- Email: [email protected]
S.11.04 Mood disorder, electroconvulsive therapy and glial cells
S.12 Pharmacogenetics and schizophrenia
$332
These monoamines are known to play a major role in affective disorders and in the action of antidepressant drugs. Studies in rat have shown that galanin given i.c.v, is a potent inhibitor of mesencephalic 5-HT neurotransmission, as indicated by a long-lasting reduction in 5-HT release in the hippocampus. This inhibitory effect was related to activation of galanin receptors located on dorsal raphe neurons. Moreover, i.c.v, galanin reduced the gene expression of 5-HT 1A autoreceptors in the DRN and also changed their functional activity. In addition, galanin produced a functional desensitization of postsynaptic 5-HT1A-receptor mediated responses. Both pharmacological and genetic studies suggest a role for galanin in depression-like behavior in rodents. Transgenic mice overexpressing galanin under the PDGF-promotor, displayed increased immobility in the forced swim test, similar to mice that were given galanin i.c.v. The increase in depression-like behavior was fully blocked by the unspecific galanin receptor antagonist M35. These results indicate an important inhibitory role of galanin as a regulator of brain 5-HT and 5-HT1A-receptor mediated transmission in a manner of potential importance for depressive states and the action of antidepressant drugs. Since the action of galanin is mediated by three different receptor subtypes with different functional properties, ongoing studies aim to identify the galanin receptor subtypes involved in mechanisms for depression.
References [1] H6kfelt, T., Xu, Z.Q., Shi, T.J., Holmberg, K., Zhang, X., 1998. Galanin in ascending systems. Focus on coexistence with 5-hydroxytwptamine and noradrenaline. Ann NY Acad Sci 863, 259263. [2] Kehr, J., Yoshitake, T., Wang, EH., Razani, H., Gimenez-Llort, L., Jansson, A., Yamaguchi, M., Ogren, S.O., 2002. Galanin is a potent in vivo modulator of mesencephalic serotonergic neurotransmission. Neuropsychopharmacology 27, 341 356. [3] Kuteeva, E., H6kfelt, T., 0gren, S.O., 2005. Behavioural characterisation of young adult transgenic mice overexpressing galanin under the PDGF-B promoter. Regul Pept 125, 67 78.
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Hypothalamic-Pituitary-Adrenal (HPA) axis and hippocampal neurogenesis in mice
L. Lanfumey 1 *, E. Paizanis 1, M. Melfort 1, C. Joubert 2, N. Barden 3, M. Hamon 1 . ]INSERM-UPMC, UMR 677, Paris
Cedex 13, France; eCNRS, UMR 7593, France; 3University of Laval, Anatomy and Physiology, Canada Numerous factors regulate granule cell precursor proliferation (GCPP) in adult brain. Thus, high glucocorticoid levels, resulting from hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, exert a negative influence that may account for the marked reduction in GCPP caused by stress. Since HPA axis activity is under feed back control mediated by glucocorticoid receptors (GR), we investigated whether GCPP was affected in mice with geneticor epigenetic-induced alterations in GR expression/activity. The first experimental model was a transgenic mouse partially depleted ( 5 0 % ) in brain GR (GR-i mice, 1), and the second one consisted of wild type (WT) mice which underwent chronic mild stress (CMS, 2) sessions that also lead to GR down-regulation [3]. GCPP was identified by the incorporation of bromodeoxyuridine (BrdU) visualized with immunocytochemical techniques. Labelled cells were counted within the subgranular zone (SGZ) of the dentate gyrus in 9 10 week-old male mice. GCPP was significantly decreased ( 4 0 % ) in GR-i mutants compared to WT. In contrast, a 3-week-CMS session, which doubled serum corticosterone levels, induced a 30% increase in GCPP in the ventral dentate gyrus of WT mice. However, also in WT mice, a 45 min restraint stress reduced BrdU labeling ( 2 5 % ) in the same area. Our data showed that deficiency in GR-mediated negative feed back control of HPA axis was associated with a decreased neurogenesis in GR-i mice. In WT mice, tonic mild HPA axis activation (CMS) promoted, while acute strong HPA axis stimulation reduced neurogenesis. These results further emphasize that complex relationships exist between HPA tone and SGZ neurogenesis.
References ~Mood
disorder, electroconvulsive therapy and glial cells
A. Tingstr6m*. Lurid University, Molecular Psychiatty Unit,
Lurid, Sweden Glial pathology, and in some areas (amygdala and prefrontal cortex) specifically a reduction in oligodendrocyte numbers [1,2], has been observed in post mortem studies of patients with a history of mood disorder. Oligodendrocyte progenitors, termed NG2-positive glial cells, constitute a major part of all proliferating glial cells in the adult brain. We have previously shown that electroconvulsive seizures, clinically used for treating severe depressions, stimulate the proliferation of NG2-positive glial cells in the hippocampus and amygdala of adult rats [3,4], and others have reported similar changes in the rat prefrontal cortex [5]. It has also been shown that high levels of glucocorticoids, a frequent finding in depressive disorder, block proliferation of NG2-positive glial cells [6].
References [1] [2] [3] [4] [5] [6]
Hamidi et al, Biol Psychiatry. 2004 Mar 15; 55(6): 563 9. Uranova et al, Schizophr Res. 2004 Apt 1; 67(2 3): 269 75. Wennstrom et al, Biol Psychiatry. 2003 Nov 15; 54(10): 1015 24. Wennstrom et al, Biol Psychiatry. 2004 Mar 1; 55(5): 464 71. Madsen et al, Neuropsychopharmacology. 2005 Jan; 30(1): 27 34. Alonso G. Glia. 2000 Sep; 31(3): 219 31.
[1] Pepin M.C., Pothier F., Barden N., 1992. Impaired type II glucocorticoid-receptor function in mice bearing antisense RNA transgene. Nature 355:725 728. [2] Pardon M.C., P&ez-Diaz E, Joubert C., Cohen-Salmon C., 2000. Influence of chronic ultramild stress procedure on decision-making in mice. J Psychiatry Neurosci 25:167 177. [3] Froger N., Palazzo E., Boni C., Hanoun N., Saurini E, Joubert C., Dutriez-Casteloot I., Enache M., Maccari S., Barden N., Cohen-Salmon C., Hamon M., Lanfumey L., 2004. Neurochemical and behavioral alterations in glucocorticoid receptor-impaired transgenic mice after chronic mild stress. J Neurosci 11:27872796.
S.12 Pharmacogenetics and schizophrenia ~
Genes and subtypes of schizophrenia
S.C. Bakker 1 *, M.L.C. Hoogendoorn 2, J-P.C.J. Selten 2, R.J. Sinke 3, R.S. Kahn 2. ]University Medical Centre Utrecht,
Department of Psychiatty, HP A01.126, Utrecht, The Netherlands; : University Medical Center Utrecht, Dept. of Psychiatty, The Netherlands; 3 University Medical Center Utrecht, Dept. of Biomedical Genetics, The Netherlands Several putative schizophrenia susceptibility genes have recently been reported, with replication of the findings in different populations [1]. Although these results are very encouraging, the
$332
These monoamines are known to play a major role in affective disorders and in the action of antidepressant drugs. Studies in rat have shown that galanin given i.c.v, is a potent inhibitor of mesencephalic 5-HT neurotransmission, as indicated by a long-lasting reduction in 5-HT release in the hippocampus. This inhibitory effect was related to activation of galanin receptors located on dorsal raphe neurons. Moreover, i.c.v, galanin reduced the gene expression of 5-HT 1A autoreceptors in the DRN and also changed their functional activity. In addition, galanin produced a functional desensitization of postsynaptic 5-HT1A-receptor mediated responses. Both pharmacological and genetic studies suggest a role for galanin in depression-like behavior in rodents. Transgenic mice overexpressing galanin under the PDGF-promotor, displayed increased immobility in the forced swim test, similar to mice that were given galanin i.c.v. The increase in depression-like behavior was fully blocked by the unspecific galanin receptor antagonist M35. These results indicate an important inhibitory role of galanin as a regulator of brain 5-HT and 5-HT1A-receptor mediated transmission in a manner of potential importance for depressive states and the action of antidepressant drugs. Since the action of galanin is mediated by three different receptor subtypes with different functional properties, ongoing studies aim to identify the galanin receptor subtypes involved in mechanisms for depression.
References [1] H6kfelt, T., Xu, Z.Q., Shi, T.J., Holmberg, K., Zhang, X., 1998. Galanin in ascending systems. Focus on coexistence with 5-hydroxytwptamine and noradrenaline. Ann NY Acad Sci 863, 259263. [2] Kehr, J., Yoshitake, T., Wang, EH., Razani, H., Gimenez-Llort, L., Jansson, A., Yamaguchi, M., Ogren, S.O., 2002. Galanin is a potent in vivo modulator of mesencephalic serotonergic neurotransmission. Neuropsychopharmacology 27, 341 356. [3] Kuteeva, E., H6kfelt, T., 0gren, S.O., 2005. Behavioural characterisation of young adult transgenic mice overexpressing galanin under the PDGF-B promoter. Regul Pept 125, 67 78.
•
Hypothalamic-Pituitary-Adrenal (HPA) axis and hippocampal neurogenesis in mice
L. Lanfumey 1 *, E. Paizanis 1, M. Melfort 1, C. Joubert 2, N. Barden 3, M. Hamon 1 . ]INSERM-UPMC, UMR 677, Paris
Cedex 13, France; eCNRS, UMR 7593, France; 3University of Laval, Anatomy and Physiology, Canada Numerous factors regulate granule cell precursor proliferation (GCPP) in adult brain. Thus, high glucocorticoid levels, resulting from hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, exert a negative influence that may account for the marked reduction in GCPP caused by stress. Since HPA axis activity is under feed back control mediated by glucocorticoid receptors (GR), we investigated whether GCPP was affected in mice with geneticor epigenetic-induced alterations in GR expression/activity. The first experimental model was a transgenic mouse partially depleted ( 5 0 % ) in brain GR (GR-i mice, 1), and the second one consisted of wild type (WT) mice which underwent chronic mild stress (CMS, 2) sessions that also lead to GR down-regulation [3]. GCPP was identified by the incorporation of bromodeoxyuridine (BrdU) visualized with immunocytochemical techniques. Labelled cells were counted within the subgranular zone (SGZ) of the dentate gyrus in 9 10 week-old male mice. GCPP was significantly decreased ( 4 0 % ) in GR-i mutants compared to WT. In contrast, a 3-week-CMS session, which doubled serum corticosterone levels, induced a 30% increase in GCPP in the ventral dentate gyrus of WT mice. However, also in WT mice, a 45 min restraint stress reduced BrdU labeling ( 2 5 % ) in the same area. Our data showed that deficiency in GR-mediated negative feed back control of HPA axis was associated with a decreased neurogenesis in GR-i mice. In WT mice, tonic mild HPA axis activation (CMS) promoted, while acute strong HPA axis stimulation reduced neurogenesis. These results further emphasize that complex relationships exist between HPA tone and SGZ neurogenesis.
References ~Mood
disorder, electroconvulsive therapy and glial cells
A. Tingstr6m*. Lurid University, Molecular Psychiatty Unit,
Lurid, Sweden Glial pathology, and in some areas (amygdala and prefrontal cortex) specifically a reduction in oligodendrocyte numbers [1,2], has been observed in post mortem studies of patients with a history of mood disorder. Oligodendrocyte progenitors, termed NG2-positive glial cells, constitute a major part of all proliferating glial cells in the adult brain. We have previously shown that electroconvulsive seizures, clinically used for treating severe depressions, stimulate the proliferation of NG2-positive glial cells in the hippocampus and amygdala of adult rats [3,4], and others have reported similar changes in the rat prefrontal cortex [5]. It has also been shown that high levels of glucocorticoids, a frequent finding in depressive disorder, block proliferation of NG2-positive glial cells [6].
References [1] [2] [3] [4] [5] [6]
Hamidi et al, Biol Psychiatry. 2004 Mar 15; 55(6): 563 9. Uranova et al, Schizophr Res. 2004 Apt 1; 67(2 3): 269 75. Wennstrom et al, Biol Psychiatry. 2003 Nov 15; 54(10): 1015 24. Wennstrom et al, Biol Psychiatry. 2004 Mar 1; 55(5): 464 71. Madsen et al, Neuropsychopharmacology. 2005 Jan; 30(1): 27 34. Alonso G. Glia. 2000 Sep; 31(3): 219 31.
[1] Pepin M.C., Pothier F., Barden N., 1992. Impaired type II glucocorticoid-receptor function in mice bearing antisense RNA transgene. Nature 355:725 728. [2] Pardon M.C., P&ez-Diaz E, Joubert C., Cohen-Salmon C., 2000. Influence of chronic ultramild stress procedure on decision-making in mice. J Psychiatry Neurosci 25:167 177. [3] Froger N., Palazzo E., Boni C., Hanoun N., Saurini E, Joubert C., Dutriez-Casteloot I., Enache M., Maccari S., Barden N., Cohen-Salmon C., Hamon M., Lanfumey L., 2004. Neurochemical and behavioral alterations in glucocorticoid receptor-impaired transgenic mice after chronic mild stress. J Neurosci 11:27872796.
S.12 Pharmacogenetics and schizophrenia ~
Genes and subtypes of schizophrenia
S.C. Bakker 1 *, M.L.C. Hoogendoorn 2, J-P.C.J. Selten 2, R.J. Sinke 3, R.S. Kahn 2. ]University Medical Centre Utrecht,
Department of Psychiatty, HP A01.126, Utrecht, The Netherlands; : University Medical Center Utrecht, Dept. of Psychiatty, The Netherlands; 3 University Medical Center Utrecht, Dept. of Biomedical Genetics, The Netherlands Several putative schizophrenia susceptibility genes have recently been reported, with replication of the findings in different populations [1]. Although these results are very encouraging, the