SEARCH · PubMed Health

Results for “Phenotypic modulation”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 955 records · Page 53Linked to original sources

PubMed1993

Excitatory amino acid regulation of the enkephalin phenotype in mouse embryonic spinal cord cultures.

Expression of the preproenkephalin gene in developing spinal cord-dorsal root ganglia (SC-DRG) cultures was determined by Northern analysis following treatments with different agonists and antagonists of the glutamate receptor. Cultures (10-12 days old) were treated with various concentrations (10(-7)-10(-3) M) of N-methyl-D-aspartate (NMDA), quisqualate, kainic acid (KA), 2-amino-5-phosphonovaleric acid (APV) and 5-methyl-10,11-dihydro-5H-dibenzo[a, d]cyclohepten-5,10-imine maleate (MK801) either with or without blocking spontaneous electrical activity with 1 microM tetrodotoxin (TTX). In electrically active cultures, treatments with NMDA and KA increased preproenkephalin transcripts (mRNAppENK), showing maximum effects at 1 microM (4-fold and 2-fold, respectively), while treatments with quisqualate and MK801 caused concentration-dependent down-regulation in mRNAppENK. The most effective concentrations of NMDA (1 microM) and quisqualate (10 microM) altered mRNAppENK levels within 4 h of treatment and peaked after 24 h for NMDA and 48 h for quisqualate treatment. Co-treatment with APV completely blocked the NMDA-induced rise of mRNAppENK. During electrical blockade, none of the concentrations of NMDA tested showed any effect on enkephalin expression, neither could NMDA pre-treatment prevent the TTX-induced down-regulation of mRNAppENK. Our results indicate that the activity-dependent establishment of the enkephalin phenotype is modulated through the selective activation of the NMDA-glutamate receptor.

Amino Acids↗

PubMed2007

Prolyl-hydroxylase inhibition and HIF activation in osteoblasts promotes an adipocytic phenotype.

Bone is a dynamic environment where cells sense and adapt to changes in nutrient and oxygen availability. Conditions associated with hypoxia in bone are also associated with bone loss. In vitro hypoxia (2% oxygen) alters gene expression in osteoblasts and osteocytes and induces cellular changes including the upregulation of hypoxia inducible factor (HIF) levels. Our studies show that osteoblasts respond to hypoxia (2% oxygen) by enhancing expression of genes associated with adipocyte/lipogenesis phenotype (C/EBPbeta, PPARgamma2, and aP2) and by suppressing expression of genes associated with osteoblast differentiation (alkaline phosphatase, AP). Hypoxia increased HIF protein levels, hypoxic response element (HRE) binding, and HRE-reporter activity. We also demonstrate that prolyl-hydroxylases 2 and 3 (PHD2, PHD3), one of the major factors coordinating HIF degradation under normoxic but not hypoxic conditions, are induced in osteoblasts under hypoxic conditions. To further determine the contribution of PHDs and upregulated HIF activity in modulating osteoblast phenotype, we treated osteoblasts with a PHD inhibitor, dimethyloxaloylglycine (DMOG), and maintained cells under normoxic conditions. Similar to hypoxic conditions, HRE reporter activity was increased and adipogenic gene expression was increased while osteoblastic genes were suppressed. Taken together, our findings indicate a role for PHDs and HIFs in the regulation of osteoblast phenotype.

3T3 Cells↗

PubMed2006

Glycomics approach to structure-function relationships of glycosaminoglycans.

Extracellular modulation of phenotype is an emerging paradigm in this current postgenomics age of molecular and cell biology. Glycosaminoglycans (GAGs) are primary components of the cell surface and the cell-extracellular matrix (ECM) interface. Advances in the technology to analyze GAGs and in whole-organism genetics have led to a dramatic increase in the known important biological role of these complex polysaccharides. Owing to their ubiquitous distribution at the cell-ECM interface, GAGs interact with numerous proteins and modulate their activity, thus impinging on fundamental biological processes such as cell growth and development. Many recent reviews have captured important aspects of GAG structure and biosynthesis, GAG-protein interactions, and GAG biology. GAG research is currently at a stage where there is a need for an integrated systems or glycomics approach, which involves an integration of all of the above concepts to define their structure-function relationships. Focusing on heparin/heparan (HSGAGs) and chondroitin/dermatan sulfate (CSGAGs), this review highlights the important aspects of GAGs and summarizes these aspects in the context of taking a glycomics approach that integrates the different technologies to define structure-function relationships of GAGs.

Animals↗

PubMed1989

Diverse cellular responses elicited from human colon carcinoma cells by transforming growth factor-beta.

We have recently characterized the growth-inhibitory and cellular responses [carcinoembryonic antigen (CEA) secretion, protein secretion, protein expression, fibronectin and laminin synthesis] of the human colon carcinoma MOSER cell line to transforming growth factor-beta (TGF-beta) (Cancer Res., 47: 2950, 1987; 48: 4059, 1988). We have also recently isolated a subline (MOSER R2) from the parental MOSER cells which, unlike the parental line, is relatively resistant to the growth-inhibitory effect of TGF-beta (Biochem. Biophys. Res. Commun., 150: 711, 1988). We now report on the characterization of the cellular responses of this resistant MOSER R2 subline to TGF-beta and compare its responses to that of the highly growth-inhibition-sensitive MOSER cell line. In view of the reported relationship between CEA expression and differentiation in colon cancer and the ability of colon-derived substrata material to modulate the phenotypic properties of colon cancer cells, additional characterization and direct comparison of the effects of TGF-beta on the two cell lines were also performed with respect to (a) cellular expression of CEA and CEA cross-reactive glycoproteins; and (b) colon-derived substrata material. Unlike the growth-inhibition-sensitive MOSER cells, TGF-beta had no effects on fibronectin/laminin synthesis nor on the cellular morphology of the resistant MOSER R2 cells. TGF-beta was also unable to modulate protein secretion and deposition of substrata material by these cells. However, several other responses of the resistant cells to TGF-beta were found to be similar to that of the sensitive MOSER cells. These responses include: (a) a prolonged and stable secretion of CEA; (b) a prolonged and stable induction of elevated cellular expression of CEA and CEA cross-reactive glycoproteins; and (c) enhancement of the expression of three cellular proteins with molecular weights corresponding to 52,000, 48,000, and 42,000. We further report that the differences observed in the responses to TGF-beta in the two cell lines were not due to differences in TGF-beta binding or other receptor parameters such as the expression of distinct TGF-beta receptor subspecies.

Carcinoembryonic Antigen↗

PubMed1995

A hybrid between a resistant and a susceptible strain of mouse alters the pattern of Theiler's murine encephalomyelitis virus-induced white matter disease and favors oligodendrocyte-mediated remyelination.

Theiler's murine encephalomyelitis virus (TMEV) produces a chronic disease in its natural host, the mouse, characterised by primary inflammatory demyelination of the spinal cord. This viral infection is considered a very good model for human MS because the pathogenesis of myelin injury is mediated through the host immune response. Susceptibility and/or resistance to the demyelinating disease depend on multiple genes both in and outside the major histocompatibility complex (MHC). The pathological lesions in animals with different degrees of susceptibility vary in both their severity and in their ability to become remyelinated. In general, animals with intermediate levels of susceptibility show the best potential for remyelination. Most crosses of susceptible animals with resistant strains carrying the H-2b haplotype are resistant with only a couple of exceptions. One such exception is the (SJL/J x C57L/J)F1 hybrid, which is susceptible to the disease. To study whether the resistant genotype of C57L/J mice could modify the phenotypic expression of pathological lesions characteristic of the highly susceptible SJL/J mouse, we performed a light microscopical and ultrastructural study of the spinal cord of both parental strains and their F1 progeny. We focused particularly on the relationship between severity of inflammation, and especially macrophage infiltration, and the subsequent remyelinating potential of lesions. The results show a dramatic difference between the ability to remyelinate lesions by infected SJL/J mice vs similarly infected (SJL/L x C57L/J)F1 hybrids, and suggest an important influence by resistant genes in modulating the phenotypic expression of disease, including the ability to stimulate oligodendroglia-mediated remyelination.

Animals↗

PubMed1999

A novel phenotype in familial Creutzfeldt-Jakob disease: prion protein gene E200K mutation coupled with valine at codon 129 and type 2 protease-resistant prion protein.

A novel phenotype of familial Creutzfeldt-Jakob disease (CJD) with mutated codon 200 of the prion protein gene (PRNP) coupled with the valine codon 129 (E200K-129V haplotype) has two features never observed in subjects carrying the pathogenic mutation coupled with the methionine codon 129 (E200K-129M haplotype): (1) plaque-like prion protein (PrP) deposits in the cerebellum and (2) type 2 protease-resistant prion protein (PrP(res)). This observation further underlines the role of codon 129 on the mutated PRNP allele in modulating the phenotype of familial prion diseases.

Aged↗

PubMed2004

A Theileria annulata DNA binding protein localized to the host cell nucleus alters the phenotype of a bovine macrophage cell line.

The apicomplexan parasite Theileria annulata is the only intracellular eukaryote that is known to induce the proliferation of mammalian cells. However, as the parasite undergoes stage differentiation, host cell proliferation is inhibited, and the leukocyte is eventually destroyed. We have isolated a parasite gene (SuAT1) encoding an AT hook DNA binding polypeptide that has a predicted signal peptide, PEST motifs, nuclear localization signals, and domains which indicate interaction with regulatory components of the higher eukaryotic cell cycle. The polypeptide is localized to the nuclei of macroschizont-infected cells and was detected at significant levels in cells that were undergoing parasite stage differentiation. Transfection of an uninfected transformed bovine macrophage cell line, BoMac, demonstrated that SuAT1 can modulate cellular morphology and alter the expression pattern of a cytoskeletal polypeptide in a manner similar to that found during the infection of leukocytes by the parasite. Our findings indicate that Theileria parasite molecules that are transported to the leukocyte nucleus have the potential to modulate the phenotype of infected cells.

AT-Hook Motifs↗

PubMed2005

Prevalence and significance of mutations in the familial Mediterranean fever gene in patients with Crohn's disease.

The concurrence of Crohn's disease (CD) and familial Mediterranean fever was repeatedly reported. In this study we determined the distribution and contribution of MEFV gene mutations to CD susceptibility and clinical heterogeneity. An Israeli cohort of 209 CD patients (120 men and 89 women) was investigated for mutations in the MEFV gene. A detailed chart review, interview and physical examination were used to determine sociodemographic and clinical characteristics. MEFV and NOD2/CARD15 genotypes were analyzed in all patients and a genotype-phenotype correlation analysis was undertaken. The results of this study do not implicate MEFV mutations as major modifiers in CD. However, the E148Q MEFV variant was associated with susceptibility to perianal disease. More specifically, 19% (9/47) of CD patients with perianal disease carried the E148Q mutation compared to 6.7% (11/162) of CD patients without perianal involvement (OR 3.26, 95% CI 1.2-8.8, P=0.02). Although, for all mutations taken together, the prevalence of MEFV gene mutations among CD patients and controls was similar, the hypothesis that E148Q mutation modulates the phenotypic expression of CD is corroborated by the results of this study and needs to be further evaluated.

Adolescent↗

PubMed1995

An analysis of fetal hemoglobin variation in sickle cell disease: the relative contributions of the X-linked factor, beta-globin haplotypes, alpha-globin gene number, gender, and age.

Five factors have been shown to influence the 20-fold variation of fetal hemoglobin (Hb F) levels in sickle cell anemia (SS): age, sex, the alpha-globin gene number, beta-globin haplotypes, and an X-linked locus that regulates the production of Hb F-containing erythrocytes (F cells), ie, the F-cell production (FCP) locus. To determine the relative importance of these factors, we studied 257 Jamaican SS subjects from a Cohort group identified by newborn screening and from a Sib Pair study. Linear regression analyses showed that each variable, when analyzed alone, had a significant association with Hb F levels (P < .05). Multiple regression analysis, including all variables, showed that the FCP locus is the strongest predictor, accounting for 40% of Hb F variation. beta-Globin haplotypes, alpha-globin genes, and age accounted for less than 10% of the variation. The association between the beta-globin haplotypes and Hb F levels becomes apparent if the influence of the FCP locus is removed by analyzing only individuals with the same FCP phenotype. Thus, the FCP locus is the most important factor identified to date in determining Hb F levels. The variation within each FCP phenotype is modulated by factors associated with the three common beta-globin haplotypes and other as yet unidentified factor(s).

Adolescent↗

PubMed1998

Dual 1,25-dihydroxyvitamin D3 signal response pathways in osteoblasts: cross-talk between genomic and membrane-initiated pathways.

Osteoblasts are key regulatory cells in the control of systemic calcium ion (Ca2+) homeostasis. They, along with cells in the kidney and intestine, function as an integral part of the vitamin D endocrine system. The hormonally active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25[OH]2D3), interacts with osteoblasts at several levels to modulate their phenotype and function. The interactions involve distinct receptor systems that operate on unique time scales. Rapid nongenomic actions (milliseconds to minutes), mediated through membrane receptor systems, do not require protein synthesis and include activation of voltage-sensitive Ca2+ channels, induction of phospholipid and sphingolipid turnover, elevation of intracellular Ca2+ concentrations, priming of parathyroid hormone (PTH)-sensitive ion channels, and activation of second messenger systems. In the longer term (many hours to days), interactions mediated through binding of 1,25(OH)2D3 to nuclear receptors, present in mature osteoblasts, modulate transcription of target genes. Target genes for 1,25(OH)2D3 including those encoding for the bone matrix proteins osteopontin (OPN) and osteocalcin (OCN), possess vitamin D response elements (VDRE) upstream of the transcriptional start site. In addition, it is now clear that a number of intermediate effects (1 to 3 hours) also occur. These effects require longer times than the aforementioned rapid effects, but precede the long-term consequences of activation of nuclear receptors. These include alterations in the phosphorylation state of various proteins secreted by osteoblasts, including OPN, attributable to activation/inactivation of various intracellular protein kinases and phosphatases. Intermediate effects are likely to involve both membrane-initiated rapid actions and transcriptional effects on early genes that do not require the nuclear receptor for 1,25(OH)2D3. These intermediate effects, therefore, represent ideal targets for the study of the interaction or "cross-talk" between rapid membrane-initiated, nongenomic effects and nuclear receptor-mediated, genomic effects of 1,25(OH)2D3 on osteoblasts. Intermediate effects also invite the study of rapid, non-nuclear receptor-mediated genomic effects of 1,25(OH)2D3 on osteoblasts. Complete understanding of the mechanisms by which 1,25(OH)2D3 exerts its pleiotropic effects on osteoblasts and other target cells, contributing to control of Ca2+ homeostasis, requires integration of the concepts learned from studies of both rapid and long-term pathways.

Animals↗

PubMed1999

Molecular phenotype of the np 7472 deafness-associated mitochondrial mutation in osteosarcoma cell cybrids.

The nucleotide pair (np) 7472 insC mitochondrial DNA mutation in the tRNA(Ser)(UCN) gene is associated with sensorineural deafness, combined in some individuals with a wider syndrome including ataxia and myo-clonus. Previous studies in osteosarcoma cell cybrids revealed only a mild respiratory defect linked to the mutation. We have investigated the biochemical and molecular consequences of the mutation, using a panel of seven osteosarcoma cell cybrids containing 100% mutant mtDNA, plus two cybrids carrying 100% wild-type mtDNA from the same patient. The mutation is associated with a mild growth deficit in selective (galactose) medium that is only significant in combination with a reduced mtDNA copy number, suggesting a mechanism that might modulate clinical phenotype. The mutation results in a 65% drop in the steady-state level of tRNA(Ser)(UCN), but causes at most only a very mild and quantitative abnormality of mitochondrial protein synthesis, associated with modest hypersensitivity to doxycyclin. No evidence for a specific defect in aminoacylation was obtained, and unlike the case with the np 7445 mutation, the pattern of RNA processing of light strand transcripts of the ND6 region was not systematically altered. Comparing the np 7472 and np 7445 mutant phenotypes in cultured cells suggests that sensorineural deafness can result from a functional insufficiency of mitochondrial tRNA(Ser)(UCN), to which some cells of the auditory system are especially vulnerable.

Base Sequence↗

PubMed1995

Disruption of conserved rhodopsin disulfide bond by Cys187Tyr mutation causes early and severe autosomal dominant retinitis pigmentosa.

PURPOSE: To determine the molecular basis of an early and severe form of autosomal dominant retinitis pigmentosa and to characterize the associated phenotype. METHODS: Visual function evaluation included electrophysiologic and psychophysical testing. Molecular genetic analysis included determining the DNA sequence of sections of the rhodopsin gene amplified by polymerase chain reaction and screening for changes single-nucleotide by allele-specific oligonucleotide hybridization. RESULTS: Affected family members are heterozygous for a unique Cys187Tyr rhodopsin mutation which disrupts a highly conserved disulfide bond essential to normal rhodopsin function. The retinitis pigmentosa (RP) phenotype includes early and severe retinal dysfunction. The full-field electroretinogram showed only negligible remaining rod and cone responses by 22 years of age. Visual fields were constricted severely by early middle-age years. Macular dysfunction caused reduced visual acuity in early adult years, and macular atrophy was present in older age. The severity of phenotype generally correlated with age, with the exception of an affected 44-year-old patient who had better visual acuity, fields, electroretinogram, and dark-adapted thresholds than did three younger affected relatives, ranging in age from 22 to 38 years. CONCLUSION: An early onset, blinding form of autosomal dominant RP results from a rhodopsin Cys187Tyr mutation that eliminates a residue necessary for the formation of a highly conserved disulfide bond essential to normal rhodopsin function. The fact that one family member is significantly less affected than his younger relatives suggests that genetic or environmental factors can modulate the phenotype.

Adolescent↗

PubMed2002

Regulation of articular chondrocyte phenotype by bone morphogenetic protein 7, interleukin 1, and cellular context is dependent on the cytoskeleton.

Bone morphogenetic proteins (BMPs) induce cartilage differentiation and morphogenesis. There are profound changes in the cytoskeletal architecture during the morphogenesis of cartilage. To investigate the possibility that morphogenetic signals such as BMPs may regulate chondrocyte phenotype by modulation of cytoskeletal protein expression, we determined whether the expression and distribution of cytoskeletal proteins in chondrocytes are regulated by bone morphogenetic protein 7 (BMP 7), interleukin 1 (IL-1), and cellular context. Addition of BMP 7, a morphogen that induces chondrogenesis, to primary cultures of bovine and murine chondrocytes induced increased expression of four cytoskeletal proteins: tensin, talin, paxillin, and focal adhesion kinase (FAK). The expression of cytoskeletal proteins is dependent on cellular context; compared to monolayer, chondrocytes in suspension exhibited increased expression of cytoskeletal components. Conversely, addition of IL-1, a catabolic cytokine, induced loss of chondrocyte phenotype and decreased the expression of these cytoskeletal components. Treatment of chondrocytes with cytochalasin D (an agent that disrupts the actin cytoskeleton) inhibited BMP 7-induced upregulation of tensin, talin, paxillin, and FAK, and blocked the effect of BMP 7 on chondrocyte phenotype. Taken together these data demonstrate that cytoskeletal components play a critical role in the response to morphogens and cytokines in the regulation of chondrocyte phenotype. (c)2001 Elsevier Science.

3T3 Cells↗

PubMed1997

Phenotype of porcine monocytic cells: modulation of surface molecule expression upon monocyte differentiation into macrophages.

When porcine blood monocytes differentiate in vitro into macrophages, their morphology, as well as side scatter and forward scatter measured by flow cytometry, changed in a manner similar to that with human cells. During this differentiation, the initial high expression of CD molecules on porcine monocytes was down-regulated, with one exception--SWC9. Freshly isolated blood monocytes were SWC9-, but after culture the cells had become SWC9+. Thus, porcine monocytes were characterised as SWC3+SWC9-CD14high; macrophages were SWC3+SWC9+CD14low, the latter also displaying a down-regulation of CD11a/18, and, to a lesser degree, CD44. Both SWC9-CD14high monocytes and SWC9+CD14low macrophages were identifiable in freshly prepared monocytic cells from the spleen. Alveolar macrophages, on the other hand, were dominated by SWC9+CD14low cells, similar in phenotype to in vitro monocyte-derived macrophages. The consequences which these results have for studies on virus infections of porcine monocytic cells are discussed.

Animals↗

PubMed1997

Role of macrophage-colony-stimulating factor in regulating the accumulation and phenotype of tumor-associated macrophages.

In order to better define the role played by tumor-cell-derived macrophage-colony-stimulating factor (M-CSF) in regulating the recruitment and phenotype of tumor-associated macrophages, Polyoma large T-transformed fibroblastoid cell lines, derived from M-CSF-deficient osteopetrotic op/op mice and their phenotypically normal op/+ littermate controls, were inoculated into SCID (severe combined immunodeficiency) recipients and both the proportion and phenotype of the macrophages present within the tumors generated were determined. The results obtained indicate that, although tumors derived from M-CSF-deficient and M-CSF-producing tumor cell inoculate contain a similar proportion of macrophages, the macrophages isolated from tumors lacking M-CSF appear morphologically less mature and express lower levels of interleukin 1 beta, tumor necrosis factor alpha and FcR gamma II mRNA. Taken together, these data suggest that, although M-CSF does not appear to play a critical role in determining the macrophage content of these tumors, it does play a role in modulating the phenotype, and potentially the functional activity of the macrophages present within the tumor microenvironment.

Animals↗

PubMed2006

Cyclosporin-A does not affect skeletal muscle mass during disuse and recovery.

Cyclosporin-A (CsA) is an immunosuppressive drug that acts as an inhibitor of calcineurin, a calcium phosphatase that has been suggested to play a role in skeletal muscle hypertrophy. The aim of the present study was to determine the effect of CsA administration (25 mg kg(-1) day(-1)) on skeletal muscle mass and phenotype during disuse and recovery. Male Wistar rats received vehicle (N = 8) or CsA (N = 8) during hind limb immobilization (N = 8) and recovery (N = 8). Muscle weight (dry/wet) and cross-sectional area were evaluated to verify the effect of CsA treatment on muscle mass. Muscle phenotype was assessed by histochemistry of myosin ATPase. CsA administration during immobilization and recovery did not change muscle/body weight ratio in the soleus (SOL) or plantaris (PL). Regarding muscle phenotype, we observed a consistent slow-to-fast shift in all experimental groups (immobilized only, receiving CsA only, and immobilized receiving CsA) as compared to control in both SOL and PL (P < 0.05). During recovery, no difference was observed in SOL or PL fiber type composition between the experimental recovered group and recovered group receiving CsA compared to their respective controls. Considering the muscle/body weight ratio, CsA administration does not maximize muscle mass loss induced by immobilization. Our results also indicate that CsA fails to block skeletal muscle regrowth after disuse. The present data suggest that calcineurin inhibition by CsA modulates muscle phenotype rather than muscle mass.

Animals↗

PubMed2006

The prostacyclin receptor induces human vascular smooth muscle cell differentiation via the protein kinase A pathway.

Recent studies of cyclooxygenase-2 (COX-2) inhibitors suggest that the balance between thromboxane and prostacyclin is a critical factor in cardiovascular homeostasis. Disruption of prostacyclin signaling by genetic deletion of the receptor or by pharmacological inhibition of COX-2 is associated with increased atherosclerosis and restenosis after injury in animal models and adverse cardiovascular events in clinical trials (Vioxx). Human vascular smooth muscle cells (VSMC) in culture exhibit a dedifferentiated, migratory, proliferative phenotype, similar to what occurs after arterial injury. We report that the prostacyclin analog iloprost induces differentiation of VSMC from this synthetic, proliferative phenotype to a quiescent, contractile phenotype. Iloprost induced expression of smooth muscle (SM)-specific differentiation markers, including SM-myosin heavy chain, calponin, h-caldesmon, and SM alpha-actin, as determined by Western blotting and RT-PCR analysis. Iloprost activated cAMP/protein kinase A (PKA) signaling in human VSMC, and the cell-permeable cAMP analog 8-bromo-cAMP mimicked the iloprost-induced differentiation. Both myristoylated PKA inhibitor amide-(14-22) (PKI, specific PKA inhibitor), as well as ablation of the catalytic subunits of PKA by small interfering RNA, opposed the upregulation of contractile markers induced by iloprost. These data suggest that iloprost modulates VSMC phenotype via G(s) activation of the cAMP/PKA pathway. These studies reveal regulation of VSMC differentiation as a potential mechanism for the cardiovascular protective effects of prostacyclin. This provides important mechanistic insights into the induction of cardiovascular events with the use of selective COX-2 inhibitors.

Cell Differentiation↗

PubMed2002

Provisional mapping of quantitative trait loci modulating the acoustic startle response and prepulse inhibition of acoustic startle.

Prepulse inhibition (PPI) of the acoustic startle response (ASR) is a form of sensorimotor gating, defined as an inhibition of the startle response when a low intensity stimulus, the prepulse, precedes the startling stimulus. Deficits in PPI have been reported in schizophrenia and other psychiatric/neurological disorders, and correlate with symptom severity in schizophrenia, suggesting that deficient PPI per se or abnormalities in neural circuits regulating PPI may cause some symptoms of schizophrenia. If so, then genes conferring reduced PPI may contribute toward genetic vulnerability to schizophrenia. Studies with selectively bred rodent strains indicate that PPI is under genetic control; however, the identity of the relevant genes is unknown. The current study used recombinant congenic mouse strains derived from C57BL/6J and A/J parents to assess genetic variability in PPI and in ASR and to identify provisional quantitative trait loci (QTLs) modulating these phenotypes. Significant between-strain differences in ASR and in PPI at each of several prepulse intensities (75, 80, 85, 90, 95 dB) were found. Correlations between PPI at the various prepulse intensities were highly significant, suggesting appreciable overlap in genetic regulation of PPI across prepulse intensities. Five QTLs (chromosomes 3, 5, 7, 16) associated with PPI across all prepulse intensities, but not with ASR, were identified. Two additional QTLs (chromosomes 2, 11) associated with both PPI and ASR were found. Fifteen QTLs were associated with ASR alone. Data on genotypes of informative congenic strains were used to support probable involvement of loci modulating PPI and to narrow the probable chromosomal location of QTLs. If confirmed, these QTLs may suggest candidate genes directing novel mechanisms for regulation of PPI

Acoustic Stimulation↗