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Schizophrenia and nicotinic receptors: Gene expression and genetic linkage studies
s130
S.28 Cholinergic nicotinic receptors as drag targets in psychiatry
amyloid neurotoxicity in PC12 cells and that the mechanisms seem to be mediated via nAChRs (Svensson and Nordberg 1998). Parkinson’s disease Cholinergic deficits are seen in brains of patients with Parkinson’s disease. The cholinergic deficits appear to be more pronounced in Parkinsonian patients with dementia than without dementia. The cognitive impairments seen in Parkinson’s disease are considered to reflect impaired function of the prefrontal cortex. Attentional deficits have been suggested to be secondary to disturbances in neuronal pathways involving prefrontal, parietal-basal ganglia and thalamus. Similar to AD Parkinson’s disase is associated with a large loss of high affitity nAChRs in brain. Stimulation of nAChRs with nicotinic agonists may improve attentional functioning in Parkinson’s disease. The exact involvement of nACbR subtypes has however not yet been revealed in the disease although there is suggstions that the a6 subunit may play a role and might provide a useful pharmacological target especially the subunit has been shown to be present in the substantia nigra. Also for Parkinson’s disease compounds that induce neuroprotective effects via interaction with nAChRs are of high therapeutic interest. Schizophrenia Schizophrenia is characterized by psychosis including hallucinations, delusions, apathy but also attentional deficits and cogntive disturbances. The dopamine hypothesis suggest that schizophrenia is due to excess dopamine. Involvement of other transmitter system including the glutamate system is presently discussed. It has been shown that patients with schizophrenia don’t inhibit the PSO auditory-evoked repsonse to a second stimuli. Interestingly, it was recently reported that a defect in auditory response maps to the a7 gene locus on chromosome 15 (see Freedman this symposium). Further characterization of the impairment of nAChRs in schizophrenia has to be performed. Toorette’s syndrome Patients with hyperkinetic motor disorder Tour&e’s syndrome which is characterized by frequent occurrence of motor and verbal tics but also hyperactivity and anxiety have in some few cases been reported to be improved by nicotine treatment. The tinding suggsts that nicotinic agonists treatment might be beneficial in this disease. References
[I] Warpman U, Nordbcrg A. Epibatidine and ABT 418 reveal selective losses [2]
[3]
[4] [5]
of a@2 nicotinic receptors in Alzheimer brains. NeuroReport 1995: 6: 24192423. Warpman U, Friberg L, Gillespie A, Hellstrom-Lindahl E, Zhang X, Nordherg A. Regulation of nicotinic receptor subtypes following chronic nicotinic agonist exposure in Ml0 and SH-SYSY neuroblastoma cells. J Neurochem 1998: 70: 2028-2037. Nordberg A, Lnndqvist H, Hartvig P, Anderson J, Johansson M, HellstriimLindahl E, L.&ngstim B. Imaging of nicotinic and muscarinic receptors in Alzheimer’s disease: effect of tacrine treatment. Dementia and Geriatric Cognitive Disorders 1997: 8: 78884. Svensson AL, Nordbetg A. Tacrineinteracts with an allosteric activator site on a4@2 nAChRs in Ml0 cells. NeuroReport 1996: 7: 2201-2205. Svensson AL, Nordberg A. Tacrine and donepezil attenuate the neurotoxic effect of A$ (25-35) in rat PC12 cells. NemoReport 1998, in press.
(s.28.051 Schizophrenia and nkotinic receptors: Gene expression and genetic linkage studies S. Leonard, C.R. Breese, J. Gault, L. Adler, A. Olincy, M. Lee, R. Freedman. Department of Psychiatry University of Colorado Health Sciences Center and The Department of Vetemns Affairs Medical Cente,: Denver, Colorado, USA
Gene expression and biological function of the neuronal nicotinic acetylcholine receptor gene family have been examined in schizophrenics and subjects with no history of mental illness. Schizophrenia is a relatively common mental illness, affecting more than 1% of the general population worldwide. It presents in early adulthood and is life-long, representing a large burden to both the families and to society. This disease is partially characterized by deficits in the processing of sensory information. We have studied two of these deficits, a failure to filter or gate extraneous auditory stimuli and abnormal eye tracking. Although both of these deficits arc found in about 10% of the population, most all subjects
and neurology
who suffer from schizophrenia exhibit these defects, as do approximately one-half of their first-degree relatives who do not have schizophrenia. These deficits are, thus, inherited in an autosomal dominant manner and represent endophenotypes predisposing the subject to schizophrenia (1) (Leonard et aZ., 1996). The incidence of smoking in the mentally ill is known to be higher (70-90%) than in the normal subjects (20-30%), and is particularly high in schizophrenics (85-90%). Schizophrenics often smoke high tar cigarettes and use multiple forms of tobacco. Nicotine, in the form of gum or cigarettes has been found to normalize both the auditory sensory gating deficit, seen in most affected subjects, as well as their abnormal eye-tracking, suggesting that a nicotinic receptor mechanism is involved in the neuronal pathways regulating the filtering of sensory information (1). Further studies in an animal model of auditory gating, using antagonists of specific nicotinic that only a-bungarotoxin and methyllycaconitine, specific antagonists of the a7 nicotinic receptor, produced a loss of auditory gating similar to that seen in schizophrenics. Fimbria-fomix lesions in the rat that lesion the cholinergic input into the hippocampus, also resulted in a loss of auditory gating. This deficit was normalized by nicotine (1). These pharmacological experiments suggest that a decrease in nicotinic receptor number, and specifically a reduction in a7 nicotinic receptor expression may result in a loss of auditory gating. A mouse strain (DBA) normally exhibits lower levels of [1251]a-bungarotoxin, which binds to the a7 receptor in mammalian tissue. DBA mice have a deficit in gating of auditory stimuli that is normalized by both nicotine and GTS-2 1. The latter is a partial agonist, specific for the a7 nicotinic receptor. Ligand binding studies in human postmortem brain, for both high and low affinity nicotinic receptors, show that expression of more than one type of a subunit may be decreased in schizophrenic subjects. In normal subjects, [3H]-nicotine binding in both hippocampus and thalamus is correlated with the number of cigarettes smoked per day (2). In smokers who had quit for varying periods before death, we found receptor levels in the non-smoking range. In schizophrenics, however, we did not see the same up-regulation in smokers. At every smoking level schizophrenics had fewer high afhnity receptors than control subjects. We had previously shown that binding to [‘25r]-a-bungarotoxin, which identifies the low-a&&y nicotinic receptor, a7, in mammalian brain, was also decreased in schizophrenics (1). These decreases in both high and low affinity nicotinic receptor numbers do not appear to be related to typical neuroleptic medication. We treated rats with nicotine and haloperidol, separately and together, finding that haloperidol did not affect up-regulation of nicotinic receptors by nicotine. A detailed regional study of a7 expression in human postmortem brain indicates that it is expressed in many sensory nuclei, including lateral and medial geniculates, hippocampus and the reticular thalamic nucleus (1). The reticular thalamic nucleus (RTN), a capsular structure surrounding the thalamus, provides the principal inhibitory input into the dorsal area of the thalamus. Localization of a7 receptors appears to be mainly on non-principal cells, but labeling was otten seen on dendrites as well as on cell somata. Genetic evidence also suggests a role for the a7 nicotinic receptor in schizophrenia. The a7 nicotinic receptor subunit maps to human chromosome 15q14. A full genome scan using more than 500 polymorphic markers at a 10 CM resolution, including a polymorphic dinucleotide repeat D15Sl360 that lies within 120 kb of the a7 gene, was run on nine pedigrees with familial schizophrenia in which status of the auditory gating deficit had been determined. Linkage was found with the auditory gating deficit to the D15Sl360 marker near the a7 gene with a lod of 5.3, 0 = 0.0 (3). We have examined linkage of the a7 locus to the schizophrenia phenotype in a second cohort, collected by the NIMH Genetics Initiative, and also find evidence for genetic linkage in this independent sample. These genetic studies complement the biological data supporting the involvement of the a7 receptor in schizophrenia. We have isolated both cDNA (GenBank Accession # U40983) and genomic clones for the human a7 gene (4). The full-length gene has 10 exons and is more than 65 kb in size. The exon/intron borders appear to be conserved across species, as they are identical to those found in the chick. The human a7 promoter is G/C rich and has no TATA box. Consensus sequences for several transcription factor binding
S.28 Cholinergic nicotinic receptors as drug targets in psychiatry and neurology
sites, including SP-1, AP-2, and CREB are present. We have also found the human a7 gene to be partially duplicated (exons 5-10 and intervening introns) on the same chromosome. Although the sequence of the duplicated exons is 99% homologous with that from the full-length
s131
gene, we do not yet know if the introns are duplicated in their entirety. At the 5’-end of the duplicated a7 exons, we found four additional novel exons. The duplicated sequences (exons 5-10) are expressed with these novel exons in human brain (4).
S.28 Cholinergic nicotinic receptors as drag targets in psychiatry
amyloid neurotoxicity in PC12 cells and that the mechanisms seem to be mediated via nAChRs (Svensson and Nordberg 1998). Parkinson’s disease Cholinergic deficits are seen in brains of patients with Parkinson’s disease. The cholinergic deficits appear to be more pronounced in Parkinsonian patients with dementia than without dementia. The cognitive impairments seen in Parkinson’s disease are considered to reflect impaired function of the prefrontal cortex. Attentional deficits have been suggested to be secondary to disturbances in neuronal pathways involving prefrontal, parietal-basal ganglia and thalamus. Similar to AD Parkinson’s disase is associated with a large loss of high affitity nAChRs in brain. Stimulation of nAChRs with nicotinic agonists may improve attentional functioning in Parkinson’s disease. The exact involvement of nACbR subtypes has however not yet been revealed in the disease although there is suggstions that the a6 subunit may play a role and might provide a useful pharmacological target especially the subunit has been shown to be present in the substantia nigra. Also for Parkinson’s disease compounds that induce neuroprotective effects via interaction with nAChRs are of high therapeutic interest. Schizophrenia Schizophrenia is characterized by psychosis including hallucinations, delusions, apathy but also attentional deficits and cogntive disturbances. The dopamine hypothesis suggest that schizophrenia is due to excess dopamine. Involvement of other transmitter system including the glutamate system is presently discussed. It has been shown that patients with schizophrenia don’t inhibit the PSO auditory-evoked repsonse to a second stimuli. Interestingly, it was recently reported that a defect in auditory response maps to the a7 gene locus on chromosome 15 (see Freedman this symposium). Further characterization of the impairment of nAChRs in schizophrenia has to be performed. Toorette’s syndrome Patients with hyperkinetic motor disorder Tour&e’s syndrome which is characterized by frequent occurrence of motor and verbal tics but also hyperactivity and anxiety have in some few cases been reported to be improved by nicotine treatment. The tinding suggsts that nicotinic agonists treatment might be beneficial in this disease. References
[I] Warpman U, Nordbcrg A. Epibatidine and ABT 418 reveal selective losses [2]
[3]
[4] [5]
of a@2 nicotinic receptors in Alzheimer brains. NeuroReport 1995: 6: 24192423. Warpman U, Friberg L, Gillespie A, Hellstrom-Lindahl E, Zhang X, Nordherg A. Regulation of nicotinic receptor subtypes following chronic nicotinic agonist exposure in Ml0 and SH-SYSY neuroblastoma cells. J Neurochem 1998: 70: 2028-2037. Nordberg A, Lnndqvist H, Hartvig P, Anderson J, Johansson M, HellstriimLindahl E, L.&ngstim B. Imaging of nicotinic and muscarinic receptors in Alzheimer’s disease: effect of tacrine treatment. Dementia and Geriatric Cognitive Disorders 1997: 8: 78884. Svensson AL, Nordbetg A. Tacrineinteracts with an allosteric activator site on a4@2 nAChRs in Ml0 cells. NeuroReport 1996: 7: 2201-2205. Svensson AL, Nordberg A. Tacrine and donepezil attenuate the neurotoxic effect of A$ (25-35) in rat PC12 cells. NemoReport 1998, in press.
(s.28.051 Schizophrenia and nkotinic receptors: Gene expression and genetic linkage studies S. Leonard, C.R. Breese, J. Gault, L. Adler, A. Olincy, M. Lee, R. Freedman. Department of Psychiatry University of Colorado Health Sciences Center and The Department of Vetemns Affairs Medical Cente,: Denver, Colorado, USA
Gene expression and biological function of the neuronal nicotinic acetylcholine receptor gene family have been examined in schizophrenics and subjects with no history of mental illness. Schizophrenia is a relatively common mental illness, affecting more than 1% of the general population worldwide. It presents in early adulthood and is life-long, representing a large burden to both the families and to society. This disease is partially characterized by deficits in the processing of sensory information. We have studied two of these deficits, a failure to filter or gate extraneous auditory stimuli and abnormal eye tracking. Although both of these deficits arc found in about 10% of the population, most all subjects
and neurology
who suffer from schizophrenia exhibit these defects, as do approximately one-half of their first-degree relatives who do not have schizophrenia. These deficits are, thus, inherited in an autosomal dominant manner and represent endophenotypes predisposing the subject to schizophrenia (1) (Leonard et aZ., 1996). The incidence of smoking in the mentally ill is known to be higher (70-90%) than in the normal subjects (20-30%), and is particularly high in schizophrenics (85-90%). Schizophrenics often smoke high tar cigarettes and use multiple forms of tobacco. Nicotine, in the form of gum or cigarettes has been found to normalize both the auditory sensory gating deficit, seen in most affected subjects, as well as their abnormal eye-tracking, suggesting that a nicotinic receptor mechanism is involved in the neuronal pathways regulating the filtering of sensory information (1). Further studies in an animal model of auditory gating, using antagonists of specific nicotinic that only a-bungarotoxin and methyllycaconitine, specific antagonists of the a7 nicotinic receptor, produced a loss of auditory gating similar to that seen in schizophrenics. Fimbria-fomix lesions in the rat that lesion the cholinergic input into the hippocampus, also resulted in a loss of auditory gating. This deficit was normalized by nicotine (1). These pharmacological experiments suggest that a decrease in nicotinic receptor number, and specifically a reduction in a7 nicotinic receptor expression may result in a loss of auditory gating. A mouse strain (DBA) normally exhibits lower levels of [1251]a-bungarotoxin, which binds to the a7 receptor in mammalian tissue. DBA mice have a deficit in gating of auditory stimuli that is normalized by both nicotine and GTS-2 1. The latter is a partial agonist, specific for the a7 nicotinic receptor. Ligand binding studies in human postmortem brain, for both high and low affinity nicotinic receptors, show that expression of more than one type of a subunit may be decreased in schizophrenic subjects. In normal subjects, [3H]-nicotine binding in both hippocampus and thalamus is correlated with the number of cigarettes smoked per day (2). In smokers who had quit for varying periods before death, we found receptor levels in the non-smoking range. In schizophrenics, however, we did not see the same up-regulation in smokers. At every smoking level schizophrenics had fewer high afhnity receptors than control subjects. We had previously shown that binding to [‘25r]-a-bungarotoxin, which identifies the low-a&&y nicotinic receptor, a7, in mammalian brain, was also decreased in schizophrenics (1). These decreases in both high and low affinity nicotinic receptor numbers do not appear to be related to typical neuroleptic medication. We treated rats with nicotine and haloperidol, separately and together, finding that haloperidol did not affect up-regulation of nicotinic receptors by nicotine. A detailed regional study of a7 expression in human postmortem brain indicates that it is expressed in many sensory nuclei, including lateral and medial geniculates, hippocampus and the reticular thalamic nucleus (1). The reticular thalamic nucleus (RTN), a capsular structure surrounding the thalamus, provides the principal inhibitory input into the dorsal area of the thalamus. Localization of a7 receptors appears to be mainly on non-principal cells, but labeling was otten seen on dendrites as well as on cell somata. Genetic evidence also suggests a role for the a7 nicotinic receptor in schizophrenia. The a7 nicotinic receptor subunit maps to human chromosome 15q14. A full genome scan using more than 500 polymorphic markers at a 10 CM resolution, including a polymorphic dinucleotide repeat D15Sl360 that lies within 120 kb of the a7 gene, was run on nine pedigrees with familial schizophrenia in which status of the auditory gating deficit had been determined. Linkage was found with the auditory gating deficit to the D15Sl360 marker near the a7 gene with a lod of 5.3, 0 = 0.0 (3). We have examined linkage of the a7 locus to the schizophrenia phenotype in a second cohort, collected by the NIMH Genetics Initiative, and also find evidence for genetic linkage in this independent sample. These genetic studies complement the biological data supporting the involvement of the a7 receptor in schizophrenia. We have isolated both cDNA (GenBank Accession # U40983) and genomic clones for the human a7 gene (4). The full-length gene has 10 exons and is more than 65 kb in size. The exon/intron borders appear to be conserved across species, as they are identical to those found in the chick. The human a7 promoter is G/C rich and has no TATA box. Consensus sequences for several transcription factor binding
S.28 Cholinergic nicotinic receptors as drug targets in psychiatry and neurology
sites, including SP-1, AP-2, and CREB are present. We have also found the human a7 gene to be partially duplicated (exons 5-10 and intervening introns) on the same chromosome. Although the sequence of the duplicated exons is 99% homologous with that from the full-length
s131
gene, we do not yet know if the introns are duplicated in their entirety. At the 5’-end of the duplicated a7 exons, we found four additional novel exons. The duplicated sequences (exons 5-10) are expressed with these novel exons in human brain (4).