GABAERGIC DYSFUNCTION IN SCHIZOPHRENIA: NEW TREATMENT STRATEGIES ON THE HORIZON
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GABA-ERGIC DYSFUNCTION IN SCHIZOPHRENIA: FROM POSTMORTEM STUDIES TO ANIMAL MODELS Karoly Mirnics Vanderbilt University Nashville, TN, USA Nine years have passed since the first postmortem DNA microarray studies of schizophrenia were published, and it appears that this technology has generated several important leads that continue to shape translational neuroscience studies investigating the cellular/molecular bases of schizophrenia. Specifically, independently replicated expression profiling studies of the prefrontal cortex in schizophrenia revealed abnormalities in expression of genes encoding 1) synaptic proteins, 2) proteins related to GABA signaling, 3) immune/chaperone system proteins, 4) metabolic pathway components and 5) oligodendrocyte- related proteins. The GABA-ergic systemic dysfunction is perhaps the most consistently observed deficit associated with schizophrenia. At a molecular level, the PFC of humans with schizophrenia is characterized by an interrelated transcript deficit that consists of downregulation of BDNF, TRKB, GAD67, SST, NPY, PARV, CCK and GABRAD genes, clearly implicating the cortical GABAergic interneuron as a central component of the pathophysiology underlying the disease. Of these, reduction of the transcript encoding glutamic acid decarboxylase 67 kDa (GAD67) is the most robust and consistently replicated finding across different cohorts. GAD67, the critical GABA synthesis enzyme in the brain, is down- regulated in distinct interneuron populations of the human cortex. Each of these affected cell types mediate a different kind of inhibition: 1) a chandelier-cell subpopulation of parvalbumin (PARV)-GAD67 neurons is responsible for regulating the output of projection neurons at the axon initial segment, 2) small basket and Martinotti cells containing GAD67+ CALB+SST(±NPY) are responsible for the inhibition of the distal dendritic tree of pyramidal cells, and 3) GAD67+CALR(±CCK) inter- neurons regulate both the dendritic inputs of pyramidal cells as well as provide input to other GABAergic neurons. To understand the GABA- ergic dysfunction in schizophrenia we must develop animal models that modulate gene expression in a phenotypic and regional fashion. Therefore, we hypothesized that transgenic mouse models directed to cortical downregulation of GAD67 in distinct interneuron subtypes should both mimic the molecular and cellular human postmortem findings in schizophrenia, and have distinct consequences on cortical functioning. To test this hypothesis, we developed a novel BAC-driven transgenic mice system that is capable of cell-type specific transcript downregulation using an endogenous miRNA processing cellular mechanism. We generated several transgenic mice lines with cell-type specific downregulation of GAD67 protein in the NPY+, CCK+ and PV+ interneurons using exon-embedded miRNA. This transgenic approach allowed us rapid, cell type-specific in vivo downregulation of the transcripts of interest (reduction of GAD67 in specific interneuronal subpopulations), avoiding the labor-intensive and resource-demanding generation of conditional knockout animals. These animal models will allow us to gain a critical understanding of the mechanisms underlying cortical inhibition and the anatomical and behavioral consequences of disturbing this network. Furthermore, the mice generated in this proposal may be useful for testing current lead compounds with therapeutic indications for symptoms of schizophrenia, and aid in the knowledge-based development of drugs for this devastating disease. doi:10.1016/j.schres.2010.02.163 GABAERGIC DYSFUNCTION IN SCHIZOPHRENIA: NEW TREATMENT STRATEGIES ON THE HORIZON Alessandro Guidotti, Erbo Dong, Dennis R. Grayson, Erminio Costa University of Illinois at Chicago Chicago, IL, USA Postmortem brain studies of schizophrenia (SZ) and bipolar (BP) disorder patients show a downregulation of glutamic acid decarboxylase-67 (GAD67) and other GABAergic genes (i.e., reelin) in specific populations of telencephalic GABAergic neurons. This downregulation may be caused by an epigenetic repression of GABAergic gene transcription very likely mediated by gene promoter hypermethylation or by an altered high-order chromatin structural remodeling. To correct GABAergic neuron deficits, we propose the following two principal strategies: 1) enhancement of defective GABAergic transmission by drugs active as selective positive allosteric modulators of GABA action at pertinent GABA A receptor subtypes, and 2) use of drugs acting to correct chromatin remodeling abnormalities due to dysregulated epigenetic mechan- isms. Elaborating on the first strategy, one may consider that benzodiazepines, which are devoid of intrinsic activity at GABA A receptors including α1 subunits and act exclusively at GABA A receptors expressing α2, α3, α5 subunit combinations, should counteract the GABAergic signal transduction deficit without eliciting sedation, amnesia, tolerance, or dependence liabilities. Benzodiazepines acting at α1- expressing GABA A receptor subtypes are prescribed for psychotic patients but there are problems related to their sedative action. One benzodiazepine devoid of intrinsic activity at GABA A receptors, including α1 subunits, but acting as a full allosteric modulator at α5 and perhaps also α2 and α 3 subunits, is imidazenil. This drug is anxiolytic and anticonvulsant and moreover, fails to produce sedation or amnesia. Hence, we suggest that a combination of imidazenil with antipsychotics should be considered and eventually tested in the treatment of the GABAergic dysfunction operative in SZ and BP disorders. An alternative strategy to correct the GABAergic neuron deficit in SZ and BP disorder patients may be to use drugs that diminish the DNA-methyltransferase-1 (DNMT1) overexpression typical of these illnesses. One can speculate that a protocol to treat SZ and BP disorders may include inhibitors of DNMTs or nicotine acetylcholine receptor agonists such as A-85380 or varenicline to downregulate the expression of DNMT1. These agonists may be administered with valproate (VPA), which is used to inhibit HDACs and to activate chromatin transcriptional activity of selective GABAergic genes including, for example, GAD 67 . This is probably the reason why VPA is presently prescribed with antipsychotics as an augmentation strategy to treat multiple symptoms of BP and SZ syndromes. The site of action of the antipsychotics is not clear. Recent studies however, suggest that they may act on nuclear chromatin remodeling in GABAergic neurons. Hence, antipsychotic drugs and their coadjuvants (imidazenil, HDAC inhibitors) should be studied in animal experiments to evaluate their putative action on chromatin remodeling and their ability to correct the GABAergic downregulation typical in SZ and BP disorder with psychosis. doi:10.1016/j.schres.2010.02.164 Symposium 30 IMPROVING OVERALL OUTCOMES - EXTENDING CBTP TO COMPLEX PROBLEMS Co-Chairpersons: Til Wykes, Emmanuelle Peters Wednesday,14 April, 2010 - 10:30 am - 12:30 pm Overall Abstract: CBT for psychosis, now commonly called CBTp, was developed to try to reduce the positive symptoms of psychosis in those people whose symptoms seemed medication treatment resistant. Within the confines of this narrow remit the accumulated evidence is of such a high quality that CBTp has been included in treatment guidance both in the UK, Europe and USA. But despite this guidance there are a number of key issues that are as yet unresolved, particularly Abstracts 158
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Transcript of GABAERGIC DYSFUNCTION IN SCHIZOPHRENIA: NEW TREATMENT STRATEGIES ON THE HORIZON
GABA-ERGIC DYSFUNCTION IN SCHIZOPHRENIA:FROM POSTMORTEM STUDIES TO ANIMAL MODELS
Karoly MirnicsVanderbilt University Nashville, TN, USA
Nine years have passed since the first postmortem DNA microarraystudies of schizophrenia were published, and it appears that thistechnologyhas generated several important leads that continue to shapetranslational neuroscience studies investigating the cellular/molecularbases of schizophrenia. Specifically, independently replicated expressionprofiling studies of the prefrontal cortex in schizophrenia revealedabnormalities in expression of genes encoding 1) synaptic proteins, 2)proteins related to GABA signaling, 3) immune/chaperone systemproteins, 4) metabolic pathway components and 5) oligodendrocyte-related proteins. The GABA-ergic systemic dysfunction is perhaps themost consistently observed deficit associated with schizophrenia. At amolecular level, the PFC of humans with schizophrenia is characterizedby an interrelated transcript deficit that consists of downregulation ofBDNF, TRKB, GAD67, SST, NPY, PARV, CCK and GABRAD genes, clearlyimplicating the cortical GABAergic interneuron as a central componentof the pathophysiology underlying the disease. Of these, reduction of thetranscript encoding glutamic acid decarboxylase 67 kDa (GAD67) is themost robust and consistently replicated finding across different cohorts.GAD67, the critical GABA synthesis enzyme in the brain, is down-regulated in distinct interneuron populations of the human cortex. Eachof these affected cell types mediate a different kind of inhibition: 1) achandelier-cell subpopulationof parvalbumin (PARV)-GAD67neurons isresponsible for regulating the output of projection neurons at the axoninitial segment, 2) small basket andMartinotti cells containingGAD67+CALB+SST(±NPY) are responsible for the inhibition of the distaldendritic tree of pyramidal cells, and 3) GAD67+CALR(±CCK) inter-neurons regulate both the dendritic inputs of pyramidal cells as well asprovide input to other GABAergic neurons. To understand the GABA-ergic dysfunction in schizophreniawemust develop animalmodels thatmodulate gene expression in a phenotypic and regional fashion.Therefore, we hypothesized that transgenic mouse models directed tocortical downregulation of GAD67 in distinct interneuron subtypesshould both mimic the molecular and cellular human postmortemfindings in schizophrenia, and have distinct consequences on corticalfunctioning. To test this hypothesis, we developed a novel BAC-driventransgenic mice system that is capable of cell-type specific transcriptdownregulation using an endogenous miRNA processing cellularmechanism. We generated several transgenic mice lines with cell-typespecific downregulation of GAD67 protein in theNPY+, CCK+and PV+interneurons using exon-embedded miRNA. This transgenic approachallowed us rapid, cell type-specific in vivo downregulation of thetranscripts of interest (reduction of GAD67 in specific interneuronalsubpopulations), avoiding the labor-intensive and resource-demandinggeneration of conditional knockout animals. These animal models willallow us to gain a critical understanding of the mechanisms underlyingcortical inhibition and the anatomical and behavioral consequences ofdisturbing this network. Furthermore, the mice generated in thisproposal may be useful for testing current lead compounds withtherapeutic indications for symptoms of schizophrenia, and aid in theknowledge-based development of drugs for this devastating disease.
doi:10.1016/j.schres.2010.02.163
GABAERGIC DYSFUNCTION IN SCHIZOPHRENIA:NEW TREATMENT STRATEGIES ON THE HORIZON
Alessandro Guidotti, Erbo Dong, Dennis R. Grayson, Erminio CostaUniversity of Illinois at Chicago Chicago, IL, USA
Postmortem brain studies of schizophrenia (SZ) and bipolar(BP) disorder patients show a downregulation of glutamic aciddecarboxylase-67 (GAD67) and other GABAergic genes (i.e., reelin)in specific populations of telencephalic GABAergic neurons. Thisdownregulation may be caused by an epigenetic repression ofGABAergic gene transcription very likely mediated by genepromoter hypermethylation or by an altered high-order chromatinstructural remodeling. To correct GABAergic neuron deficits, wepropose the following two principal strategies: 1) enhancement ofdefective GABAergic transmission by drugs active as selectivepositive allosteric modulators of GABA action at pertinent GABAA
receptor subtypes, and 2) use of drugs acting to correct chromatinremodeling abnormalities due to dysregulated epigenetic mechan-isms. Elaborating on the first strategy, one may consider thatbenzodiazepines, which are devoid of intrinsic activity at GABAA
receptors including α1 subunits and act exclusively at GABAA
receptors expressing α2, α3, α5 subunit combinations, shouldcounteract the GABAergic signal transduction deficit withouteliciting sedation, amnesia, tolerance, or dependence liabilities.Benzodiazepines acting at α1- expressing GABAA receptor subtypesare prescribed for psychotic patients but there are problems relatedto their sedative action. One benzodiazepine devoid of intrinsicactivity at GABAA receptors, including α1 subunits, but acting as afull allosteric modulator at α5 and perhaps also α2 and α 3subunits, is imidazenil. This drug is anxiolytic and anticonvulsantand moreover, fails to produce sedation or amnesia. Hence, wesuggest that a combination of imidazenil with antipsychotics shouldbe considered and eventually tested in the treatment of theGABAergic dysfunction operative in SZ and BP disorders. Analternative strategy to correct the GABAergic neuron deficit in SZand BP disorder patients may be to use drugs that diminish theDNA-methyltransferase-1 (DNMT1) overexpression typical of theseillnesses. One can speculate that a protocol to treat SZ and BPdisorders may include inhibitors of DNMTs or nicotine acetylcholinereceptor agonists such as A-85380 or varenicline to downregulatethe expression of DNMT1. These agonists may be administered withvalproate (VPA), which is used to inhibit HDACs and to activatechromatin transcriptional activity of selective GABAergic genesincluding, for example, GAD67. This is probably the reason why VPAis presently prescribed with antipsychotics as an augmentationstrategy to treat multiple symptoms of BP and SZ syndromes. Thesite of action of the antipsychotics is not clear. Recent studieshowever, suggest that they may act on nuclear chromatinremodeling in GABAergic neurons. Hence, antipsychotic drugs andtheir coadjuvants (imidazenil, HDAC inhibitors) should be studiedin animal experiments to evaluate their putative action onchromatin remodeling and their ability to correct the GABAergicdownregulation typical in SZ and BP disorder with psychosis.
doi:10.1016/j.schres.2010.02.164
Symposium 30IMPROVING OVERALL OUTCOMES - EXTENDING CBTP TOCOMPLEX PROBLEMSCo-Chairpersons: Til Wykes, Emmanuelle PetersWednesday, 14 April, 2010 - 10:30 am - 12:30 pm
Overall Abstract: CBT for psychosis, now commonly called CBTp, wasdeveloped to try to reduce the positive symptoms of psychosis in thosepeople whose symptoms seemed medication treatment resistant.Within the confines of this narrow remit the accumulated evidence isof such a high quality that CBTp has been included in treatmentguidance both in the UK, Europe and USA. But despite this guidancethere are a numberof key issues that are as yet unresolved, particularly
Abstracts158
