1985 Apr;60(4):356-66. Abstract

Mattia A, Marquis KL, Leccese AP, el-Fakahany EE, Moreton JE. Electroencephalographic, behavioral and receptor binding correlates of phencyclinoids in the rat. J Pharmacol Exp Ther. 1988 Aug;246(2):797-802. Abstract

Sebban C, Tesolin-Decros B, Ciprian-Ollivier J, Perret L, Spedding M. Effects of phencyclidine (PCP) and MK 801 on the EEGq in the prefrontal cortex of conscious rats; antagonism by clozapine, and antagonists of AMPA-, alpha(1)- and 5-HT(2A)-receptors. Br J Pharmacol. 2002 Jan;135(1):65-78. Abstract

Stockard JJ, Werner SS, Aalbers JA, Chiappa KH. Electroencephalographic findings in phencyclidine intoxication. Arch Neurol. 1976 Mar;33(3):200-3. Abstract

Wuebben Y, Winterer G. Hypofrontality -- a risk-marker related to schizophrenia? Schizophr Res. 2001 Mar 30;48(2-3):207-17. Abstract

Yamamoto J. Cortical and hippocampal EEG power spectra in animal models of schizophrenia produced with methamphetamine, cocaine, and phencyclidine. Psychopharmacology (Berl). 1997 Jun;131(4):379-87. Abstract

View all comments by Jeremy Seamans

Comments on Related News

Related News: Clozapine: The Safest Antipsychotic?

Comment by:  John McGrath, SRF Advisor
Submitted 23 July 2009
Posted 23 July 2009
  I recommend the Primary Papers

The results of this study are surprising. In those with schizophrenia, those on clozapine had by far the lowest relative risk of death (compared to patients on other antipsychotics). Compared to older medications, atypical antipsychotics, to date, do not seem to be impacting on the relative risk of death.

I congratulate the authors on this impressive study. The study is another reminder of the utility of population-based record linkage studies. Thank heavens for the Nordic countries' health registers.

A few years ago we wondered if the differential mortality rate for schizophrenia was worsening over time (Saha et al., 2007). In addition to differential access to health care, we worried that the adverse effects of atypical antipsychotics might be a “ticking time bomb” for worsening mortality in the decades to come. The new Finnish study shows a more nuanced picture emerging.

While the results are thought provoking, let’s not forget about the main game. We all agree that there is still much more work to be done in optimizing the general physical health of people with schizophrenia.


Saha S, Chant D, McGrath J. A systematic review of mortality in schizophrenia: is the differential mortality gap worsening over time? Arch Gen Psychiatry . 2007 Oct 1 ; 64(10):1123-31. Abstract

View all comments by John McGrath

Related News: Clozapine: The Safest Antipsychotic?

Comment by:  Francine Benes, SRF Advisor
Submitted 4 November 2009
Posted 4 November 2009

Clozapine: A First-Line Antipsychotic?
Tiihonen et al., of the University of Kuopio in Finland, compared mortality rates in over 66,000 patients with schizophrenia with the entire population of Finland and concluded that clozapine should be used as a first-line drug in the treatment of this disorder. Clozapine is a very effective antipsychotic, and for patients who have received it for several years, the improvement in clinical status can be quite remarkable (Lindstrom, 1988; Agid et al., 2008). Additionally, the improved mortality rate of patients on clozapine may be attributable, at least in part, to the close monitoring of their white blood cell count (WBC).

The stipulation that weekly or biweekly blood samples must be drawn is not an issue that can be viewed lightly, because approximately 1-2 percent of patients on clozapine may show significant decreases in their WBC. This may be a harbinger of agranulocytosis, a potentially lethal form of morbidity in which the bone marrow loses its ability to generate leukocytes; death remains a significant risk for patients taking this drug (Taylor et al., 2009). To some, this may seem like a small price to pay for an improved quality of life. For others, however, it represents an unacceptable degree of risk. Additionally, many patients consider the requirement for frequent blood drawing as intrusive and/or painful and refuse to have it done (personal observation).

Perhaps the greatest source of resistance to using clozapine as a “first-line” drug is the psychiatrist who is faced with this decision. In general, most believe that they would be exposing their patient to unnecessary risk and prefer to look toward other, more “benign” antipsychotic drugs (APDs) for treatment options. In practice, however, the second-generation atypical APDs are not necessarily better candidates for “first-line” use, because they may be even more likely to cause excessive weight gain, diabetes mellitus, and cardiovascular disease (Wehring et al., 2003; Henderson et al., 2005) and result in increased mortality (Meatherall and Younes, 2002). In addition to the risk of agranulocytosis, clozapine may also cause unacceptable amounts of sedation, drooling, and weight gain. Typical APDs, on the other hand, are associated with other side effects that can be quite debilitating. These include extrapyramidal movement disorders, such as 1) akathisia, a condition that may cause a worsening of symptoms as a result of agitation; 2) drug-induced Parkinsonism, in which hypokinesia usually complicates the negative symptoms of schizophrenia; and 3) tardive dyskinesia, a syndrome in which there are involuntary movements of the tongue and lips that can result in significant disability and even disfigurement (Peacock et al., 1996).

In considering the choice of an APD for a “first-episode” patient with schizophrenia, all of these factors must be considered. It is impossible to know how a particular patient with no prior history of having taken an APD will respond to any given drug. What may be an excellent “first-line” drug for one patient may not be so for another. So, the choice of a “first-line” drug requires that the doctor and patient work together to identify the APD that is most appropriate at a particular time in the course of the illness, particularly if the patient has a treatment-sensitive or treatment-resistant form of schizophrenia (Wang et al., 2004).


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Henderson DC, Nguyen DD, Copeland PM, Hayden DL, Borba CP, Louie PM, Freudenreich O, Evins AE, Cather C, Goff DC. Clozapine, diabetes mellitus, hyperlipidemia, and cardiovascular risks and mortality: results of a 10-year naturalistic study. J Clin Psychiatry. 2005;66:1116-21. Abstract

Lindstrom LH. The effect of long-term treatment with clozapine in schizophrenia: a retrospective study in 96 patients treated with clozapine for up to 13 years. Acta Psychiatr Scand. 1988;77:524-9. Abstract

Meatherall R, Younes J. Fatality from olanzapine induced hyperglycemia. J Forensic Sci. 2002;47:893-6. Abstract

Peacock L, Solgaard T, Lublin H, Gerlach J . Clozapine versus typical antipsychotics. A retro- and prospective study of extrapyramidal side effects. Psychopharmacology (Berl). 1996; 124:188-96. Abstract

Taylor DM, Douglas-Hall P, Olofinjana B, Whiskey E, Thomas A. Reasons for discontinuing clozapine: matched, case-control comparison with risperidone long-acting injection. Br J Psychiatry. 2009;194:165-7. Abstract

Wang PS, Ganz DA, Benner JS, Glynn RJ, Avorn J. Should clozapine continue to be restricted to third-line status for schizophrenia?: a decision-analytic model. J Ment Health Policy Econ. 2004;7:77-85. Abstract

Wehring HJ, Kelly DL, Love RC, Conley RR. Deaths from diabetic ketoacidosis after long-term clozapine treatment. Am J Psychiatry. 2003;160:2241-2. Abstract

View all comments by Francine Benes

Related News: Clozapine: The Safest Antipsychotic?

Comment by:  Edward Orton (Disclosure)
Submitted 18 November 2009
Posted 18 November 2009
  I recommend the Primary Papers

Dr. Benes notes that clozapine is "...a very effective antipsychotic, and...improvement in clinical status can be quite remarkable." The mortality figures reported by Tihonen et al. have proved quite striking to schizophrenia researchers. The perception within the psychiatry community that clozapine is too risky for first-line therapy needs further assessment and discussion. Only about 5 percent of schizophrenics in the U.S. receive clozapine (Lieberman, 2009), leaving the vast majority of patients undermedicated because of this perception. The major issue with starting a patient on clozapine is WBC monitoring. I would like to call upon the NIMH to establish a major study in which schizophrenics are introduced to clozapine on an inpatient basis for 30-60 days to establish safety. It is well known that most WBC events associated with clozapine occur in the first few weeks of treatment. Also, I note that current prescribing practice with clozapine actually allows for monthly blood monitoring after 12 months of continuous clozapine use. Thus, the burden of monitoring diminishes sharply after one year.


Lieberman J. A Beacon of Hope: Prospects for Preventing and Recovering from Mental Illness. NARSAD Research Quarterly 2 (1), Winter 2009.

View all comments by Edward Orton

Related News: Working Memory Findings Defy What Theories Imply

Comment by:  Deanna M. Barch
Submitted 13 July 2010
Posted 13 July 2010

Mechanisms of Capacity Limitations in Working Memory
Gold and colleagues have provided an extremely elegant example of how a precisely controlled behavioral study can be used to directly test implications generated by neurobiological theories of cognitive impairment in schizophrenia. Further, they have provided novel and important data in schizophrenia that should cause us to re-examine theories about the mechanisms underling working memory impairments in this illness.

As noted by Gold, it has been hypothesized that altered GABAergic, glutamatergic, and/or dopaminergic inputs into reverberating and oscillatory networks in prefrontal or parietal cortex among individuals with schizophrenia should render such networks unstable and lead to less precise working memory representations that are particularly prone to decay (Lisman et al., 2008; Durstewitz and Seamans, 2008; Rolls et al., 2008; Lewis et al., 2008). However, Gold and colleagues have shown that working memory representations in schizophrenia (at least of color memory) are neither less precise nor show evidence of exceptionally rapid decay. Instead, individuals with schizophrenia showed clearly reduced working memory capacity.

These data contribute to a systemic body of work generated by Gold and colleagues, who have investigated the many aspects of working memory that could be impaired in schizophrenia. They have also shown that iconic decay is not increased in schizophrenia (Hahn et al., 2010), that feature binding is intact (Gold et al., 2003), and that certain aspects of attentional control over working memory are intact (Gold et al., 2006), though others are impaired (Fuller et al., 2006). However, working memory capacity has consistently been shown to be reduced in schizophrenia across numerous studies (Gold et al., 2006; van Raalten et al., 2008; Silver et al., 2003). If we take these results seriously (and we should), they require us to look closely at the neural mechanisms postulated to modulate capacity limitations in working memory in order to generate clues to the mechanisms that may be leading to reduced working memory capacity in schizophrenia.

The neural mechanisms leading to working memory capacity limitations are still very much an open source of debate. However, one influential theory is that the number of “items” that can be maintained in working memory is limited by the number of gamma cycles (30-100 Hz) that can be embedded within a theta cycle (Lisman, 2010). Related to the idea that originally drove the design of the Gold study, Lisman and others have hypothesized that individual items within working memory are represented by oscillating neural populations with spike rates phase-locked in a gamma cycle. The oscillatory activity representing different items must be kept isolated, potentially by keeping gamma activity for different items out of phase with each other. One way to accomplish this would be to couple such gamma cycles into a lower frequency theta oscillation that can help regulate and separate activity associated with different items (as well as maintain information about order). Lisman and others have argued that capacity constraints of approximately four items in working memory (Cowan, 2001) thus reflect the number of gamma cycles that can be embedded in a theta cycle (approximately four) (Lisman, 2010; Wolters and Raffone, 2008).

Gold’s results suggest that it may not be the maintenance of the individual gamma-oscillating neural populations representing individual items that is impaired in schizophrenia. Instead, it may be either the ability to establish such synchronous neural activity associated with a specific item, or the ability to couple a number of different gamma-oscillating sub-networks into a theta cycle. Interestingly, a growing number of studies have shown altered gamma activity during working memory in schizophrenia (Barr et al., 2010; Basar-Eroglu et al., 2007; Light et al., 2006; Kissler et al., 2000), as well as some evidence for altered theta activity (Haenschel et al., 2009). However, additional work is needed to specifically examine gamma-theta coupling in schizophrenia and its role in determining capacity limitations in this disease.

The type of network models of working memory put forth by Wang and colleagues suggest that the dynamics of excitatory and inhibitory inputs drive the number of independent “activity bumps” (i.e., items) that can be maintained in a network (Compte et al., 2000). A related idea about the mechanisms driving capacity limitations and variations in these limits across individuals has been put forth by Klingberg and colleagues, who have argued that the dynamics of such lateral inhibitory mechanisms in parietal cortex limit memory capacity to be between two and seven items (Edin et al., 2009). However, they have also argued that such capacity limits can be overcome, at least temporarily, by excitatory inputs into parietal cortex from prefrontal cortex (Edin et al., 2009). They have suggested that this provides a mechanistic account of top-down control over working memory capacity by prefrontal cortex. As such, given the evidence for at least some types of abnormalities in top-down control of attention in schizophrenia (Fuller et al., 2006; Hahn et al., 2010), and evidence for altered connectivity between prefrontal and parietal regions (Barch and Csernansky, 2007; Karlsgodt et al., 2008), another possible source of reduced capacity in working memory in schizophrenia may be a reduction in prefrontal-mediated excitatory input into parietal networks that maintain items in working memory.

One might argue that the same GABA, glutamate, or dopamine mechanisms thought to impair the maintenance of representations in working memory could also impair the initial establishment of gamma oscillating networks representing items, their coupling to a lower-frequency theta cycle, or even the ability of prefrontal cortex to provide excitatory inputs into neural networks supporting the representation of items in working memory. If so, such models will also need to explain how such impairments could lead to reduced working memory capacity in schizophrenia without a change in precision or decay, a challenge for most current neural network models of working memory. As such, the data provided by Gold and colleagues suggest an exciting new pathway for research on working memory in schizophrenia that may allow us to develop more precise mechanistic hypotheses as to the source of these cognitive impairments and their relationship to pathophysiology of this illness.

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