RESUMO
BACKGROUND: The tail suspension test (TST) is a mouse screening test for antidepressants. METHODS: An F2 intercross was derived from NMRI and 129S6 inbred strains (n = 747). Mice underwent standardized TST with 2 sessions: (1) baseline and (2) imipramine (30 mg/kg, intraperitoneally) TST. RESULTS: A whole genome scan of this intercross mapped significant basal TST quantitative trait loci (QTL) on chromosomes (chr) 5 (peak 61 cM, Lod 5.7), 12 (peak 43 cM, Lod 5.2), and 18 (peak 51 cM, Lod 3.0). A suggestive QTL on chr 4 (peak 62 cM; Lod 3.1) overlapped regions containing previously mapped QTLs. For TST imipramine response, QTL were mapped on chr 1, 4, and 5. The chromosome 5 locus affected basal TST, antidepressant immobility response, and tail suspension-induced hyperthermia (TSIH) behaviors. An outbred NMRI F2 population provided further evidence for a chr 5 QTL. This chr 5 region harbors a cluster of gamma aminobutyric acid (GABA)-A receptor subunits and the human syntenic region includes chr 4p, 1p11, 12q24, and 22q11.24. A significant TSIH QTL (Tsih1) mapped on chr 4 near the Leptin receptor (Lepr). CONCLUSIONS: These QTL provide potential regions of interest for human genetic studies in stress-diathesis models of psychiatric illness and antidepressant responsiveness.
Assuntos
Antidepressivos/uso terapêutico , Mapeamento Cromossômico , Modelos Animais de Doenças , Elevação dos Membros Posteriores/fisiologia , Locos de Características Quantitativas/genética , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/genética , Animais , Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Cromossomos de Mamíferos/genética , Cruzamentos Genéticos , Febre/genética , Predisposição Genética para Doença/genética , Imipramina/farmacologia , Imipramina/uso terapêutico , Imobilização/fisiologia , Imobilização/psicologia , Imuno-Histoquímica , Injeções Intraperitoneais , Escore Lod , Camundongos , Camundongos Endogâmicos , Receptores de Superfície Celular/genética , Receptores de GABA-A/efeitos dos fármacos , Receptores de GABA-A/genética , Receptores para Leptina , Estresse Psicológico/etiologia , Terminologia como AssuntoRESUMO
Advanced intercross lines (AIL) and interval-specific congenic strains (ISCS) were used to fine map previously coarsely defined quantitative trait loci (QTL) on Chromosomes 1, 10, and 19, influencing behaviors in the open Field (OF) and light-dark (LD) paradigms in mice. F12(A x B) AIL mice (N = 1130) were phenotyped, genotyped, and mapped. The ISCS were studied only in the telomeric Chromosome 10 region of interest, containing the exploratory and excitability QTL1 (Exq1). The Chromosome 10 Exq1 and Chromosome 19 Exq4 loci mapped robustly in the AIL. The most significant QTL findings (2.0 LOD score intervals; peak; LOD score) came from the TD15 and LD transitions traits, yielding estimated intervals of 2.2 cM for Exq1 (71.3-73.5 cM; peak 72.3 cM; LOD 11.9) and 9.0 cM for Exq4 (29.0-38.2 cM; peak 34 cM; LOD 4.2). The replicated QTLs on Chromosome 1 failed to map in this AIL population. The ISCS data confirmed Exq1 loci in general. However, the ISCS data were complex and less definitive for localizing the Exq1 loci. These exploratory and fear-like behaviors result from inheriting "many small things," namely, QTL explaining 2%-7% of the phenotypic variance. These results highlight the challenges of positionally cloning loci of small effect for complex traits. In particular, fine-mapping success may depend on the genetic architecture underlying complex traits.
