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SfN 2005: Cortical Deficits in Schizophrenia: Have Genes, Will Hypothesize

4 December 2005. For the recent Society for Neuroscience Annual Conference in Washington, D.C., Patricio O'Donnell of Albany Medical College in New York organized a symposium called "Cortical Deficits in Schizophrenia: From Genes to Function." O'Donnell was generous enough to combine his notes with those of SRF editor Hakon Heimer so that we could bring you this session summary.

The symposium was proposed on the premise that, although recent years have witnessed an explosion in the identification of schizophrenia-predisposing genes, an integrative perspective on how they can affect pathophysiological mechanisms is still missing. The speakers presented different views on possible pathophysiological scenarios that could arise in a predisposed brain.

Danny Weinberger of the National Institute of Mental Health, in his talk entitled "Schizophrenia susceptibility genes: Biological epistasis and cortical signal to noise," reviewed the history of the search for schizophrenia-related genes. Despite the identification of numerous gene candidates, he noted, there remain "nagging problems," including generally weak risk effects, multiple comparisons, variable alleles and haplotypes, and few functional polymorphisms identified. However, the real endgame is probably not a statistical relationship between gene loci and disease, but rather a biological explanation for how variation in the function of a particular gene would translate into a biological change that is relevant for the expression of schizophrenia or any mental illness.

Weinberger highlighted that most genes identified to date are related to either brain development or synaptic plasticity (see, e.g., Harrison and Weinberger, 2005). The latter may, in fact, be responsible for prefrontal cortical inefficiency due to a loss in signal-to-noise ratio (by increasing "noise"), as revealed by neurophysiological studies in patients. Weinberger elaborated this concept of increased noise as possibly derived from alterations in either GABA or dopamine transmission within the prefrontal cortex. Some of the genes associated with schizophrenia, such as GAD1, the gene associated with the GABA-synthesizing enzyme GAD67, the dopamine-inactivating enzyme COMT, or the dopamine-modulating receptor mGluR3, do provide strong support for this possibility. Other genes, such as DISC1, may impact cortical function by inducing improper wiring, especially in the hippocampus.

Finally, Weinberger indicated that a critical component in genetic predisposition is a nonlinear interaction among diverse genes. This seems to be the case for GAD1, COMT, and mGluR3. In a recent family-based association analysis, Weinberger and colleagues have found that both GAD1 and GRM3 have effects on COMT (Nicodemus et al., 2005). There is also evidence that DISC1 has differential effects on COMT (Nicodemus et al., 2005).

Amanda Law of Oxford University, in her talk entitled "Neuregulin 1 and schizophrenia: A pathway for altered cortical circuits," spoke about her group's recent investigations into understanding the molecular and biological mechanisms behind the genetic association of the NRG1 gene with schizophrenia. She presented data on isoform gene expression of the NRG1 variants, Types I-IV in the human postmortem hippocampus, and then examined the effects of four disease-associated SNPs which make up an original risk haplotype identified by Stefansson et al. (2002) on transcript abundance. Among the numerous isoforms of this complex (25 exons +) gene, it appears that the important isoforms involved in schizophrenia are Type I NRG1, which appears to be associated to the disease state, and the novel Type IV isoform, which is associated with genetic risk for the disease.

The work of Law and colleagues shows increases in Type I NRG1 in the hippocampus in schizophrenia confirming earlier work from her colleagues in Weinberger’s group who showed increased Type I in the dorsolateral prefrontal cortex in a smaller and separate brain series (Hashimoto et al., 2004). She also presented data that showed that a single disease-associated polymorphism (which is physically next to the transcription start site of Type IV) and the at-risk haplotype predict levels of Type IV in the brain, with the risk allele and haplotype being associated with increased levels of the novel isoform. The risk allele is a putative transcription binding site for serum-response factor (SRF) with a loss of binding when carrying the risk allele and replacement with a DNA binding protein high mobility group 1 protein. SRF is known to regulate genes involved in synaptic plasticity and actin dynamics, and has been shown to play a critical role in neuronal migration and hippocampal development, based on its effects on regulation of genes involved in actin dynamics (Alberti et al., 2005).

Law and colleagues postulate that they have identified a functional disease SNP in NRG1 which is associated with Type IV expression in brain. This suggest to them they have thereby found a molecular mechanism underlying the genetic association of NRG1 with schizophrenia which involves transcriptional regulation of the novel Type IV isoform. In addition, they have found decreased expression of NRG1 (pan probe to all variants) in cerebellar Purkinje and Golgi cells in the same patients. She presented data showing that Type IV is the primary isoform expressed in these cells, but the relationship to isoform changes and genetic risk for schizophrenia is still being investigated. Law presented a series of hypotheses and pathway models involving complex intracellular pathways connecting altered SRF regulation of NRG1 in schizophrenia, NRG1 regulation of lim kinase 1 (LIMK1) and Slingshot, as pathways underlying neuronal migration through their effects on actin dynamics.

Turning to research on the role of NRG1 in development, Law discussed the work of John Rubenstein of University of California, San Francisco, and collaborators demonstrating that NRG1 modulates GABA interneuron migration from the ganglionic eminence to their final cortical destination (see, e.g., Flames et al., 2004), as well as the role of NRG1 in the formation and survival of radial glia and their differentiation into cortical astrocytes (Schmid et al., 2003). Law discussed the potential consequences of differential isoform expression, mediated by genetic risk in schizophrenia, in the context of recent work showing that NRG1 down-regulates NMDA receptor transmission in prefrontal cortical pyramidal neurons and slices (Gu et al., 2005) and reverses LTP in the hippocampus via internalization of AMPA receptors (Kwon et al., 2005), stating that their findings of increased NRG1 Type IV (associated with genetic risk) and increased Type I associated with disease state would translate into reduced glutamatergic transmission, consistent with one of the most prominent neurotransmitter hypothesis of schizophrenia. In all, Law’s presentation highlighted a series of complex intracellular events surrounding differential NRG1 isoform expression in schizophrenia, discussing how this may contribute to abnormalities of cell migration and altered synaptic plasticity in the disease.

David Lewis ("Gene expression abnormalities in schizophrenia: Pathogenetic mechanisms and pathophysiological consequences") of the University of Pittsburgh reviewed work on GABAergic interneurons as a critical neural population affected in schizophrenia (for review, see Lewis et al., 2005), possibly underlying working memory deficits. Postmortem studies have consistently shown a reduction in the expression of GAD67 mRNA in the prefrontal cortex of subjects with schizophrenia, and this expression deficit appears to be restricted to a subpopulation of GABA neurons (first shown by Akbarian et al., 1995).

But all GABAergic neurons in cortex are not the same. For example, they are distinguished by one of three calcium-binding proteins they express: parvalbumin, calretinin, or calbindin. Much of Lewis's work has focused on the parvalbumin-expressing cells which seem to be selectively affected in schizophrenia. And it's not that there are fewer of them, but rather that they express less parvalbumin, not to mention almost no GAD67. (Hashimoto et al., 2003).

Parvalbumin-containing interneurons have been most consistently observed as deficient in schizophrenia, but somatostatin-positive interneurons may also be affected. This population of GABAergic neurons overlaps substantially, but not completely, with calbindin-positive neurons. Studies of calbindin are confounded by the expression of this transcript in layer three pyramidal cells as well as in interneurons, especially in human cortex, so somatostatin is a more specific marker for a subpopulation of interneurons. In microarray, qPCR, and in situ hybridization studies presented by Lewis's group at the 2005 Society for Neuroscience meeting, the expression of somatostatin mRNA was found to be decreased in subjects with schizophrenia (Hashimoto et al Soc Neurosci Abstr 2005; Morris et al Soc Neurosci Abstr 2005)

Lewis presented evidence that the trophic factor BDNF, acting via its receptor Trk-B—which is expressed to a much greater degree in parvalbumin and somatostatin-containing interneurons than in the calretinin subtype of cortical GABA neurons—is important for interneuron maturation (Huang, 1999). In individuals with schizophrenia, changes in the expression of TrkB strongly correlate with the expression of GAD67, parvalbumin (PV), and somatostatin (SST), mRNAs, and underexpression of TrkB in genetically engineered mice results in reduced expression of GAD67, PV, and SST, but not of calretinin (CR), suggesting that reduced neurotrophin signaling through the TrkB receptor may be a pathogenetic mechanism contributing to the alterations in subpopulations of GABA neurons in schizophrenia (Hashimoto, 2005).

Based on their distinctive synaptic targets and the intrinsic properties of networks of parvalbumin and somatostatin neurons, suggested Lewis, alterations in these two populations of GABA neurons may contribute in different ways to disrupting the synchronized neural activity in the prefrontal cortex that is critical for working memory function.

What about brain areas other than prefrontal cortex? Lewis mentioned there are differences in GAD67 expression in other cortical areas in schizophrenia, though apparently not in hippocampus (reviewed in Lewis et al., Nat Rev Neuro 2005), suggesting that GABA perturbations in these areas could contribute to cognitive deficits subserved by these areas.

Patricio O'Donnell presented data on a developmental animal model of schizophrenia. He argued that the use of such models is justified as experimental tools that can help in identifying pathophysiological processes caused by early manipulations affecting brain development. That is, some of these models may be reproducing deficits caused by high-risk alleles combined with environmental factors. O’Donnell reviewed extensive work done in animals with a neonatal ventral hippocampal lesion, in which pyramidal neurons in the prefrontal cortex become hyperexcitable, as appears to be the case in schizophrenia (O'Donnell et al., 2002). The value of the model is further supported by the finding that many of the behavioral manifestations of this model emerge after adolescence (Goto and O'Donnell, 2002; Goto and O'Donnell, 2003), which has led O'Donnell's group to look more closely at peri-adolescent changes in prefrontal cortical physiology.

In normal animals, two critical phenomena were observed as emerging after adolescence: 1) the ability to induce persistent activity by combined D1 and NMDA receptor activation (Tseng and O'Donnell, 2005), and 2) the excitation of interneurons by D2 dopamine receptors. In animals with a neonatal lesion, these late-maturation phenomena were not acquired. O’Donnell argued that in a predisposed brain (in the model, the lesion; in patients, the effects of predisposing genes), it is possible that local cortical circuits are abnormally wired (with interneurons likely affected). However, it would be only after adolescence that high demand on these circuits would reveal their dysfunctional nature, causing symptoms (hyperlocomotion, intolerance to stress, and cognitive deficits in the model; negative symptoms and cognitive deficits in patients) to emerge long after the brain circuits were affected.

In summary, the symposium brought a surprisingly convergent set of findings that could be summarized into the notion that genetic predisposition can result in abnormal cortical circuits, and GABA interneurons seem to be critical for this cortical malfunction. This picture opens diverse new possible avenues to explore potential therapeutic approaches.

References:
Nicodemus KK, Straub RE, Egan MF, Weinberger DR. Evidence for statistical epistasis between (COMT) val158met polymorphism and multiple putative schizophrenia susceptibility genes [abstract]. Am J Med Gen B: Psych Gen. 138B;1:130-1.

T. Hashimoto, D. Arion, T. Unger, K. Mirnics, D.A. Lewis. Analysis of the GABA-related transcriptome in the prefrontal cortex of subjects with schizophrenia. Program No. 675.4. 2005 Abstract Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience, 2005. Online.

H.M. Morris, T. Hashimoto, D.A. Lewis. Analysis of somatostatin mRNA expression in the prefrontal cortex of individuals with schizophrenia. Program No. 675.5. 2005 Abstract Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience, 2005. Online.

Comments on News and Primary Papers
Comment by:  Patricia Estani
Submitted 2 January 2006
Posted 2 January 2006
  I recommend the Primary Papers
Comments on Related News


Related News: Polymorphisms and Schizophrenia—The Ups and Downs of Neuregulin Expression

Comment by:  William Carpenter, SRF Advisor (Disclosure)
Submitted 22 April 2006
Posted 22 April 2006
  I recommend the Primary Papers

Related News: Polymorphisms and Schizophrenia—The Ups and Downs of Neuregulin Expression

Comment by:  Stephan Heckers, SRF Advisor
Submitted 29 April 2006
Posted 29 April 2006
  I recommend the Primary Papers

The gene Neuregulin 1 (NRG1) on chromosome 8p has been identified as one of the risk genes for schizophrenia. It is unclear how the DNA sequence variation linked to schizophrenia leads to abnormalities of mRNA expression. This would be important to know, in order to understand the downstream effects of the neuregulin gene on neuronal functioning in schizophrenia.

Law and colleagues explored this question in post-mortem specimens of the hippocampus of control subjects and patients with schizophrenia. This elegant study of the expression of four types of NRG1 mRNA (types I-IV) is exactly what we need to translate findings from the field of human genetics into the field of schizophrenia neuropathology. The findings are complex and cannot be translated easily into a model of neuregulin dysfunction in schizophrenia. I would like to highlight two findings.

First, the level of NRG1 type I mRNA expression was increased in the hippocampus of schizophrenia patients. This confirms an earlier study of NRG1 mRNA expression in schizophrenia. It remains to be seen how this change in NRG1 type I mRNA expression relates to the finer details of neuregulin dysfunction in schizophrenia.

Second, one single nucleotide polymorphism (SNP8NRG243177) of the risk haplotype linked to schizophrenia in earlier studies predicts NRG1 type IV mRNA expression. The SNP determines a binding site for transcription factors, providing clues for how DNA sequence variation may lead, via modulation of mRNA expression, to neuronal dysfunction in schizophrenia. It is exciting to see that we can now test specific hypotheses of molecular mechanisms in the brains of patients who have suffered from schizophrenia. The study by Law et al. is an encouraging step in the right direction.

View all comments by Stephan Heckers

Related News: Polymorphisms and Schizophrenia—The Ups and Downs of Neuregulin Expression

Comment by:  Bryan Roth, SRF Advisor
Submitted 5 May 2006
Posted 5 May 2006
  I recommend the Primary Papers

I think this is a very interesting and potentially significant paper. It is important to point out, however, that it deals with changes in mRNA abundance rather than alterations in neuregulin protein expression. No measures of isoform protein expression were performed, and it is conceivable that neuregulin isoform protein expression could be increased, decreased, or not changed. A second point is that although statistically significant changes in mRNA were measured, they are modest.

Finally, although multiple comparisons were performed, the authors chose not to perform Bonferroni corrections, noting in the primary paper that, "Correction for random effects, such as Bonferroni correction, would be an excessively conservative approach, particularly given that we have restricted our primary analyses to planned comparisons (based on strong prior clinical association and physical location of the SNPs) of four SNPs and a single haplotype comprised of these SNPs. Because the SNPs are in moderate LD, the degree of independence between markers is low and, therefore, correcting for multiple testing would result in a high type II error rate. The prior probability and the predictable association between the deCODE haplotype and expression of NRG1 isoforms (especially type IV, which is its immediate physical neighbor) combined with the LD between SNPs in this haplotype makes statistical correction for these comparisons inappropriate. Nevertheless, our finding regarding type IV expression and the deCODE haplotype and SNP8NRG243177 requires independent replication."

It will thus be important to determine if these changes in neuregulin mRNA isoform abundance are mirrored by significant changes in neuregulin isoform protein expression and if the findings can be independently replicated with other cohorts.

View all comments by Bryan Roth

Related News: New Genetic Variations Link Schizophrenia and Bipolar Disorder

Comment by:  Mary Reid
Submitted 28 September 2006
Posted 29 September 2006

It's of interest that Vazza and colleagues suggest that 15q26 is a new susceptibility locus for schizophrenia and bipolar disorder. I have suggested that reduced function of the anti-inflammatory SEPS1 (selenoprotein S) at 15q26.3 may reproduce the neuropathology seen in schizophrenia.

View all comments by Mary Reid

Related News: New Genetic Variations Link Schizophrenia and Bipolar Disorder

Comment by:  Patricia Estani
Submitted 5 October 2006
Posted 6 October 2006
  I recommend the Primary Papers

Related News: The New "Inverted U”—Cellular Basis for Dopamine Response Pinpointed

Comment by:  Andreas Meyer-Lindenberg
Submitted 8 February 2007
Posted 8 February 2007

This fascinating paper contributes to our mechanistic understanding of a fundamental nonlinearity governing the response of prefrontal neurons during working memory to dopaminergic stimulation: the “inverted U” response curve (Goldman-Rakic et al., 2000), which proposes that an optimum range of dopaminergic stimulation exists, and that either too little or too much dopamine impairs tuning, or the relationship between task-relevant (“signal”) and task-irrelevant (“noise”) firing of these neurons. On the level of behavior, this is predicted to result in impaired working memory performance outside the optimum middle range, and this has been confirmed in a variety of species. This is a topic of high relevance for schizophrenia where prefrontal dysfunction and related cognitive deficits, and dopaminergic dysregulation, have long been in the center of research interest (Weinberger et al., 2001), and may be linked (Meyer-Lindenberg et al., 2002). In particular, evidence for abnormally decreased dopamine levels in prefrontal cortex would predict that patients with schizophrenia are positioned to the left of the optimum. This line of thought has recently received impetus from genetic studies on COMT, the major enzyme catabolizing dopamine in prefrontal cortex (Tunbridge et al., 2004). Neuroimaging studies have shown that genetic variants with high COMT activity are positioned to the left, those with lower activity nearer the optimum of the inverted U curve, and that this position predicts nonlinear response to amphetamine stimulation (Mattay et al., 2003), as well as interactions between dopamine synthesis and prefrontal response (Meyer-Lindenberg et al., 2005). Variants with sub- (Egan et al., 2001; Nicodemus et al., 2007) or superoptimal (Gothelf et al., 2005) stimulation were associated with schizophrenia risk. Task-related and task-unrelated prefrontal function reacted in opposite ways to genetic variation in dopamine synthesis, suggesting a tuning mechanism (Meyer-Lindenberg et al., 2005). Recently, interacting genetic variants in COMT have also been found to affect prefrontal cortex function in an inverted U fashion (Meyer-Lindenberg et al., 2006).

A seminal contribution to the cellular mechanisms of the inverted U curve is the paper by Williams (one of the authors of the current study) and Goldman-Rakic in Nature 1995 (Williams and Goldman-Rakic, 1995). In this work, dopamine D1 receptor antagonists were used and shown to increase prefrontal cell activity in low levels, whereas high levels inhibited firing. This implicated a mechanism related to D1 receptors and suggested that the neurons studied were to the right of the optimum on the inverted U curve, that is, their dopamine stimulation was excessive. The present study, from Amy Arnsten’s lab at Yale, further defines the cellular mechanisms underlying the inverted U curve in recordings from PFC neurons of awake behaving monkeys exposed to various levels of stimulation by a dopamine 1 receptor agonist. A spatial working memory paradigm was used, enabling the determination of the degree to which the neurons were tuned by comparing the firing rate to stimuli in the preferred spatial stimulus direction (“signal”) to the firing rate to nonpreferred stimuli (“noise”). The authors recorded both from neurons that were highly tuned (supposedly receiving optimum stimulation) and neurons that were less tuned. As would be predicted from the model, highly tuned neurons did not improve, or worsened, during stimulation, while weakly tuned neurons became more focused in their activity profile. It is not quite clear to me why the previous paper (Williams and Goldman-Rakic, 1995) found neurons that were predominantly to the right of the optimum, while this work identified neurons using a similar paradigm that were either to the left or near the optimum. Perhaps it is because Williams and Goldman-Rakic (Williams and Goldman-Rakic, 1995) screened neurons for a response to the D1 antagonist first. In both studies, extracellular dopamine was not actually measured, meaning that the state of basal stimulation can only be inferred indirectly from the response to the iontophoresed agonist or antagonist. Importantly, the effect of D1 stimulation was always suppressive; effects on tuning were due to the fact that the reduction in response to the signal and the noise were different in extent, such that for weakly tuned neurons and low levels of D1 stimulation, the noise firing was more suppressed than that of the signal, resulting in increased signal to noise. In a second set of pharmacological experiments, which included validation in a rat working memory model, the authors show that these effects are cAMP, but not PKC-dependent, suggesting a preferential cellular mechanism through Gs-proteins, which might be useful for exploration of more specific drug targets.

This work has interesting implications for our understanding of prefrontal function in schizophrenia. Since dopamine stimulation was found to be almost exclusively suppressive, cortical dopamine depletion in schizophrenia would be predicted to lead to relatively increased, but inefficient (untuned) cortical cognitive response, as has indeed been observed (Callicott et al., 2000). However, it is an open question precisely how cortical physiology assessed by imaging relates to these cellular events. The data by Arnsten suggest that each patch of prefrontal cortex will contain a population of neurons at various states of tuning that will respond differently to drug-induced or cognitively related changes in extracellular dopamine, with some improving, some decreasing their tuning. Depending on whether imaging signals and tasks are more sensitive to overall firing rate, or to specific signal-to-noise properties, the resulting blood flow change might be quite different. Perhaps this contributes to some of the puzzling discrepancies between hypo- and hyperactivation both being observed in comparable tasks and regions of prefrontal cortex in schizophrenia.

References:

1. Goldman-Rakic PS, Muly EC 3rd, Williams GV. D(1) receptors in prefrontal cells and circuits. Brain Res Brain Res Rev. 2000 Mar;31(2-3):295-301. Review. No abstract available. Abstract

2. Weinberger DR, Egan MF, Bertolino A, Callicott JH, Mattay VS, Lipska BK, Berman KF, Goldberg TE. Prefrontal neurons and the genetics of schizophrenia. Biol Psychiatry. 2001 Dec 1;50(11):825-44. Review. Abstract

3. Meyer-Lindenberg A, Miletich RS, Kohn PD, Esposito G, Carson RE, Quarantelli M, Weinberger DR, Berman KF. Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia. Nat Neurosci. 2002 Mar;5(3):267-71. Abstract

4. Tunbridge EM, Bannerman DM, Sharp T, Harrison PJ. Catechol-o-methyltransferase inhibition improves set-shifting performance and elevates stimulated dopamine release in the rat prefrontal cortex. J Neurosci. 2004 Jun 9;24(23):5331-5. Abstract

5. Mattay VS, Goldberg TE, Fera F, Hariri AR, Tessitore A, Egan MF, Kolachana B, Callicott JH, Weinberger DR. Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine. Proc Natl Acad Sci U S A. 2003 May 13;100(10):6186-91. Epub 2003 Apr 25. Abstract

6. Meyer-Lindenberg A, Kohn PD, Kolachana B, Kippenhan S, McInerney-Leo A, Nussbaum R, Weinberger DR, Berman KF. Midbrain dopamine and prefrontal function in humans: interaction and modulation by COMT genotype. Nat Neurosci. 2005 May;8(5):594-6. Epub 2005 Apr 10. Abstract

7. Egan MF, Goldberg TE, Kolachana BS, Callicott JH, Mazzanti CM, Straub RE, Goldman D, Weinberger DR. Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6917-22. Epub 2001 May 29. Abstract

8. Nicodemus KK, Kolachana BS, Vakkalanka R, Straub RE, Giegling I, Egan MF, Rujescu D, Weinberger DR. Evidence for statistical epistasis between catechol-O-methyltransferase (COMT) and polymorphisms in RGS4, G72 (DAOA), GRM3, and DISC1: influence on risk of schizophrenia. Hum Genet. 2007 Feb;120(6):889-906. Epub 2006 Sep 28. Abstract

9. Gothelf D, Eliez S, Thompson T, Hinard C, Penniman L, Feinstein C, Kwon H, Jin S, Jo B, Antonarakis SE, Morris MA, Reiss AL. COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome. Nat Neurosci. 2005 Nov;8(11):1500-2. Epub 2005 Oct 23. Abstract

10. Meyer-Lindenberg A, Nichols T, Callicott JH, Ding J, Kolachana B, Buckholtz J, Mattay VS, Egan M, Weinberger DR. Impact of complex genetic variation in COMT on human brain function. Mol Psychiatry. 2006 Sep;11(9):867-77, 797. Epub 2006 Jun 20. Abstract

11. Williams GV, Goldman-Rakic PS. Modulation of memory fields by dopamine D1 receptors in prefrontal cortex. Nature. 1995 Aug 17;376(6541):572-5. Abstract

12. Callicott JH, Bertolino A, Mattay VS, Langheim FJ, Duyn J, Coppola R, Goldberg TE, Weinberger DR. Physiological dysfunction of the dorsolateral prefrontal cortex in schizophrenia revisited. Cereb Cortex. 2000 Nov;10(11):1078-92. Abstract

View all comments by Andreas Meyer-Lindenberg

Related News: The New "Inverted U”—Cellular Basis for Dopamine Response Pinpointed

Comment by:  Terry Goldberg
Submitted 6 April 2007
Posted 6 April 2007

In this landmark study, Arnsten and colleagues used a full dopamine agonist in awake behaving monkeys to make key points about the inverted U response at the cellular level and how this maps to the behavioral level. There were a number of surprises. The first was that stimulation of the D1 receptor had consistently suppressive effects on neuronal firing during delays in a working memory task. The second was that when responses were optimized, suppressive effects differentially affected non-preferred directional neurons, rather than preferred direction neurons. Thus, it appeared that noise was reduced rather than signal amplified. Too much D1 stimulation resulted in suppression of both classes of neurons.

The implications of this work are important because it suggests that there is a neurobiological algorithm at work that can reliably produce this unexpected physiological pattern (perhaps as the authors suggest on the basis of baseline activity). It remains to be elucidated whether the D1 receptor effects are mediated by glutamatergic neurons or GABA interneurons, or both. There is another layer of complexity to the story. As Arnsten and colleagues note, possible excitatory influences of D1 stimulation may not have been observed because endogenous dopamine had already triggered this process. It is unclear if D2 receptors in the cortex have a role in shaping or terminating this activity.

Last, it is tempting to speculate about the implications of these findings for other types of tasks that engage prefrontal cortex in humans. What does tuning mean in the context of tasks like the N Back which demands updating, the ID/ED test from the CANTAB, which involves suppression of salient distractors at early set shifting stages, or a task which demands heavy doses of cognitive control like the flanker task, all of which have been shown to be sensitive to manipulations of the dopamine system (Goldberg et al., 2003; Jazbec et al., 2007; Diaz-Asper et al., in press; Blasi et al., 2005)?

View all comments by Terry Goldberg

Related News: Polymorphisms and Schizophrenia—The Ups and Downs of Neuregulin Expression

Comment by:  Patricia Estani
Submitted 9 June 2007
Posted 10 June 2007
  I recommend the Primary Papers

Related News: Model of Schizophrenia Cortical Deficits Reversed With Antioxidants

Comment by:  Barbara K. Lipska
Submitted 21 August 2014
Posted 22 August 2014

This is a highly original and exciting paper demonstrating that juvenile antioxidant treatment can be effective in preventing a number of severe deficits in the neonatal hippocampal lesion model of schizophrenia. The authors chose an unusual approach to reversing and preventing behavioral, electrophysiological, and neurochemical changes described in many previous papers as characteristic of this animal model as well as human schizophrenia (Lipska et al., 1993; Lipska and Weinberger, 2000; Tseng et al., 2009). First, they showed that the neonatal excitotoxic lesion of the hippocampus results in oxidative stress in the prefrontal cortex early in development, perhaps caused by the loss of projections from the ventral hippocampus to the prefrontal cortex during a critical period in development. Second, they were able to prevent a number of abnormalities that mimic certain aspects of human schizophrenia by treating presymptomatic animals with several classes of antioxidant drugs. These drugs have the potential to be effective in humans and offer a much needed alternative to the current therapeutic treatment of schizophrenia.

Early intervention in people at risk for schizophrenia has been at the forefront of research in recent years due to the increased emphasis in society on mental illness, but few realistic, effective, and safe solutions have been found. Breaking the vicious circle of the developmental trajectory and preventing long-term disability accompanying this illness are of utmost importance and have been well recognized (see, e.g., Lieberman et al., 2013). The results of the study by Cabungcal et al. may bring us closer to finding a better way of treatment but require a lot more work to be done. For instance, would we know whom to pretreat? How does smoking factor into the oxidative stress, and contribute or interact with these new potential medications? Are antioxidants proposed as the sole solution, or would they be considered additives to more traditional therapies? Are they really safe and effective in humans? We will be impatiently waiting for research addressing these questions.

References:

Lipska BK, Jaskiw GE, Weinberger DR. Postpubertal emergence of hyperresponsiveness to stress and to amphetamine after neonatal excitotoxic hippocampal damage: a potential animal model of schizophrenia. Neuropsychopharmacology . 1993 Aug ; 9(1):67-75. Abstract

Lipska BK, Weinberger DR. To model a psychiatric disorder in animals: schizophrenia as a reality test. Neuropsychopharmacology . 2000 Sep ; 23(3):223-39. Abstract

Tseng KY, Chambers RA, Lipska BK. The neonatal ventral hippocampal lesion as a heuristic neurodevelopmental model of schizophrenia. Behav Brain Res . 2009 Dec 7 ; 204(2):295-305. Abstract

Lieberman JA, Dixon LB, Goldman HH. Early detection and intervention in schizophrenia: a new therapeutic model. JAMA . 2013 Aug 21 ; 310(7):689-90. Abstract

View all comments by Barbara K. Lipska