- Email: [email protected]
184. The expanding world of ataxias
Friday Abstracts
disorders. In order to increase our understanding for the role of these neuronal systems to the elaboration of physiological or pathophysiological conditions we have used a genetic approach in the mouse by creating animals in which the gene for certain key components of these neurotransmitter systems have been deleted or suppressed by homologous recombination. The dopamine transporter (DAT) calibrates the intensity and duration of dopaminergic transmission in the brain by rapidly recycling dopamine (DA) back into presynaptic terminals. Deletion of the DAT gene (DATKO) leads to a pronounced hyperdopaminergic state due to the fact that DA spends 300 times longer in the extracellular space of the DATKO mice than their wild type littermates. Absence of DAT also results in major changes in the homeostatic control of DA transmission both pre- and post-synaptically. Interestingly, DATKO mice are hyperactive especially when exposed to a novel environment. Additionally, these mice are impaired in spacial cognitive processes. DATKO mice show a marked decrease in locomotion in response to psychostimulants such as, cocaine, amphetamime and methylphenidate and this effect depends on enhanced serotoninergic transmission. The parallels that can be drawn between the phenotypic properties of the DATKO mice and certain symptoms and drug responses of individuals with attention deficit hyperactivity disorder raises the possibility that common mechanisms might underlie the pharmacological actions of psychostimulants if not their phenotypes. DATKO mice also recapitulate the characteristics of the amphetamine model of psychosis in the rodent in that they display marked hyperactivity, stereotypy and impaired sensory motor gating. The DATKO mice should be useful in elucidating the contribution of the various neurotransmitter systems to these behaviors. Several lines of investigations have implicated NMDA receptors in the pathology of psychosis but the hypothesis has not been genetically tested. We recently reported (Mohn et al Cell 98, 427, 1999) the generation of a mouse line that has been genetically altered to express 5 to 10 percent of the normal levels of NR1, an essential subunit of the NMDA receptor. These mice display behavioral abnormalities that are consistent with other pharmacological models of schizophrenia (PCP and MK801 intoxication). NR1 deficient mice display increased locomotion and stereotypy as well as deficits in social behaviors similar to those elicited by PCP and MK801. Phenotypes associated with the NR1 deficient mice are more effectively ameliorated by the atypical antipsychotic clozapine then its typical counterpart haloperidol. The phenotypes of the NR1 deficient mice as well as their responses to antipsychotics are observed without any demonstrable changes in the homeostasis of DA in these animals. These results demonstrate in genetically defined animals that pharmacological manipulation of a presumably normal neurotransmitter (DA or serotonin) pathway can correct the phenotypic consequences of alterations in another pathway (glutamate). Studies in this animal model support the hypothesis that dysfunction of glutamatergic transmission may underlie some forms of schizophrenia and reveal the contribution of monoaminergic systems in this paradigm.
182. NARCOLEPSY AND HYPOCRETINS (OREXINS) E. Mignot
BIOL PSYCHIATRY 2000;47:1S–173S
55S
We have determined that canine narcolepsy is caused by disruption of a G protein-coupled receptor gene, the hypocretin (orexin) receptor 2 gene (Hcrtr2) in three canine breeds. New developments also indicate that human narcolepsy is not associated with frequent hypocretin gene mutations but that most patients have undetectable hypocretin-1 levels in the cerebrospinal fluid. These results identify hypocretins as major sleep modulating neurotransmitters and opens novel potential therapeutic approaches for narcoleptic patients and other sleep disorders.
183. MOUSE MODELS OF HUNTINGTON’S DISEASE C.A. Ross Johns Hopkins University School of Medicine Huntington’s disease is an autosomal dominant progressive neurodegenerative disorder involving abnormalities of movement (both involuntary and voluntary), cognitive decline, and emotional disturbances. It is caused by an expanding CAG repeat coding for polyglutamine in the huntingtin gene on chromosome 4, and is a memeber of the family of polyglutamine diseases, all involving progressive neuronal degeneration. Mouse models for several of these disorders have been made in the past few years. Data will be presented from the mouse models of Huntington’s disease and the related disorder, DRPLA, made by our group in collaboration with the group of David Borchelt. The mice show a progressive phenotype involving incoordination, involuntary movements, weight loss, and eventually death. At post-mortem examination, the mice have intranuclear inclusions (which are characteristic of polyglutamine disorders) and evidence of neuronal degeneration. Several other mouse models of polyglutamine diseases have been created using different techniques. The models reproduce different features of the disease. It is important to examine each model critically to determine what aspects of the disease it best reproduces. Mouse models can be powerful tools for understanding the pathogenesis of neuropsychiatric diseases, and for developing experimental therapeutics.
PRESIDENTIAL INVITED LECTURE The Expanding World of Ataxias Friday, May 12, 11:15 AM–12:00 PM Location: Regency A & B Speaker: Stefan Pulst
Stanford University School of Medicine Narcolepsy is a disabling sleep disorder affecting 1 in 2,000 individuals. It is characterized by excessive daytime sleepiness, cataplexy and striking abnormal transitions from wakefulness into REM sleep. Current treatment strategies involve monoaminergic drugs such as amphetaminelike stimulants and antidepressants. Human narcolepsy is HLA associated multigenic and environmentally influenced. We have used a positional cloning strategy to identify narcolepsy mutations in a canine model with autosomal recessive transmission. Linkage analysis in canine backcrosses, Fluorescence In Situ Hybridization (FISH), the building of a genomic canine. Bacterial Artificial Chromosome (BAC) library and homology mapping experiments between human chromosome 6 and canine chromosome 12 were instrumental to the success of this project.
184. THE EXPANDING WORLD OF ATAXIAS S.M. Pulst Cedars Sinai Medical Center, Los Angeles, CA 90048 The classification and phenotypic definitions of the inherited ataxias have undergone a significant change in the last decade. A phenotype-based classification has been largely replaced by a system based on the genotype. The genes for several dominant ataxias have been identified.
56S
Friday Abstracts
BIOL PSYCHIATRY 2000;47:1S–173S
The predominant mutational mechanism is based on expansion of CAG DNA trinucleotide repeats leading to extended glutamine repeat (polyQ) tracts at the protein level. Except for the mutation in SCA6, which occurs in the CACN1A4 calcium channel, the SCA proteins (ataxins) are novel proteins of unknown function. SCA4, 5, 10, and 11 have been mapped by genetic linkage analysis, but the genes have not yet been identified. SCA8 is caused by expansion of a CTG repeat in a transcript that does not appear to code for a protein. It is possible that the transcript functions as an antisense RNA. SCA12 is caused by expansion of a CAG upstream of the transcription start site of the PPP2R2B gene encoding a brain-specific regulatory subunit of the protein phosphatase PP2A. Animal models using a variety of promoters and cDNA constructs have been generated and recreate aspects of the human disease. In transgenic mouse lines expressing ataxin-1 under the control of the Purkinje cell specific PcP2 promoter intranuclear inclusions are detected in Purkinje cells. However, inclusion body formation was not necessary for pathogenesis, but nuclear location of ataxin-1 was. In contrast, expression of ataxin-2 under control of the PcP2 promoter resulted in cytoplasmic localization of the protein and neuronal degeneration was seen without the formation of intranuclear inclusions. Animal models will be indispensable for the analysis of molecular mechanisms of dysfunction and degeneration in vivo and for the development of novel treatments.
WORKSHOPS Magnetic Stimulation of the Brain: Correlates of Antidepressant Response Friday, May 12, 12:15 PM–2:15 PM Location: Comiskey Chair: Leon Grunhaus
185. MAGNETIC STIMULATION OF THE BRAIN: CORRELATES OF ANTIDEPRESSANT RESPONSE L. Grunhaus (1), S.H. Lisanby (2), M.S. George (3), F. Maeda (4) (1) Sheba Medical Center, Psychiatry Division, Tel Hashomer, Israel 52621; (2) Department of Biological Psychiatry, College of Physicians & Surgeons of Columbia University, New York State Psychiatric Institute, New York; (3) Departments of Psychiatry, Radiology, and Neurology, The Medical University of South Carolina; Ralph H. Johnson Veterans Affairs Hospital, Charleston; (4) Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215 Transcranial Magnetic Stimulation (TMS) was introduced in 1986 as a method for non-invasibly stimulating the central nervous system. In recent years TMS has developed into a tool for exploring neurophysiological and neuropsychological function, and also as a treatment modality in neuropsychiatry. The effects of TMS vary depending upon technical aspects like frequency and power of stimulation, type and location of the stimulating coil, and the underlying neurophysiological state of the patient. Thus, in TMS a unique environment is created in which researchers can study and elucidate important questions regarding CNS function. Patients with major depression have been those most extensively studied with TMS. In this workshop we will discuss recent findings regarding the effects of TMS in patients with major depression
and will also discuss new understandings regarding the neurobiology of depression as evidenced through TMS. The first speaker, Holly Lisanby, an established researcher in the field of ECT, will discuss her findings regarding the effects of ECT on cortical excitability as studied with TMS. In her report she will discuss unique data regarding magnetic motor threshold, paired-pulse stimulation, and silent periods, and how they are affected by ECT. Interestingly, her findings support a gabaergic hypothesis for ECT actions. Mark George, one of the pioneering figures in the field of TMS in neuropsychiatry will discuss his findings regarding cerebral blood flow and the effects of TMS in depressed individuals. We shall learn that cerebral perfussion changes are associated with response to rTMS and that older individuals may need to have the stimulation power of TMS increased due to age-related changes in cortical thickness. Fumiko Maeda from the group of Pascual Leone will discuss the interesting and developing area of cortical excitability and response to TMS in depressed patients. Their findings suggest that careful studies of cortical excitability may be useful in the prediction of treatment response in depression and that neurophysiological abnormality maybe modified by effective treatment. Finally, Leon Grunhaus will discuss his replication study comparing ECT and rTMS. These authors have previously published their results suggesting that ECT and rTMS are comparable in patients with major depression. Preliminary analysis of their replication study supports the findings presented in their original report. In addition the authors will discuss issues relating cortical output maps and response to TMS. During this workshop participants will be allowed ample time for discussion of both technical and clinical issues regarding TMS.
Molecular Genetics of Substance Abuse: Analyzing Complex Traits Friday, May 12, 12:15 PM–2:15 PM Location: Acapulco Chair: David Goldman Co-Chair: Rebekah S. Rasooly
186. MOLECULAR GENETICS OF SUBSTANCE ABUSE: ANALYZING COMPLEX TRAITS D. Goldman (1), M.T. Tsuang (2), J.A. Knowles (3), T.B. Friedman (4) (1) Laboratory of Neurogenetics, NIAAA, Rockville, MD; (2) Harvard University, Boston, MA; (3) New York Psychiatric Institute, New York, NY; (4) Laboratory of Molecular Genetics, NIDCD, Rockville, MD Dramatic advances in molecular genetics represent both a challenge and a promise for understanding substance abuse. Evidence from adoption and twin studies suggest that a person’s vulnerability to becoming addicted to drugs has a moderate to high heritable component. The challenge for the molecular genetics of drug addiction, like many other biobehavioral disorders, is that they are complex disorders of hereogeneous origins, and they lack a simple pattern of Mondelian inheritance. Multiple genes with relatively small effects are likely to influence vulnerability to addiction, and there may be no simple correspondence between the phenotype, as currently defined, and the genotype. Dr. Tsuang will discuss his use of twin studies to identify substance abuse
disorders. In order to increase our understanding for the role of these neuronal systems to the elaboration of physiological or pathophysiological conditions we have used a genetic approach in the mouse by creating animals in which the gene for certain key components of these neurotransmitter systems have been deleted or suppressed by homologous recombination. The dopamine transporter (DAT) calibrates the intensity and duration of dopaminergic transmission in the brain by rapidly recycling dopamine (DA) back into presynaptic terminals. Deletion of the DAT gene (DATKO) leads to a pronounced hyperdopaminergic state due to the fact that DA spends 300 times longer in the extracellular space of the DATKO mice than their wild type littermates. Absence of DAT also results in major changes in the homeostatic control of DA transmission both pre- and post-synaptically. Interestingly, DATKO mice are hyperactive especially when exposed to a novel environment. Additionally, these mice are impaired in spacial cognitive processes. DATKO mice show a marked decrease in locomotion in response to psychostimulants such as, cocaine, amphetamime and methylphenidate and this effect depends on enhanced serotoninergic transmission. The parallels that can be drawn between the phenotypic properties of the DATKO mice and certain symptoms and drug responses of individuals with attention deficit hyperactivity disorder raises the possibility that common mechanisms might underlie the pharmacological actions of psychostimulants if not their phenotypes. DATKO mice also recapitulate the characteristics of the amphetamine model of psychosis in the rodent in that they display marked hyperactivity, stereotypy and impaired sensory motor gating. The DATKO mice should be useful in elucidating the contribution of the various neurotransmitter systems to these behaviors. Several lines of investigations have implicated NMDA receptors in the pathology of psychosis but the hypothesis has not been genetically tested. We recently reported (Mohn et al Cell 98, 427, 1999) the generation of a mouse line that has been genetically altered to express 5 to 10 percent of the normal levels of NR1, an essential subunit of the NMDA receptor. These mice display behavioral abnormalities that are consistent with other pharmacological models of schizophrenia (PCP and MK801 intoxication). NR1 deficient mice display increased locomotion and stereotypy as well as deficits in social behaviors similar to those elicited by PCP and MK801. Phenotypes associated with the NR1 deficient mice are more effectively ameliorated by the atypical antipsychotic clozapine then its typical counterpart haloperidol. The phenotypes of the NR1 deficient mice as well as their responses to antipsychotics are observed without any demonstrable changes in the homeostasis of DA in these animals. These results demonstrate in genetically defined animals that pharmacological manipulation of a presumably normal neurotransmitter (DA or serotonin) pathway can correct the phenotypic consequences of alterations in another pathway (glutamate). Studies in this animal model support the hypothesis that dysfunction of glutamatergic transmission may underlie some forms of schizophrenia and reveal the contribution of monoaminergic systems in this paradigm.
182. NARCOLEPSY AND HYPOCRETINS (OREXINS) E. Mignot
BIOL PSYCHIATRY 2000;47:1S–173S
55S
We have determined that canine narcolepsy is caused by disruption of a G protein-coupled receptor gene, the hypocretin (orexin) receptor 2 gene (Hcrtr2) in three canine breeds. New developments also indicate that human narcolepsy is not associated with frequent hypocretin gene mutations but that most patients have undetectable hypocretin-1 levels in the cerebrospinal fluid. These results identify hypocretins as major sleep modulating neurotransmitters and opens novel potential therapeutic approaches for narcoleptic patients and other sleep disorders.
183. MOUSE MODELS OF HUNTINGTON’S DISEASE C.A. Ross Johns Hopkins University School of Medicine Huntington’s disease is an autosomal dominant progressive neurodegenerative disorder involving abnormalities of movement (both involuntary and voluntary), cognitive decline, and emotional disturbances. It is caused by an expanding CAG repeat coding for polyglutamine in the huntingtin gene on chromosome 4, and is a memeber of the family of polyglutamine diseases, all involving progressive neuronal degeneration. Mouse models for several of these disorders have been made in the past few years. Data will be presented from the mouse models of Huntington’s disease and the related disorder, DRPLA, made by our group in collaboration with the group of David Borchelt. The mice show a progressive phenotype involving incoordination, involuntary movements, weight loss, and eventually death. At post-mortem examination, the mice have intranuclear inclusions (which are characteristic of polyglutamine disorders) and evidence of neuronal degeneration. Several other mouse models of polyglutamine diseases have been created using different techniques. The models reproduce different features of the disease. It is important to examine each model critically to determine what aspects of the disease it best reproduces. Mouse models can be powerful tools for understanding the pathogenesis of neuropsychiatric diseases, and for developing experimental therapeutics.
PRESIDENTIAL INVITED LECTURE The Expanding World of Ataxias Friday, May 12, 11:15 AM–12:00 PM Location: Regency A & B Speaker: Stefan Pulst
Stanford University School of Medicine Narcolepsy is a disabling sleep disorder affecting 1 in 2,000 individuals. It is characterized by excessive daytime sleepiness, cataplexy and striking abnormal transitions from wakefulness into REM sleep. Current treatment strategies involve monoaminergic drugs such as amphetaminelike stimulants and antidepressants. Human narcolepsy is HLA associated multigenic and environmentally influenced. We have used a positional cloning strategy to identify narcolepsy mutations in a canine model with autosomal recessive transmission. Linkage analysis in canine backcrosses, Fluorescence In Situ Hybridization (FISH), the building of a genomic canine. Bacterial Artificial Chromosome (BAC) library and homology mapping experiments between human chromosome 6 and canine chromosome 12 were instrumental to the success of this project.
184. THE EXPANDING WORLD OF ATAXIAS S.M. Pulst Cedars Sinai Medical Center, Los Angeles, CA 90048 The classification and phenotypic definitions of the inherited ataxias have undergone a significant change in the last decade. A phenotype-based classification has been largely replaced by a system based on the genotype. The genes for several dominant ataxias have been identified.
56S
Friday Abstracts
BIOL PSYCHIATRY 2000;47:1S–173S
The predominant mutational mechanism is based on expansion of CAG DNA trinucleotide repeats leading to extended glutamine repeat (polyQ) tracts at the protein level. Except for the mutation in SCA6, which occurs in the CACN1A4 calcium channel, the SCA proteins (ataxins) are novel proteins of unknown function. SCA4, 5, 10, and 11 have been mapped by genetic linkage analysis, but the genes have not yet been identified. SCA8 is caused by expansion of a CTG repeat in a transcript that does not appear to code for a protein. It is possible that the transcript functions as an antisense RNA. SCA12 is caused by expansion of a CAG upstream of the transcription start site of the PPP2R2B gene encoding a brain-specific regulatory subunit of the protein phosphatase PP2A. Animal models using a variety of promoters and cDNA constructs have been generated and recreate aspects of the human disease. In transgenic mouse lines expressing ataxin-1 under the control of the Purkinje cell specific PcP2 promoter intranuclear inclusions are detected in Purkinje cells. However, inclusion body formation was not necessary for pathogenesis, but nuclear location of ataxin-1 was. In contrast, expression of ataxin-2 under control of the PcP2 promoter resulted in cytoplasmic localization of the protein and neuronal degeneration was seen without the formation of intranuclear inclusions. Animal models will be indispensable for the analysis of molecular mechanisms of dysfunction and degeneration in vivo and for the development of novel treatments.
WORKSHOPS Magnetic Stimulation of the Brain: Correlates of Antidepressant Response Friday, May 12, 12:15 PM–2:15 PM Location: Comiskey Chair: Leon Grunhaus
185. MAGNETIC STIMULATION OF THE BRAIN: CORRELATES OF ANTIDEPRESSANT RESPONSE L. Grunhaus (1), S.H. Lisanby (2), M.S. George (3), F. Maeda (4) (1) Sheba Medical Center, Psychiatry Division, Tel Hashomer, Israel 52621; (2) Department of Biological Psychiatry, College of Physicians & Surgeons of Columbia University, New York State Psychiatric Institute, New York; (3) Departments of Psychiatry, Radiology, and Neurology, The Medical University of South Carolina; Ralph H. Johnson Veterans Affairs Hospital, Charleston; (4) Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215 Transcranial Magnetic Stimulation (TMS) was introduced in 1986 as a method for non-invasibly stimulating the central nervous system. In recent years TMS has developed into a tool for exploring neurophysiological and neuropsychological function, and also as a treatment modality in neuropsychiatry. The effects of TMS vary depending upon technical aspects like frequency and power of stimulation, type and location of the stimulating coil, and the underlying neurophysiological state of the patient. Thus, in TMS a unique environment is created in which researchers can study and elucidate important questions regarding CNS function. Patients with major depression have been those most extensively studied with TMS. In this workshop we will discuss recent findings regarding the effects of TMS in patients with major depression
and will also discuss new understandings regarding the neurobiology of depression as evidenced through TMS. The first speaker, Holly Lisanby, an established researcher in the field of ECT, will discuss her findings regarding the effects of ECT on cortical excitability as studied with TMS. In her report she will discuss unique data regarding magnetic motor threshold, paired-pulse stimulation, and silent periods, and how they are affected by ECT. Interestingly, her findings support a gabaergic hypothesis for ECT actions. Mark George, one of the pioneering figures in the field of TMS in neuropsychiatry will discuss his findings regarding cerebral blood flow and the effects of TMS in depressed individuals. We shall learn that cerebral perfussion changes are associated with response to rTMS and that older individuals may need to have the stimulation power of TMS increased due to age-related changes in cortical thickness. Fumiko Maeda from the group of Pascual Leone will discuss the interesting and developing area of cortical excitability and response to TMS in depressed patients. Their findings suggest that careful studies of cortical excitability may be useful in the prediction of treatment response in depression and that neurophysiological abnormality maybe modified by effective treatment. Finally, Leon Grunhaus will discuss his replication study comparing ECT and rTMS. These authors have previously published their results suggesting that ECT and rTMS are comparable in patients with major depression. Preliminary analysis of their replication study supports the findings presented in their original report. In addition the authors will discuss issues relating cortical output maps and response to TMS. During this workshop participants will be allowed ample time for discussion of both technical and clinical issues regarding TMS.
Molecular Genetics of Substance Abuse: Analyzing Complex Traits Friday, May 12, 12:15 PM–2:15 PM Location: Acapulco Chair: David Goldman Co-Chair: Rebekah S. Rasooly
186. MOLECULAR GENETICS OF SUBSTANCE ABUSE: ANALYZING COMPLEX TRAITS D. Goldman (1), M.T. Tsuang (2), J.A. Knowles (3), T.B. Friedman (4) (1) Laboratory of Neurogenetics, NIAAA, Rockville, MD; (2) Harvard University, Boston, MA; (3) New York Psychiatric Institute, New York, NY; (4) Laboratory of Molecular Genetics, NIDCD, Rockville, MD Dramatic advances in molecular genetics represent both a challenge and a promise for understanding substance abuse. Evidence from adoption and twin studies suggest that a person’s vulnerability to becoming addicted to drugs has a moderate to high heritable component. The challenge for the molecular genetics of drug addiction, like many other biobehavioral disorders, is that they are complex disorders of hereogeneous origins, and they lack a simple pattern of Mondelian inheritance. Multiple genes with relatively small effects are likely to influence vulnerability to addiction, and there may be no simple correspondence between the phenotype, as currently defined, and the genotype. Dr. Tsuang will discuss his use of twin studies to identify substance abuse