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Hippocampal Site Seen Revving Up as Psychosis Emerges

25 September 2009. Researchers have some idea of the broad areas of the brain that act up in schizophrenia, but finer resolution in these regions has been hard to achieve. When a team of investigators, led by Scott Small of Columbia University in New York City, used state-of-the-art functional magnetic resonance imaging to scrutinize the usual suspects, an area in one stood out: the CA1 subfield of the hippocampus. In the September Archives of General Psychiatry, the researchers report that this subfield becomes overactive in schizophrenia and that this dysfunction foretells which high-risk subjects will develop psychosis. Their evidence also suggests that psychotropic drugs are not to blame.

Recent advances in high-resolution fMRI, with gadolinium as the contrast agent, made the study possible. They enabled first author Scott Schobel of Columbia University and his colleagues to map cerebral blood volume in small brain areas. This let them gauge oxygen use and hence, activity levels, in these subregions.

Schobel and colleagues shone their fMRI searchlight on regions of interest fingered in prior studies of psychosis (see SRF related news story; related news story; related news story; related news story; related news story; related news story). These include the hippocampus, basal ganglia, frontal lobes, and amygdala (Shenton et al., 2001; for more recent reviews, see Gur et al., 2007; Allen et al., 2008).

Snapshots of psychosis
The researchers used a multipronged approach to pinpointing the brain regions that might underlie schizophrenia and related psychoses. First, they imaged the brains of 18 subjects who met criteria for schizophrenia or schizoaffective disorder. They compared their cerebral blood volume in the different subregions with that of an equal number of healthy subjects who were matched to them on age and sex.

The findings suggest that, in schizophrenia, oxygen use increases in the hippocampal CA1 subfield and the orbitofrontal cortex. In contrast, it seems to decrease in the dorsolateral prefrontal cortex.

However interesting, these differences could reflect the harm done by chronic psychosis, and Schobel’s team wanted a snapshot of early disease processes. This led them to study 18 prodromal subjects who met clinical criteria for being at ultra high risk of developing psychosis. These subjects presented symptoms that did not quite rise to the level seen in psychosis. For example, prodromal subjects might profess unusual ideas that seem less compelling than delusions.

During the two years of follow-up, seven of the prodromal subjects became psychotic. Of the three dysfunctional areas seen in subjects with more established disease, only the CA1 subfield appeared awry in these subjects. Notably, high activity in this area predicted the eventual emergence of psychosis. In fact, it did so with a positive predictive value of 71 percent and a negative predictive value of 82 percent. Not only do these findings yield insight into the earliest stages of psychosis, they raise hopes for a marker to flag those at greatest risk with the idea of someday preventing the disease from taking its toll.

While something had gone wrong in the CA1 area in the two clinical groups, its relationship to symptoms remained unknown. To assess symptom severity, Schobel and colleagues used the Positive and Negative Symptom Scale in subjects with schizophrenia and the Scale of Prodromal Symptoms in the high-risk group. For positive symptoms, the two scales rely on similar items, enabling the researchers to combine them into one measure.

Regression analyses showed that positive symptom scores, particularly delusions, correlated with CA1 activity in the two groups combined (β = .53, P = .01). However, these symptoms appeared unrelated to activity in the orbitofrontal cortex or the dorsolateral prefrontal cortex.

Unfortunately, the two scales differed too much in their assessment of negative symptoms to combine them, limiting Schobel and colleagues to looking at these symptoms in each group of subjects alone. They found that, in those with schizophrenia, negative symptoms appeared independent of activity in the three regions. A different story unfolded in the prodromal group. Their CA1 blood volume did relate to negative symptoms (β = .59, P = .03), including avolition and social dysfunction.

Saying no to drug confounds
In addition to teasing out early versus later disease processes, Schobel and colleagues faced the usual challenge of ruling out possible medication effects on brain activity, since most diagnosed subjects receive psychotropic drugs. However, in this study, only one prodromal subject who developed psychosis was undergoing treatment with antipsychotic medication at baseline. Even so, to boost confidence that medication had not influenced their findings, the researchers compared CA1 blood volume in the three prodromal subjects who were taking antipsychotic medication with that in the 15 subjects who were not. They found no differences between them. Other analyses discounted antidepressant use as a contributor.

Of course, animal studies give researchers ultimate control over subjects’ medications, so the researchers turned to mice. Each day for three weeks, they gave five mice the atypical antipsychotic risperidone, while five others received the drug vehicle alone. They imaged their brains before and after treatment. In the CA1 subfield and, indeed, all regions of the hippocampus, the two groups showed similar activity. Thus, the possibility of a medication confound appears, in this instance, to be less likely.

Schobel and colleagues assert that their study suggests that schizophrenia and related psychoses target the CA1 site in particular. The abnormal activity they observed in established psychosis, which also predicts progression from the prodrome to outright disease and correlates with psychotic symptoms, taken together, are evidence that schizophrenia involves “a basal hypermetabolic state in the hippocampus.” This conclusion contrasts with the traditional view that the hippocampus does too little in schizophrenia, although recently the notion of a hyperactive hippocampus has been gaining a foothold (see SRF related news story). The new findings may further its momentum.—Victoria L. Wilcox.

Schobel SA, Lewandowski NM, Corcoran CM, Moore H, Brown T, Malaspina D, Small SA. Differential targeting of the CA1 subfield of the hippocampal formation by schizophrenia and related psychotic disorders. Arch Gen Psychiatry. 2009 Sept;66(9):938-46. Abstract

Comments on Related News

Related News: Relational Memory Deficits Traced to Parietal Cortex/Hippocampus

Comment by:  Deborah Levy
Submitted 19 May 2006
Posted 19 May 2006

Comment by Deborah Levy, Debra Titone, and Howard Eichenbaum.
It is easy to appreciate why relational memory organization is such a compelling topic in studies of psychotic conditions. Relational memory allows one to flexibly manipulate information to discern new relationships based on known facts. The memory representations that support implicit reasoning of this type emerge effortlessly when the medial temporal lobe functions normally, whether navigating from a detour in a usual route or extrapolating that which is common across a set of individual memory traces. Relational thinking gone awry is a fundamental component of psychotic thinking. Inferential reasoning, referential ideas, and delusional extrapolations all involve making connections between unrelated things. These unwarranted connections, in turn, lead to erroneous (and potentially unrealistic) conclusions.

The kind of relational memory studied by Ongur et al. (2006) involves transitive inference (TI), or the capacity to use knowledge of how individual memory traces overlap, to correctly infer a new relationship that is predicated on already stored information. For example, it is straightforward to make the TI that Sally is taller than Peter if one knows the two related premises, Sally is taller than Frank and Frank is taller than Peter.

The study by Ongur et al. follows up on two studies initiated by Titone’s translation of Eichenbaum’s paradigm for testing TI in rodents. The first study established that schizophrenic patients show TI deficits compared with controls (Titone et al., 2004). Using a modification of the same TI paradigm adapted for use in the imaging environment, the second study assessed which brain regions were selectively activated when nonpsychiatric controls made TI relational judgments (relative to non-TI relational judgments). Of particular interest was whether the hippocampus (HP) would be one of the regions to show selective activation, since Eichenbaum’s work in rodents had demonstrated that animals with HP lesions or whose HPs have been disconnected from their subcortical and cortical connections lose the capacity for TI (Dusek and Eichenbaum, 1997; 1998). The imaging study showed a selective association between TI and activation of right HP, pre-supplementary motor area, left prefrontal cortex, left parietal cortex, and thalamus (Heckers et al., 2004; see also Preston et al., 2004). Having established the neural circuitry subserving TI in the healthy brain, the stage was set to compare the patterns of regional brain activation in schizophrenic and control subjects, the focus of the study by Ongur et al.

In addition to shedding some light on a potential relational memory impairment in schizophrenia, the Ongur et al. paper is useful for illustrating some of the complexities that arise in designing and interpreting the results of imaging studies generally and of transitive inference studies in particular. Below we discuss several of them and the many intriguing questions that call for resolution in future work.

One main source of complexity is that the key condition that demonstrates the capacity for TI is also the most difficult, especially for schizophrenic patients. Ongur et al. report that in controls, accuracy does not differ between the BD and non-BD sequential inference trials. However, the mean accuracy score of the controls is in the direction of the BD condition being less accurate. In addition, had response latencies been reported for those two conditions as well, it is very likely that correct response latencies for BD would have been longer than those for non-BD sequential inference trials in both groups. Thus, with these particular stimuli it is not straightforward to distinguish discrete effects of TI from the increased difficulty of TI judgments relative to non-TI judgments on performance or on regional brain activation. In other words, did schizophrenics perform more poorly on BD than controls because BD is more difficult than non-BD or because their capacity for TI is compromised? Was the increased activation bilaterally of inferior parietal cortex during BD (relative to non-BD) in controls a function of TI or of task difficulty? Was the increased activation of right inferior parietal cortex in schizophrenics during BD (relative to non-BD) a function of TI or of task difficulty? (See Stark and Squire, 2003.)

Schizophrenic patients performed the critical TI task (BD vs. non-BD) significantly worse than controls, which is to be expected given the previously mentioned increased task difficulty of the BD condition. Indeed, as a group they performed no better than chance. The groups also differed in pattern of regional brain activation. In the whole brain analysis, controls activated inferior parietal bilaterally, whereas schizophrenics activated right inferior parietal, inferior frontal, and premotor cortices. Neither group significantly activated HP. The only region to show a significant activation difference between the groups was right inferior parietal cortex. Because performance and activation are confounded, the pattern of results does not lend itself to a simple interpretation. That is, did these differences in regional activation occur because schizophrenics could not perform a task that depends on these regions, or did the poor performance occur because schizophrenics could not activate critical regions? The same confound affects the ability to interpret the results of the ROI analysis of HP. Was HP activation decreased during BD in schizophrenics because they were not performing a task that depends on HP, or was performance poor because patients were not able to activate HP?

Several aspects of these results make it difficult to characterize the role of the HP in the neural circuitry subserving TI in humans. First, in the whole brain analysis, controls activated HP only in the analysis of a general comparison of “TI versus non-TI” conditions. The specific critical TI comparison condition (BD vs. non-BD) did not activate HP in controls in the whole brain analysis, a finding that would have been expected based on Eichenbaum and colleagues’ rodent work (Dusek and Eichenbaum, 1997; 1998). Second, was the decreased activation of HP during BD in the patients related to excessively high basal levels of activation? Third, the one region that did show a difference between BD and non-BD in controls and that distinguished schizophrenics from controls was right inferior parietal cortex, not HP. Based on the results of the whole brain analysis, it would be interesting to see the results of an ROI analysis of inferior parietal, inferior frontal, premotor cortex, and anterior cingulate. Fourth, to what extent do sensitivity and power contribute to the difference between the results of the whole brain and ROI analyses and between the more general TI versus non-TI contrast and the specific BD versus non-BD contrast? Fifth, was the increased activation of inferior frontal regions during BD in schizophrenics an effort to compensate for under-recruitment of inferior parietal cortex bilaterally or HP (see Bonner-Jackson et al., 2005)?

Although the results of the Ongur et al. (2006) study are promising, to characterize the neural basis of relational memory deficits in schizophrenia, at least two additional challenges must be met. The first is to differentiate TI from task difficulty. Our recent modification of the TI paradigm that was used in the Titone et al. (2004), Heckers et al (2004), and Ongur et al. (2006) studies disambiguates TI deficits from difficulty effects. The preliminary results are quite promising in showing that schizophrenics show behavioral deficits in TI independent of difficulty. The second is to unconfound behavioral performance and neural activation. One way to do this is to match the comparison groups on behavioral performance. Another is to separately analyze imaging data from individuals with schizophrenia who can do TI at greater than chance levels and those who cannot.


Bonner-Jackson A, Haut K, Csernansky JG, Barch DM. The influence of encoding strategy on episodic memory and cortical activity in schizophrenia. Biol Psychiatry. 2005 Jul 1;58(1):47-55. Abstract

Dusek JA, Eichenbaum H. The hippocampus and memory for orderly stimulus relations. Proc Natl Acad Sci U S A. 1997 Jun 24;94(13):7109-14. Abstract

Dusek JA, Eichenbaum H. The hippocampus and transverse patterning guided by olfactory cues. Behav Neurosci. 1998 Aug;112(4):762-71. Abstract

Heckers S, Zalesak M, Weiss AP, Ditman T, Titone D. Hippocampal activation during transitive inference in humans. Hippocampus. 2004;14(2):153-62. Abstract

Ongur D, Cullen TJ, Wolf DH, Rohan M, Barreira P, Zalesak M, Heckers S. The neural basis of relational memory deficits in schizophrenia. Arch Gen Psychiatry. 2006 Apr;63(4):356-65. Abstract

Preston AR, Shrager Y, Dudukovic NM, Gabrieli JD. Hippocampal contribution to the novel use of relational information in declarative memory. Hippocampus. 2004;14(2):148-52. No abstract available. Abstract

Stark CE, Squire LR. Hippocampal damage equally impairs memory for single items and memory for conjunctions. Hippocampus. 2003;13(2):281-92. Abstract

Titone D, Ditman T, Holzman PS, Eichenbaum H, Levy DL. Transitive inference in schizophrenia: impairments in relational memory organization. Schizophr Res. 2004 Jun 1;68(2-3):235-47. Abstract

View all comments by Deborah Levy

Related News: Relational Memory Deficits Traced to Parietal Cortex/Hippocampus

Comment by:  Patricia Estani
Submitted 3 June 2006
Posted 3 June 2006
  I recommend the Primary Papers

Related News: Relational Memory Deficits Traced to Parietal Cortex/Hippocampus

Comment by:  Terry Goldberg
Submitted 19 June 2006
Posted 19 June 2006

Ongur, Heckers, and colleagues present an interesting set of findings about memory in schizophrenia. Using a transitive inference paradigm to explore relational memory (inferring that A>C if one knows A>B and B>C), they showed both a selective behavioral deficit for one particular type of transitive inference (“BD”) that can only be done through logic and not through reinforcement alone and abnormalities in BOLD activation in parietal cortex, hippocampus, and anterior cingulate in schizophrenia. The study is exciting because it pinpoints a relatively specific mnemonic processing abnormality, a task not as easy as it may appear. Our own behavioral work (Goldberg, Elvevaag, and colleagues) has emphasized quantitative but not qualitative behavioral memory processing impairments in paradigms that included levels of encoding, false memory, and AB-ABr interference. A computational model of this work seemed to demonstrate marked reductions in connectivity (but not “neuronal number” or “noise”) in inputs into “entorhinal cortex” and from entorhinal to hippocampus fit the data well. Given the Heckers findings, it will be interesting to see how the model handles transitive inference.

As in every study, no matter the degree of excellence, there are issues. The study pivots on the presentation of eight BD pairings. Is this really enough? There have been consistent murmurings in the field that the transitive logical computations themselves may occur in prefrontal cortex. While the pre-SMA activation may technically fit the bill, one wonders if a region oft thought to be responsible for simple chaining of motor sequences is really up to the task of determining transitive relations. Perhaps most interesting is the finding of parietal cortical hypoactivation in schizophrenia during transitive inference, but is it specific to engagement in a transitivity judgment, or is it more generally a visual discrimination processing abnormality?

View all comments by Terry Goldberg

Related News: Resolving Conflicting Information: Does the Anterior Cingulate Matter?

Comment by:  Nicolas RüschGianfranco Spalletta
Submitted 6 November 2007
Posted 6 November 2007

This very interesting paper by Mansouri and colleagues demonstrates that executive functioning in monkeys as measured by a variant of the Wisconsin Card Sorting Test is primarily related to lesions in the dorsolateral prefrontal cortex. The finding is consistent with magnetic resonance imaging findings on structural correlates of executive dysfunction in persons with schizophrenia, one of the more prominent cognitive deficits in this disorder.

Manual morphometry studies found a link between dorsolateral prefrontal volume loss and executive dysfunction in schizophrenia (Antonova et al., 2004). A recent voxel-based morphometry study (Rüsch et al., 2007) compared frontal gray matter volume differences in patients with schizophrenia and high versus low performance in the Wisconsin Card Sorting Test. Consistent with the new study of Mansouri et al., the strongest difference between both groups was found in the dorsolateral prefrontal cortex, with gray matter volume loss in this area being related to executive dysfunction. Gray matter volume loss in the anterior cingulate was also significantly, but less strongly, related to executive functioning.

However, Rüsch and colleagues also found volumetric correlations between this dorsolateral prefrontal area and thalamic and cerebellar regions, which points to extended gray matter networks involved in executive dysfunction. Thus, the frontal cortical areas frequently associated with executive dysfunction, impressively studied by Mansouri and colleagues, could be at the core of an executive circuit that also comprises subcortical areas such as the thalamus.

Finally, executive functions, at least in humans, are a multifaceted concept which is influenced by a number of factors in a highly complex fashion, especially in psychosis. Indeed, it would not only be related to a mere neural substrate, but rather it would reflect the influence of psychological and social factors such as education, intelligence, and social learning which may secondarily affect brain structure (Corrigan and Penn, 2001).

Neurobiological correlates of executive functioning (Barch, 2006) are a stimulating challenge for researchers and clinicians alike, not only for their theoretical interest, but also for their diagnostic, rehabilitative-therapeutic and prognostic implications. Therefore, executive functioning and its relation to functional and structural connectivity across the brain, both in healthy controls and in individuals with schizophrenia, clearly deserves further investigation using electrophysiological methods as well as functional magnetic resonance and diffusion tensor imaging.


Antonova E, Sharma T, Morris R, Kumari V. The relationship between brain structure and neurocognition in schizophrenia: a selective review. Schizophr Res. 2004 Oct 1;70(2-3):117-45. Abstract

Barch DM. What can research on schizophrenia tell us about the cognitive neuroscience of working memory? Neuroscience. 2006 Apr 28;139(1):73-84. Abstract

Corrigan PW, Penn DL (2001). Social cognition and schizophrenia. Washington DC: American Psychological Association.

Rüsch N, Spoletini I, Wilke M, Bria P, Di Paola M, Di Iulio F, Martinotti G, Caltagirone C, Spalletta G. Prefrontal-thalamic-cerebellar gray matter networks and executive functioning in schizophrenia. Schizophr Res. 2007 Jul 1;93(1-3):79-89. Abstract

View all comments by Nicolas Rüsch
View all comments by Gianfranco Spalletta

Related News: Dopamine Problems? Blame the Hippocampus

Comment by:  Anissa Abi-Dargham, SRF Advisor
Submitted 29 November 2007
Posted 29 November 2007

What struck me most about the paper of Lodge and Grace is the overall consistency of the body of work between the preclinical and clinical observations, even down to the effect size for the dopaminergic alteration. Dopamine release in schizophrenia is at least double that in controls; whether measured after amphetamine (on average 17 percent displacement of the benzamide radiotracer versus 7 percent in controls) (Laruelle et al., 1999) or at baseline (19 percent D2 occupancy by dopamine in patients versus 9 percent in controls) (Abi-Dargham et al., 2000), the increase in dopamine activity in VTA of the MAM rats reported here is also a doubling of what is measured in saline-treated rats.

This work presents an important contribution to the field because it clarifies the role of the hippocampus in one of the cardinal features of the disorder as modeled in MAM rats. The fact that MAM treatment is one of the most valid animal models of schizophrenia—it replicates many of the disturbances, neurochemical, cellular, dendritic, morphometric, and behavioral, observed in schizophrenia—makes the finding very compelling.

The role of an abnormal hippocampal node in an important circuit central to the pathophysiology of schizophrenia has face validity: there are now many converging lines of evidence in patients with schizophrenia for alterations in hippocampal volume, cytoarchitecture, function, and neurochemical indices. What this paper presents that is unique is evidence, in a valid model of schizophrenia, for an etiological link between the faulty hippocampus and the faulty VTA. The next step will be to test an association between pathology of the hippocampus and that of the VTA and related striatal output in patients with schizophrenia. This is a study we currently are conducting, and is an example of translational research where a theory gets support and contributions by going back and forth between preclinical and clinical testing. If there is an association in the same patients between the hippocampal pathology and dopamine dysregulation, it will suggest that what is described for the MAM model here may be true for schizophrenia, too, i.e., that the pathology of the dopamine system is driven by a faulty hippocampal input.


Laruelle M, Abi-Dargham A, Gil R, Kegeles L, Innis R. Increased dopamine transmission in schizophrenia: relationship to illness phases. Biol Psychiatry. 1999;46:56-72. Abstract

Abi-Dargham A, Rodenhiser J, Printz D, Zea-Ponce Y, Gil R, Kegeles LS, Weiss R, Cooper TB, Mann JJ, Van Heertum RL, Gorman JM, Laruelle M. Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proc Natl Acad Sci U S A. 2000;97:8104-8109. Abstract

View all comments by Anissa Abi-Dargham

Related News: Dopamine Problems? Blame the Hippocampus

Comment by:  Elizabeth Tunbridge
Submitted 20 December 2007
Posted 20 December 2007
  I recommend the Primary Papers

In their recent paper Lodge and Grace elegantly demonstrate that hyperactivity of the ventral hippocampus underlies the elevated number of spontaneously active ventral tegmental dopamine neurons, and the concomitant increase in amphetamine-induced locomotor activity, found in MAM-treated rats. Since neonatal MAM treatment recapitulates some of the neurochemical, anatomical, and behavioral abnormalities associated with schizophrenia, these findings raise the possibility that the abnormal subcortical dopamine function associated with this disorder might also result from hippocampal dysfunction.

These findings are consistent with a wealth of evidence suggesting that the hippocampus is a prominent site of dysfunction in the schizophrenic brain (reviewed in Harrison, 2004), and it will be exciting to see the results of the clinical studies described by Anissa Abi-Dargham above.

In the future, it will be important to try to integrate these findings with other models aiming to explain the subcortical dopaminergic hyperactivity seen in schizophrenia. One well-known hypothesis is that these abnormalities might result from hypofunction of the prefrontal cortex (PFC; Weinberger, 1987; Bertolino et al., 2000). Animal studies demonstrate that PFC activity impacts on striatal dopamine function (e.g., Shim et al., 1996) and vice versa (Kellendonk et al., 2006). Thus, it will be of interest to assess the relative contributions of hippocampal and prefrontal dysfunction to these subcortical abnormalities in schizophrenia. Such investigations will necessarily involve the use of both patient populations and appropriate animal model systems. A difficult question will be to establish whether any one of these three regions represents a site of a primary “lesion” in schizophrenia or, perhaps more likely, whether their dysfunction reflects abnormalities in the circuits that link them.


Bertolino A, Breier A, Callicott JH, Adler C, Mattay VS, Shapiro M, Frank JA, Pickar D, Weinberger DR. The relationship between dorsolateral prefrontal neuronal N-acetylaspartate and evoked release of striatal dopamine in schizophrenia. Neuropsychopharmacology. 2000 Feb;22(2):125-32. Abstract

Harrison PJ. The hippocampus in schizophrenia: a review of the neuropathological evidence and its pathophysiological implications. Psychopharmacology (Berl). 2004 Jun;174(1):151-62. Epub 2004 Mar 6. Review. Abstract

Kellendonk C, Simpson EH, Polan HJ, Malleret G, Vronskaya S, Winiger V, Moore H, Kandel ER. Transient and selective overexpression of dopamine D2 receptors in the striatum causes persistent abnormalities in prefrontal cortex functioning. Neuron. 2006 Feb 16;49(4):603-15. Abstract

Shim SS, Bunney BS, Shi WX. Effects of lesions in the medial prefrontal cortex on the activity of midbrain dopamine neurons. Neuropsychopharmacology. 1996 Nov;15(5):437-41. Abstract

Weinberger DR. Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry. 1987 Jul;44(7):660-9. Abstract

View all comments by Elizabeth Tunbridge

Related News: ICOSR 2009—Psychosis: Is It All From Your Hippocampus?

Comment by:  David Yates
Submitted 25 April 2009
Posted 5 June 2009

Might it be helpful to reflect upon the schizophrenia that comes after epilepsy? I am not clear whether or not there were familial studies to discover any greater incidence in relatives, but may there have been postmortem tissue studies around the temporal lobes, that would have included hippocampus structures, which might connect with the current studies.

View all comments by David Yates

Related News: ICOSR 2009—Psychosis: Is It All From Your Hippocampus?

Comment by:  David Oberlander
Submitted 16 April 2009
Posted 5 June 2009

Isn't it true that schizophrenia can also be considered a 'hypo-glutamatergic' state? Would AMPA-receptor upmodulators (so-called ampakines) have a role given this hypothesis? Specifically in that I seem to recall looking at slides of BDNF/NGF induction after these AMPA upmodulators were given. These neurotrophic effects affect hippocampus size, albeit in a distinct way from the neurotrophism of SSRIs. These AMPA receptor modulators also produce some improvement in cognitive skills.

View all comments by David Oberlander

Related News: ICOSR 2009—Psychosis: Is It All From Your Hippocampus?

Comment by:  Hakon Heimer
Submitted 6 June 2009
Posted 6 June 2009

Reply to David Oberlander

Ampakines continue to show the ability to rescue cognitive deficits in animal studies (e.g., in a PCP model of schizophrenia by Broberg et al., 2009; and in a nonhuman primate sleep deprivation study by Hampson et al., 2009). However, a placebo-controlled clinical trial with the ampakine CX516 as an add-on to either clozapine, olanzapine, or risperidone did not produce cognitive benefits in schizophrenia patients (Goff et al., 2007).

View all comments by Hakon Heimer

Related News: NYAS 2011—New Molecular Targets for Schizophrenia

Comment by:  Jim Woodgett
Submitted 26 April 2011
Posted 27 April 2011

Several of the reports from the NYAS meeting describe the potential role of GSK-3β in DISC1 functions. This is one of two isoforms, and the other, GSK-3α, tends to get short shrift from researchers. This is problematic for several reasons. Firstly, the two isoforms, despite being derived from distinct genes, are essentially identical within their catalytic domains. Consequently, there are no small molecule inhibitors that that are isoform selective, and the two proteins are highly redundant (albeit not completely) in function. Secondly, in the case of DISC1, there are new data indicating a role for GSK-3α in DISC1 functions. Small molecule (isoform indiscriminate) inhibitors of GSK-3 restore behavioral deficits of DISC1 L100P animals, and this is also achieved by genetic inactivation of one allele of GSK-3α (Lipina et al., 2011). Examination of the brains of the DISC1 and DISC1/GSK-3α+/- animals revealed that dendritic spine density deficits observed in DISC1 L100P brains were restored upon deletion of one copy of GSK-3α (Lee et al., 2011).

From a therapeutic point of view, there appears to be no easy way to selectively inhibit only one isoform of GSK-3 (the only means is via RNA interference), so perhaps it is fortunate that both isoforms appear to play similar roles? Birds, on the other hand, appear to have selectively lost GSK-3α, though the consequences in terms of brain development and function are currently unclear (Alon et al., 2011).


Lipina TV, Kaidanovich-Beilin O, Patel S, Wang M, Clapcote SJ, Liu F, Woodgett JR, Roder JC. (2011). Genetic and pharmacological evidence for schizophrenia-related Disc1 interaction with GSK-3. Synapse 65(3):234-48. Abstract

Lee FH, Kaidanovich-Beilin O, Roder JC, Woodgett JR, Wong AH. (2011) Genetic inactivation of GSK3α rescues spine deficits in Disc1-L100P mutant mice. Schizophr Res. Abstract

Alon LT, Pietrokovski S, Barkan S, Avrahami L, Kaidanovich-Beilin O, Woodgett JR, Barnea A, Eldar-Finkelman H. (2011) Selective loss of glycogen synthase kinase-3α in birds reveals distinct roles for GSK-3 isozymes in tau phosphorylation. FEBS Lett. 585(8):1158-62. Abstract

View all comments by Jim Woodgett