Advancing Drug Discovery for Schizophrenia

Agenda

*Presentation times are subject to change.

Abstracts

Genetic and Epigenetic Approaches to Studying Schizophrenia

Patrick F. Sullivan, MD, The University of North Carolina at Chapel Hill

In the past two years, there has been substantial progress in uncovering the genetic basis of schizophrenia. Results to date are notable in the novelty of findings and relatively poor correspondence to prior ideas about the etiology of schizophrenia. The purpose of this talk is to review these findings and to discuss the technological advancements that are fueling discovery as the role of genetic and epigenetic variation in the genesis of schizophrenia becomes more clear. 

Genetic Architecture of Psychotic Illness

Edward Scolnick, MD, The Broad Institute of Massachusetts Institute of Technology and Harvard University

Large whole genome association studies have identified loci associated with risk for schizophrenia and bipolar illness, exome sequencing studies have also been carried out.  Results will be presented with implications for new approaches for drug discovery and diagnosis

What Can We Learn From Animal Models of Schizophrenia?

Eric J. Nestler, MD, PhD, Mount Sinai Medical Center New York

Progress in understanding the etiology and pathophysiology of schizophrenia has been frustratingly slow, as has the discovery of significant, novel therapeutic mechanisms. The exceedingly challenging neurobiology of higher brain function, and the ethical and practical difficulties of examining the living human brain, have no doubt contributed to this relatively slow progress. Another important factor is the extremely challenging nature of modeling schizophrenia in laboratory animals. This is due to the inaccessibility, in animals, of many of the key symptoms of schizophrenia, the subjective nature of the symptoms, the lack of objective biomarkers, and the early state of knowledge of the underlying genetics and neurobiology of the syndrome. What we have learned from genetic studies of schizophrenia thus far is especially complicating vis a vis animal models, because most genes of relatively strong effect that have been implicated in schizophrenia are also implicated in bipolar disorder and even autism, while it is questionable what can be learned from placing genes of very small effect into laboratory animals. Indeed, most available animal models of schizophrenia have significant limitations, ranging from weak validation to poor predictive power for drug efficacy in humans. The generation of convincing and useful animal models of schizophrenia thus represents a major set of challenges that will not have easy answers. On the other hand, given current limitations of clinical studies, it is hard to imagine significant progress in schizophrenia pathophysiology or therapeutics without good animal models.

KCNH2 3.1: A Novel Therapeutic Target for Psychosis

Daniel Weinberger, MD, National Institute of Mental Health

The discovery of genes associated with risk for schizophrenia holds promise to identify  therapeutic targets based on etiopathogenesis.  We recently reported association with schizophrenia to the Herg family potassium channel gene, KCNH2 (Huffaker et al Nature Medicine 2009).  Risk associated variants predict expression of a novel, brain and primate specific isoform, KCNH2 3.1, which has unique physiologic properties and is upregulated in schizophrenia prefrontal and hippocampal cortices. Because many antipsychotic drugs bind to KCNH2 channels, accounting for QT prolongation, and atypical agents such as clozapine are particularly potent KCNH2 inhibitors, we hypothesized that activity at KCNH2 channels may be a therapeutic mechanism of antipsychotic drugs and that targeting the 3.1 isoform not expressed in heart would have a particularly favorable therapeutic to toxic ratio.  We have tested the first hypothesis in two independent samples of patients who underwent placebo controlled studies of antipsychotic therapy, including an inpatient sample from the CBDB/NIMH experimental therapeutics unit (n=59) and Caucasian subjects treated with olanzapine as part of the CATIE trial from whom we also had drug clearance data (total N = 89).  In both groups, KCNH2 genotype predicted response to treatment (e.g. positive symptoms p<.0007, thought disturbance p<.0004 in the CBDB sample, positive symptoms p<.04 in CATIE).  We are testing the second hypothesis in human and model cell lines that over express KNCH2 3.1.and also in a mouse model that over expresses KCNH2 3.1 in cortex and that shows predicted abnormalities in k+ channel kinetics and in working memory.  

Linking DNA Structural Variation to Brain Dysfunction and Schizophrenia

Maria Karayiorgou, MD, Columbia University Medical Center 

Structural variation in the genome in the form of copy-number variants (submicroscopic gains or losses of segments of DNA) has now been identified as a major cause for schizophrenia. One such copy-number variant is on chromosome 22q11.2. Recent studies are beginning to paint a clear and consistent picture of the impairments in psychological and cognitive competencies that are associated with microdeletions in chromosome 22q11.2. Parallel studies in humans and animal models are starting to uncover the complex genetic and neural substrates altered by this microdeletion. In addition to offering a deeper understanding of the effects of this genetic lesion, these findings may guide analysis of other copy-number variants associated with psychiatric disorders.           

Targeting the Neuro-Epigenome in the Prevention and Treatment of Psychosis

Alessandro Guidotti, MD, University of Illinois at Chicago

Schizophrenia (SZ) and bipolar disorder (BP) patients show a downregulation of GAD₆₇, reelin, and other genes expressed in telencephalic GABAergic neurons, likely associated with promoter hypermethylation mediated by an overexpression of DNA methyltransferase (DNMT) (Guidotti et al. 2009,TIPS 30:55). The inhibitory action of DNMT on gene expression may also occur through formation of chromatin repressor complexes that include histone deacetylases (HDAC) or histone methyltransferases, thereby shifting chromatin from a conformation permissive for transcription to one that is repressive.

A pharmacological strategy to induce a permissive chromatin conformation and reduce the hypermethylation of GABAergic promoters is to administer drugs, such as the HDAC inhibitor valproate (VPA), which induces DNA-demethylation when administered at doses that facilitate chromatin remodeling.

Our studies in mice suggest that when associated with VPA, clinically relevant doses of clozapine elicit a synergistic potentiation of VPA-induced GABAergic promoter demethylation. Olanzapine and quetiapine (two clozapine congeners) also facilitate chromatin remodeling but at doses higher than used clinically, whereas haloperidol and risperidone are inactive. Hence, the synergistic potentiation of VPA's action on chromatin remodeling by clozapine appears to be a unique property of the dibenzepines and is independent of their action on catecholamine or serotonin receptors.

By activating DNA-demethylation, the association of clozapine or its derivatives with VPA or other more potent and selective HDAC inhibitors may be considered a promising prevention and treatment strategy to normalize the GABAergic promoter hypermethylation and GABAergic gene expression downregulation detected in the postmortem brain of SZ and BP patients.

Advanced Paternal Age Alters Complex Behaviors and Brain DNA Methylation in Offspring

Jay Gingrich, MD, PhD, Columbia University Medical Center

Male fertility requires ongoing cell division of spermatogonia in the testes throughout life.  At each cell division, genetic and epigenetic information must be preserved in the strands of newly synthesized DNA to maintain stability of the germline. Failure to maintain the fidelity of information contained within the genome of spermatogonia can have a substantial impact on offspring health.  For example, with advancing paternal age de novo genetic mutations in the sperm are causative of achondroplasia, Crouzon, Pfeiffer, and other single-gene, autosomal dominant disorders in offspring. Advanced paternal age (APA) also contributes substantially to the risk of several genetically complex neuropsychiatric disorders such as autism spectrum disorders(ASD), schizophrenia (SZ), and bipolar disorder (BD) but at rates 100-1000-fold higher than seen in spontaneous single gene mutations. The mechanism by which APA confers vulnerability to complex neuropsychiatric disorders remains unknown.  Here we show that offspring of advanced age mouse sires exhibit significant behavioral differences from control offspring produced by young sires. We further show that brain DNA methylation patterns of old father offspring (OFO) differ significantly from the young father offspring (YFO) at specific genomic features. We conclude that advanced paternal age is associated with the accumulation of epimutations in the paternal germline that are then passed stochastically to their offspring. These differences in brain DNA methylation provide a likely mechanism to explain the influence of advanced paternal age on the risk of offspring neurobehavioral abnormalities. 

Neuronal Epigenome Mapping in Developing and Diseased Prefrontal Cortex

Schahram Akbarian, MD, PhD, University of Massachusetts

Little is known about epigenetic regulators of gene expression, including DNA methylation and post-translational histone modifications, in schizophrenia and related disease, including autism. Here, we study the genome-wide distribution of histone H3-trimethyl-lysine 4 (H3K4me3), a mark associated with transcription start sites and CpG rich sequences, in prefrontal cortex (PFC) of subjects diagnosed with schizophrenia or autism, in comparison to controls collected across a wide age range from pre/perinatal period to 70 years. In total, more than 2 billion base pairs were sequenced from immunoprecipitates of neuronal chromatin. Subjects with schizophrenia or autism showed no evidence for a disruption of the developmental transition of H3K4me3 landscapes that defined the normal PFC during early infancy. We identified 'epigenetic risk' loci with robust disease-associated H3K4me3 changes in variable subsets of cases, often in conjunction with highly abnormal expression of the corresponding transcript(s), affecting multiple genes regulating synaptic connectivity, social behaviors and cognition. Therefore, alterations in chromatin structures of prefrontal neurons could contribute to the neurobiology of some cases on the psychosis and autism spectrum, warranting further exploration of the underlying genetic and epigenetic risk architectures.

Development of Novel Antipsychotic Drugs: New Approaches to Old Problems

Jeffrey Lieberman, MD, Columbia University Medical Center

Dopamine D2 receptor antagonism is a unifying property of all antipsychotic drugs in use for schizophrenia. While often effective at ameliorating psychosis, these drugs are largely ineffective at treating negative and cognitive symptoms, can produce serious side effects involving different organ systems. For years psychiatric researchers and pharmaceutical companies have intensively sought to develop mechanistically novel antipsychotic drugs based on targets other than dopamine receptors. Development strategies have focused on precedented targets and mechanisms (D-2, D-3 and 5-HT2A antagonism); novel mechanisms (partial agonism, functional selectivity); and novel targets (glutamatergic, cholinergic, GABAergic) including intracellular signaling mechanisms (AKT, GSK). In addition, increasing attention is being focused on the complex genetics of the illness and the signaling pathways implicated in its pathophysiology. This presentation will review the limitations of existing therapeutic agents and development strategies including several of the major genetic findings that identify signaling pathways representing potential targets for novel pharmacological intervention (genes in the 22q11 locus, DISC1, Neuregulin1/ErbB4, and components of the Akt/GSK-3 pathway).

Allosteric Modulators of Metabotropic Glutamate Receptor 5 for Treatment of Schizophrenia

P. Jeffrey Conn, PhD, Vanderbilt University Medical Center 

A large number of cellular and behavioral studies suggest that selective agonists of the metabotropic glutamate receptor (mGluR) mGluR5 could provide a novel approach to treatment of schizophrenia.   Unfortunately, it has been difficult to develop compounds that act as selective orthosteric agonists of mGluR5 that have properties that are likely to be suitable for development of therapeutic agents.  We have been highly successful in developing a novel approach to activation of these receptors by developing highly selective allosteric potentiators of mGluR5.  These compounds do not activate the GPCR directly but dramatically potentiate the response of these receptors to the endogenous agonist.  These allosteric potentiators offer high selectivity for the targeted receptor and provide an exciting new approach to development of novel selective activators of mGluR5 and other GPCR subtypes.  In vivo studies reveal that these compounds have robust effects in animal models that have been used to predict efficacy of novel antipsychotic agents.   In addition, mGluR5 PAMs enhance multiple forms of synaptic plasticity in the CNS and have cognition-enhancing effects in animal models.  These studies provide an exciting new approach to discovery of novel highly selective activators of specific GPCR subtypes for treatment of schizophrenia and other CNS disorders.  In addition, recent advances in discovery of a broad range of mGluR5 modulators with different functional profiles is allowing development of a more complete understanding of the properties of individual mGluR5 PAMs that may be most suitable for development of novel therapeutic agents.

Chemical Genomic Studies of DISC1/GSK3-Mediated Signaling in Neuropsychiatric Disorders

Stephen Haggarty, PhD, Harvard Medical School

There exists a critical need to gain insight into the underlying etiology and pathophysiology of schizophrenia and other neuropsychiatric disorders in order to advance the development of new types of targeted therapeutic interventions. Recent studies of the Disrupted in Schizophrenia 1 (DISC1) gene, which is disrupted by a balanced chromosomal translocation in a Scottish family with a high incidence of schizophrenia, major depression, and bipolar disorder, have revealed a key role for DISC1-mediated signaling in diverse aspects of neuroplasticity. One of the direct binding targets of DISC1 is the multifunctional serine/threonine kinase GSK3, which is known to play a key role in the regulation of neurogenesis and synaptic function. GSK3 has also been shown to be inhibited in vivo by the mood stabilizer lithium and antipsychotics. On the basis of these findings, as well as emerging human genetic studies implicating other components of the GSK3 signaling pathway in the etiology of schizophrenia, we have begun using chemical genomic approaches to identify small-molecule probes that target known and novel components of DISC1/GSK3 signaling.

Using pharmacological and viral-mediated gene expression to modulate AKT kinase activity, we have demonstrated a key role for AKT kinase activity in determining the cellular and mood-related behavioral effects of lithium. In contrast, selective and direct GSK3 inhibition by an ATP-competitive, highly selective, brain penetrant, GSK3 inhibitor (CHIR-99021) was found to bypass the requirement for AKT activation. In order to try to develop pathway selective inhibitors of GSK3, and to develop small-molecule probes that enable the selective targeting of individual DISC1 domains, we have used small-molecule microarray screening to measure the interaction of DISC1 variants in a high-throughput manner. Finally, efforts to use induced pluripotent stem cell-derived human neurons for high-throughput screening of DISC1/GSK3 signaling using genetically accurate cell models will be presented. 

Collectively, these studies will enable a better understanding of the role of DISC1/GSK3 in regulating signaling pathways implicated in schizophrenia, as well as potentially lead to improved treatments.

Targeting the PI3K/AKT Pathway: Novel Therapeutic Options for Schizophrenia

Amanda J. Law, PhD, National Institute of Mental Health 

Neuregulin 1 (NRG1) and ErbB4, critical neurodevelopmental genes, are implicated in schizophrenia, but the mediating mechanisms are unknown. We tested the hypothesis that aberrant PI3K/AKT signaling represents a pathogenic consequence of schizophrenia-associated genetic variation in ErbB4 and that pharmacological manipulation of this pathway may represent a novel therapeutic avenue for the treatment of psychosis. We have used a translational neuroscience approach, incorporating patient-derived lymphoblastoid B cells, molecular genetics, human brain mRNA expression profiling and pharmacological studies in rodents to test this hypothesis. Our results pinpoint a genetically regulated pathway associated with schizophrenia and with ErbB4 genetic risk variation involving upregulation of a PI3K-linked ErbB4 receptor CYT-1 and of the phosphoinositide 3-kinase, p110δ (PIK3CD). In human lymphoblastoid cells, NRG1-mediated phosphatidyl-inositol,3,4,5triphosphate [PI(3,4,5)P3] production and cell migration is associated with ErbB4 risk genotype and PIK3CD levels, and is impaired in patients with schizophrenia. In human brain, the association of ErbB4 genotype and PIK3CD expression is maintained and antipsychotic drug administration downregulates PIK3CD expression, implicating p110δ as a therapeutic target. Specific inhibition of p110δ using a small molecule inhibitor blocks the effects of amphetamine in a mouse pharmacological model of psychosis. Our data provide novel insight into how ErbB4 may contribute to schizophrenia, reveal a previously unidentified link between NRG1-ErbB4 and p110δ; and suggest that p110δ merits further consideration as a molecular target for rationally designed drugs for the treatment of psychiatric disorders.

Evaluation of Potent, Selective and Peripherally Available Kynurenine Aminotransferase II (KAT II) Inhibitors for the Treatment of Cognitive Deficits in Schizophrenia

Brian Campbell, PhD, Pfizer

Kynurenic acid (KYNA) is a biologically active by-product of tryptophan metabolism which is reported to act as an endogenous antagonist of NMDA receptors, and may also interfere with nicotinic a7 receptor function. Since KYNA levels are elevated in schizophrenic patients, it has been hypothesized that this may contribute to cognitive deficits observed in schizophrenia. Though inhibitors of kynurenine aminotransferase II (KAT II), the primary enzyme involved in brain KYNA synthesis, have been proposed as a target to treat symptom domains in schizophrenia, research into this hypothesis has been hampered by lack of potent, selective, and brain penetrant tools. We report here the discovery and pharmacological characterization of a new class of KAT II inhibitors with nanomolar potency, >1000-fold selectivity over other kynurenine pathway enzymes, and excellent brain penetration. Systemic administration rapidly decreased KYNA by as much as 80% in brain dialysates in a dose-dependent manner. In addition, profiling of these compounds through a range of animal models relevant for domains of schizophrenia revealed efficacy in models of working memory in both rodents and non-human primates, and also in a rat model of attention (sustained attention task). Furthermore they showed activity in an anhedonia model (chronic mild stress) which may suggest therapeutic utility for the negative symptoms of schizophrenia. Interestingly the compounds are inactive in classical models of antipsychotic activity suggesting that KATII inhibitors may be suitable as adjunctive agents, given along with antipsychotics, to treat the cognitive and negative symptoms associated with schizophrenia which are so poorly managed today. 

Large Scale Neuronal Analysis as a Functional Endophenotype for Schizophrenia

Bita Moghaddam, PhD, University of Pittsburgh

In the absence of clear biomarkers in schizophrenia, behavior remains the key endpoint measure for assessing symptom severity in patients and for establishing the validity of animal models of the disorder. Although we have static measures for most forms of affective, perceptual, and cognitive behaviors (e.g., percent correct in a test of working memory), behavior is a dynamic process. Thus, it is increasingly appreciated that a mechanistic understanding of the pathophysiology of schizophrenia is contingent upon (I) a better understanding of the dynamic coordination of neuronal processes that serve the behaviors that are disrupted in schizophrenia and (II) understanding the functional role of implicated genes or epigenetic factors in micro and macro neuronal circuits that subserve this physiology.  In both animal and clinical studies, our traditional phenomenological approach to assessing behaviors, i.e. presence, absence, or correct/incorrect expression of a behavior is being complemented by dynamic measures that assess changes in coordinated neuronal activity during behavior.   In animal studies these measures now involve analysis of multiscale "functional integrations" among discrete or distributed networks that support the temporal organization of behavior.  In this presentation, recent mulitscale electrophysiological approaches for phenotypic characterization of animal models of schizophrenia will be discussed. These data have important implications for establishing translational fingerprints for validating animal models at a physiological level and for testing of novel therapeutic targets.

Translational Neuroscience for Schizophrenia

Akira Sawa, MD, Johns Hopkins University School of Medicine

Mechanistic understanding and identification of state and trait biomarkers for neuropsychiatric disorders have been hampered by difficulties to access CNS tissues in vivo.  Here we will present efforts to develop neurons from biopsied tissues from patients and controls and to utilize them for translational and clinical applications.  These efforts may represent an invaluable contribution to study mental illnesses, as these cells allow dynamic investigations on disease-associated mechanisms, molecular markers associated with disease traits and states.  In the first half, we will present several methodologies to obtain human neurons either by purification from biopsied samples or induction peripheral cells, such as olfactory neurons, neurons derived from induced pluripotent stem cells, and induced neuronal cells (iN cells), and then review the advantages and limitations of each system in comparison with the autopsied brains.  In the second half, we present whole genome molecular profiling studies (gene expression and epigenetic modifications studied by microarray and ChIP-seq, respectively) on olfactory neurons and iPS cells from patients with schizophrenia.  Finally, we will discuss how such human tissue/cell engineering approach is to be combined with studies of animal models to identify the disturbance of neuronal circuitry relevant to schizophrenia.

Behavioral Selectivity of Beta-Arrestin-Dependent Signaling of Dopamine D2 Receptor in the CNS

Marc G. Caron, Duke University Medical Center

In the brain, dopamine is implicated in the control of locomotion, cognition, emotion and affect as well as reward to drugs and natural stimuli. These effects are mediated by a subfamily of G protein-coupled receptors (GPCR-7TM). Based on the unexpected observation that mice lacking the b-arrestin2 gene have markedly diminished locomotor responses to dopamine receptor stimulation, we showed that D2 dopamine receptors (D2R) mediated this effect through the ability of b-arrestin2 to engage the Akt /GSK3 signaling pathway through the scaffolding of a signaling complex of b-arrestin2/Akt/PP2A. A large body of evidence indicates that arrestins normally associated with desensitization of GPCRs can support G protein-independent modes of signaling.  Deregulation of the dopamine system has been suggested for certain symptoms of schizophrenia.  Interestingly, antipsychotics that target many GPCRs are mixed partial/inverse agonists at D2R-G protein activation, but are uniformly antagonists at b-arrestin2-D2R interactions. Genetic deletion of the downstream GSK3b gene in D2R, but not in D1R, expressing medium spiny neurons recapitulates loss of dopamine responsiveness. Thus, the functional selectivity of D2R signaling and the possibility to identify bias ligands for this pathway may provide new approaches for more selective therapies for CNS conditions associated with deregulation of the dopamine system.

The Dopamine D1-D2 Receptor Heteromer: Novel Signaling Complex with Potential Role in Schizophrenia

Susan George, MD, University of Toronto 

We have identified a novel receptor signaling complex composed of dopamine D1 and D2 receptors, which activated rapid intracellular calcium release. The receptors form a heteromer that signals through Gq, phospholipase C and IP3 receptors, in distinct contrast to D1 and D2 homooligomers. We showed the D1-D2 receptor heteromer exists in native cells using confocal FRET between the endogenously expressed receptors in cultured striatal neurons and brain sections in situ. Activation of the D1-D2 heteromer selectively activated a signaling cascade resulting in enhanced phosphorylation of calcium calmodulin kinase IIa and BDNF, responsible for neuronal growth and differentiation. The D1-D2 heteromer was exclusively localized in neurons expressing both dynorphin and enkephalin. The highest concentration of these cell bodies was in nucleus accumbens and globus pallidus, with very low numbers in caudate putamen. The D1-D2 receptor heteromer was sensitized and the agonist detected high affinity state was up-regulated in striatum of amphetamine treated rats and in globus pallidus from brains of individuals who had schizophrenia. Thus we have identified a novel dopamine receptor signaling complex that may have a role in schizophrenia.

The Schizophrenia Risk Gene CAV1 is Both Pro-psychotic and Required for Antipsychotic Drug Activity at 5-HT_2A Serotonin Receptors in vivo

John Allen, PhD, University of North Carolina

Caveolin-1 (Cav-1) is a scaffolding protein important for regulating receptor signaling cascades by partitioning signaling molecules into membrane microdomains.  Disruption of the CAV1 gene has recently been identified as a rare structural variant associated with schizophrenia.  We previously determined that Cav-1 interacts with 5-HT_2A serotonin receptors which are the principal molecular targets for LSD-like hallucinogens and important sites for atypical antipsychotic drug action.  This study investigates the in vivo role of Cav-1 on 5-HT_2A signaling and pharmacology through detailed study of Cav-1 knockout mice. Although Cav-1 knockout mice displayed no baseline behavioral disruptions, Cav-1 knockout mice, similar to schizophrenic individuals, exhibited increased sensitivity to the psychotomimetic NMDA receptor antagonist phencyclidine (PCP).  Thus, PCP disruption of prepulse inhibition (PPI) and PCP-induced mouse locomotor activity were both enhanced by genetic deletion of Cav-1.  Interestingly, genetic deletion of Cav-1 rendered the atypical antipsychotics clozapine and olanzapine and the 5-HT_2A-selective antagonist M100907 ineffective at normalizing PCP-induced disruption of PPI.   We also discovered that genetic deletion of Cav-1 attenuated 5-HT_2A-induced c-Fos and egr-1 expression in mouse frontal cortex and also reduced 5-HT_2A-mediated Ca²⁺ mobilization in primary cortical neuronal cultures.  The behavioral effects of the 5-HT_2A agonist DOI including head twitch responses and disruption of prepulse inhibition (PPI) were attenuated by genetic deletion of Cav-1, indicating that Cav-1 is required for both inverse agonist (i.e. atypical antipsychotic drug) and agonist actions at 5-HT_2A receptors.  This study demonstrates that disruption of gene CAV1 -a rare structural variant associated with schizophrenia- is not only pro-psychotic but also attenuates atypical antipsychotic drug actions. 

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