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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
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