S.24 Rodent models of CNS disorders S213 S.24 Rodent models of CNS disorders S.24.01 Gene–environment interaction in a genetic rat model of depression A. Math´ e 1 ° , A. El Khoury 1 , S.H.M. Gruber 1 , A. Sodergren 1 , P. Jim´ enez 1 , H. Husum 2 , G. Wortwein 3 . 1 Karolinska Institutet, Department of Psychiatry M56 Huddinge, Stockholm, Sweden; 2 H Lundbeck A/S, Psychopharmacology, Copenhagen, Denmark; 3 Rigshospitalet-Copenhagen University, Neuropsychiatry Laboratory, Copenhagen, Denmark Both genes and environment are of importance in pathogenesis of mood disorders. Animal models show that maternal separation (MS) affects behavior and physiology of the offspring leading to adult stress hyper-reactivity and HPA-axis dysfunction. MS has so far been carried out in genetically normal animals, not taking into account the genetic loading. To address this issue, we designed a novel paradigm by superimposing early life trauma onto a genetic model of depression, the FSL and their controls, FRL rats. Converging evidence indicates that neuropeptides, e.g. NPY and CGRP play a role in pathogenesis of mood disorders. NPY is decreased in hippocampus of depression models and CSF of depressed patients. In contrast, CGRP is elevated in CSF from depressed patients and in rat anxiety models. We superimposed MS during postnatal days 2−14 onto FSL and FRL. Following sacrifice, the brains were dissected and neuropeptides assayed. NPY was reduced while CGRP was elevated in FSL hippocampus and frontal cortex. The two peptides correlated negatively in these regions. In hippocampus, MS exacerbated the strain CGRP difference, but had no effect on NPY. MS raised CGRP in amyg- dala of the FRL. Thus, in hippocampus and frontal cortex, brain regions implicated in neurobiology of depression, CGRP and NPY changes were in opposite direction, and CGRP appeared to be more responsive to adverse experience. In conclusion, our findings support the hypothesis that genetic disposition and developmental stress contribute to the susceptibility to depression by exerting selective neuropeptide- and brain region-specific effects on adult neurobiology. References [1] Jim´ enez-Vasquez PA, Diaz-Cabiale Z, Caberlotto L, Bellido I, Over- street D, Fuxe K, Math´ e, AA, 2007, Electroconvulsive stimuli selec- tively affect behavior and neuropeptide Y (NPY) and NPY Y(1) re- ceptor gene expressions in hippocampus and hypothalamus of Flinders Sensitive Line rat model of depression. Eur Neuropsychopharmacol 17, 298. [2] W¨ ortwein G, Husum H, Andersson W, Bolwig TG, Math´ e, AA, 2006, Effects of maternal separation on neuropeptide Y and calcitonin gene- related peptide in “depressed” Flinders Sensitive Line rats: a study of gene–environment interactions. Prog Neuropsychopharmacol Biol Psychiatry 30, 684. [3] Miller JC, Jim´ enez P, Math´ e, AA, 2006, Restraint stress influences AP-1 and CREB DNA-binding activity induced by chronic lithium treatment in the rat frontal cortex and hippocampus. Int J Neuropsycho- pharmacol, Epub ahead of print, October 12, 2006. S.24.02 High and low anxiety rat and mouse models: behaviour and neuropeptides R. Landgraf ° . Max-Planck-Institute of Psychiatry, Neuroendocrinology, Munich, Germany Bidirectionally bred HAB/LAB rats and mice represent inborn extremes in anxiety-related behaviour. The phenotypical char- acterization include stress-coping strategies and neuroendocrine responses upon stressor exposure with HAB animals being hyper- anxious, preferring passive coping, emitting more stressor-induced ultrasonic vocalization calls and showing typical peculiarities of the HPA axis. In most cases, unselected Wistar rats and CD1 mice, respectively, displayed intermediate behaviours. In both HAB/LAB rats and mice, the behavioural phenotype has been found to be correlated with the expression of the neuropeptide vasopressin (AVP) at the level of the hypothalamic PVN. As shown exemplarily in HAB rats and LAB mice, single nucleotide polymorphisms (SNPs) in regulatory structures of the AVP gene underlie AVP-mediated phenotypic phenomena; in HAB rats, a SNP in the promoter of the AVP gene leads to reduced binding of the transcriptional repressor CBF-A, thus causing AVP over- expression and over-release. Conversely, in LAB mice, a SNP in the AVP gene seems to cause an amino acid exchange in the signal peptide, presumably leading to a deficit in AVP likely to underlie the total hypo-anxiety of LAB mice in combination with signs of central diabetes insipidus. Another feature of LAB mice is over- expression of glyoxalase-I [1,2]. The functional characterization of AVP, glyoxalase-I and other candidates in a freely segregating F2 panel will determine their involvement in anxiety beyond that of reliable biomarkers. The further identification of candidate genes and SNPs will not only help to explain inter-individual variation in emotional behaviour, but will also reveal novel targets for anxiolytic interventions. References [1] Kr¨ omer SA, Keßler MS, Milfay D, Birg IN, Bunck M, Czibere L, Pan- huysen M, P¨ utz B, Deussing JM, Holsboer F, Landgraf R, Turck CW, 2005, Identification of glyoxalase-I as a protein marker in a mouse model of extremes in trait anxiety. J Neurosci 25, 4375–4384. [2] Landgraf R, Keßler M, Bunck M, Murgatroyd C, Spengler D, Zim- belmann M, Nußbaumer M, Czibere L, Turck CW, Singewald N, Rujescu D, Frank E, 2007, Candidate genes of anxiety-related behavior in HAB/LAB rats and mice: focus on vasopressin and glyoxalase-I. Neurosci Biobehav Rev 31, 89–102. S.24.03 Models of schizophrenia and early life trauma in rodents B.A. Ellenbroek ° . Evotec AG, Hamburg, Germany Schizophrenia is a complex disorder, in which genetic, early and late environmental factors interact. Many different strategies have been developed to mimic this process in rats or mice. However, so far no model exists in which all the different factors have been combined. In the present paper, I will discuss a number of different approaches, involving both genetic and early environ- mental manipulation in rats. Studies in the D1 mutant rats show that these animals have a reduction in D1 functioning and sub- sequently deficits in cognitive functioning, especially in relation to flexibility. In addition, early maternal deprivation in normal rats leads to a delayed development of the dopaminergic system and a retardation of normal motor development. Although these animals do not show clear deficits in cognitive functioning, they do show deficits in prepulse inhibition that develop after puberty. Finally, attention will be paid to the few studies that investigated the gene ° environment interaction. These data show that early maternal deprivation induced different symptoms depending on the strain of rats. Thus, in both Wistar and Sprague Dawley rats prepulse inhibition is reduced after maternal deprivation, though basal startle is unchanged. In Lewis rats, on the other hand, basal startle is reduced but prepulse inhibition unchanged, whereas neither parameter was affected in Fischer F344 rats.