Biomedical subjects

Joseph A Gogos

Publications and source records attributed to Joseph A Gogos.

At least 19 recordsLinked to original sources

PubMed2006

Akt1 deficiency affects neuronal morphology and predisposes to abnormalities in prefrontal cortex functioning.

There is accumulating evidence that AKT signaling plays a role in the pathogenesis of schizophrenia. We asked whether Akt1 deficiency in mice results in structural and functional abnormalities in prefrontal cortex (PFC). Exploratory transcriptional profiling revealed concerted alterations in the expression of PFC genes controlling synaptic function, neuronal development, myelination, and actin polymerization, and follow-up ultrastructural analysis identified consistent changes in the dendritic architecture of pyramidal neurons. Behavioral analysis indicated that Akt1-mutant mice have normal acquisition of a PFC-dependent cognitive task but abnormal working memory retention under neurochemical challenge of three distinct neurotransmitter systems. Thus, Akt1 deficiency creates a context permissive for gene-gene and gene-environment interactions that modulate PFC functioning and contribute to the disease risk associated with this locus, the severity of the clinical syndrome, or both.

Animals↗

PubMed2006

Modeling madness in mice: one piece at a time.

Mouse models that recapitulate the full phenotypic spectrum of a psychiatric disorder, such as schizophrenia, are impossible. However, a more piecemeal recreation of phenotypic components is feasible and promises to harness the power of animal models using approaches that are either off limits or confounded by drug treatment in humans. In that context, animal models will have a central and indispensable role in the process of discovering the causes of psychiatric disorders and generating novel, mechanism-based treatments. Here, we discuss current approaches used to generate animal models of psychiatric disorders, address the different components of these disorders that can be modeled in animals, and describe currently available analytical tools. We also discuss accumulating empirical data and take an in-depth look at what we believe to be the future of animal models made possible by recent advances in psychiatric genetics.

Animals↗

PubMed2006

Schizophrenia susceptibility genes: emergence of positional candidates and future directions.

Schizophrenia is a devastating psychiatric disorder that affects approximately 1% of the population worldwide. It is characterized by so-called 'positive symptoms'--including delusions and hallucinations--'negative symptoms'--including blunted emotions and social isolation--and cognitive deficits--including impairments in attention and working memory. Studies of the inheritance of schizophrenia have revealed that it is a multifactorial disease that is characterized by multiple genetic susceptibility elements, each contributing a modest degree of risk. Linkage studies have identified several potential schizophrenia susceptibility loci, and in recent years major progress has been made in the identification of positional candidate susceptibility genes from these loci. A central goal of future research will be to use this genetic knowledge to generate specific animal models, characterize genetic interactions, investigate the disease pathophysiology and assist drug-discovery efforts.

Animals↗

PubMed2006

Disc1 is mutated in the 129S6/SvEv strain and modulates working memory in mice.

Disrupted-In-Schizophrenia (DISC1) is a leading candidate schizophrenia susceptibility gene. Here, we describe a deletion variant in mDisc1 specific to the 129S6/SvEv strain that introduces a termination codon at exon 7, abolishes production of the full-length protein, and impairs working memory performance when transferred to the C57BL/6J genetic background. Our findings provide insights into how DISC1 variation contributes to schizophrenia susceptibility in humans and the behavioral divergence between 129S6/SvEv and C57BL/6J mouse strains and have implications for modeling psychiatric diseases in mice.

Amino Acid Sequence↗

PubMed2006

Schizophrenia genetics: uncovering positional candidate genes.

The efforts to decipher the genetic causes of schizophrenia, one of the most devastating mental illnesses, have reached a turning point. Several linkage findings in schizophrenia have been replicated and, in the last few years, have been followed by systematic fine-mapping efforts to identify positional susceptibility genes. Here, we outline the evidence supporting each of the proposed positional candidate genes and identify some general areas of caution in their interpretation. Several of these findings hold considerable promise both for understanding the neuropathology of this brain disorder, the causes of which remain a mystery, but also for development of novel, mechanism-based treatments for the patients.

Alleles↗

PubMed2005

Transcriptional and behavioral interaction between 22q11.2 orthologs modulates schizophrenia-related phenotypes in mice.

Microdeletions of 22q11.2 represent one of the highest known genetic risk factors for schizophrenia. It is likely that more than one gene contributes to the marked risk associated with this locus. Two of the candidate risk genes encode the enzymes proline dehydrogenase (PRODH) and catechol-O-methyltransferase (COMT), which modulate the levels of a putative neuromodulator (L-proline) and the neurotransmitter dopamine, respectively. Mice that model the state of PRODH deficiency observed in humans with schizophrenia show increased neurotransmitter release at glutamatergic synapses as well as deficits in associative learning and response to psychomimetic drugs. Transcriptional profiling and pharmacological manipulations identified a transcriptional and behavioral interaction between the Prodh and Comt genes that is likely to represent a homeostatic response to enhanced dopaminergic signaling in the frontal cortex. This interaction modulates a number of schizophrenia-related phenotypes, providing a framework for understanding the high disease risk associated with this locus, the expression of the phenotype, or both.

Animals↗

PubMed2004

The molecular genetics of the 22q11-associated schizophrenia.

Schizophrenia has a strong genetic component but the mode of inheritance of the disease is complex and in all likelihood involves interaction among multiple genes and also possibly environmental or stochastic factors. A number of studies have shown that the 22q11 deletion syndrome (22q11DS) is a true genetic subtype of schizophrenia and as such may play an extremely important role in deciphering the genetic basis of schizophrenia. Microdeletions of the 22q11 locus are associated with a staggering increased risk to develop schizophrenia. The same locus has also been implicated by some linkage studies. Systematic examination of individual genes from the 1.5 Mb critical region has identified so far the PRODH and ZDHHC8 as strong candidate schizophrenia susceptibility genes from this locus. Discovery of these genes implicates neuromodulatory aminoacids and protein palmitoylation as important for disease development. Other genes, including the gene encoding for COMT, have been implicated by candidate gene approaches. It therefore appears that the 22q11-associated schizophrenia may have the characteristics of a contiguous gene syndrome, where deficiency in more than one gene contributes to the strikingly increased disease risk. Mouse models for individual candidate genes will provide the investigators with the opportunity to start understanding the function of these genes and how they may impact on schizophrenia. Mouse models that carry long-range deletions will likely capture the interactions among the culprit genes and help explain the genetic contribution of this locus to the high risk for schizophrenia. In-depth human and animal model studies of 22q11DS promise to answer critical questions relating to the devastating illness of schizophrenia, whose causes remain largely unknown.

Animals↗

PubMed2004

Lack of increased oxidative stress in catechol-O-methyltransferase (COMT)-deficient mice.

The effect of catechol-O-methyltransferase (COMT) deficiency on methamphetamine-induced hydroxyl radical production in the brain was assessed by the salicylate trapping method. Methamphetamine-induced hyperthermia was also studied. Furthermore, the effect of COMT deficiency on the activities of glutathione S-transferase, quinone reductase and liver mono-oxygenases was assessed with and without l-dopa challenge. Finally, two alternative pathways of l-dopa metabolism were evaluated. Methamphetamine increased 2,3-dihydroxybenzoic acid levels only slightly (n.s.) at the lowest dose level (2.5 mg/kg x 4 i.p.). This was accompanied by a simultaneous increase in salicylate levels so that the 2,3-dihydroxybenzoic acid/salicylate ratio decreased correspondingly. Most importantly, no COMT genotype-dependent changes were observed. However, hyperthermia was induced even at the lowest methamphetamine dose, the COMT-deficient mice being most sensitive. COMT deficiency did not significantly change the activities of liver glutathione S-transferase, quinone reductase or 7-ethoxyresorufin and 7-pentoxyresorufin O-dealkylation. In COMT-deficient female mice, l-dopa (30-80 mg/kg b.i.d. for 2 days) did not induce any significant changes in liver or brain glutathione S-transferase and quinone reductase activity or liver 7-ethoxyresorufin O-deethylation activity. The levels of l-dopa conjugates in urine were also negligible in COMT-deficient mice. Skin tyrosinase activity was increased in 7- to 8-day-old hairless COMT-deficient pups. The present results suggest that despite the increased hyperthermic response, COMT deficiency does not increase methamphetamine-induced hydroxyl radical production or change significantly the activity of certain enzymes involved in defense against reactive oxygen species. In conclusion, we found no evidence of increased oxidative stress in the liver or brain of adult mice lacking COMT activity.

Animals↗

PubMed2004

Evidence that the gene encoding ZDHHC8 contributes to the risk of schizophrenia.

Using a relatively dense genetic map of 72 single-nucleotide polymorphisms (SNPs) distributed across the entire 1.5-Mb locus on chromosome 22q11 associated with susceptibilit to schizophrenia, we previously identified two subregions that were consistently associated with the disease. In the distal subregion, we detected an association signal with five neighboring SNPs distributed over a haplotypic block of 80 kb encompassing six known genes. One of these five SNPs, rs175174, had the strongest association of all 72 SNPs that we tested. Here we show that rs175174 regulates the level of the fully functional transcript by modulating the retention of intron 4 of the gene ZDHHC8, which encodes a putative transmembrane palmitoyltransferase. Zdhhc8-knockout mice had a sexually dimorphic deficit in prepulse inhibition, a gene dosage-dependent decrease in exploratory activity in a new environment and a decreased sensitivity to the locomotor stimulatory effects of the psychomimetic drug dizocilpine (MK801). SNP rs175174 shows differences in transmission distortion between sexes in individuals with schizophrenia. Our results indicate that there is an unexpected connection between impaired palmitate modification of neuronal proteins and the psychiatric phenotypes associated with microdeletions of chromosome 22q11.

Acyltransferases↗

PubMed2004

Spontaneous neural activity is required for the establishment and maintenance of the olfactory sensory map.

We have developed a genetic approach to examine the role of spontaneous activity and synaptic release in the establishment and maintenance of an olfactory sensory map. Conditional expression of tetanus toxin light chain, a molecule that inhibits synaptic release, does not perturb targeting during development, but neurons that express this molecule in a competitive environment fail to maintain appropriate synaptic connections and disappear. Overexpression of the inward rectifying potassium channel, Kir2.1, diminishes the excitability of sensory neurons and more severely disrupts the formation of an olfactory map. These studies suggest that spontaneous neural activity is required for the establishment and maintenance of the precise connectivity inherent in an olfactory sensory map.

Action Potentials↗

PubMed2004

Decreased phosphorylation of NMDA receptor type 1 at serine 897 in brains of patients with Schizophrenia.

NMDA receptor hypofunction in schizophrenia has been inferred by a large number of clinical and preclinical observations; however, whether and how NMDA receptors are exactly involved in the pathogenesis of schizophrenia are still unknown and subject to interpretation. Here we show, in two independent samples of brains from patients with schizophrenia, a significant decrease in the phosphorylation level at serine 897 (S897) of the NMDA receptor type 1 (NR1) subunit. Our finding, together with a previous report that antipsychotics increase phosphorylation of NR1 at S897 in vivo, strongly suggests that insufficient phosphorylation at S897 may contribute to the neuronal pathology underlying schizophrenia.

Antibody Specificity↗

PubMed2004

Genomewide scan in families with schizophrenia from the founder population of Afrikaners reveals evidence for linkage and uniparental disomy on chromosome 1.

We report on our initial genetic linkage studies of schizophrenia in the genetically isolated population of the Afrikaners from South Africa. A 10-cM genomewide scan was performed on 143 small families, 34 of which were informative for linkage. Using both nonparametric and parametric linkage analyses, we obtained evidence for a small number of disease loci on chromosomes 1, 9, and 13. These results suggest that few genes of substantial effect exist for schizophrenia in the Afrikaner population, consistent with our previous genealogical tracing studies. The locus on chromosome 1 reached genomewide significance levels (nonparametric LOD score of 3.30 at marker D1S1612, corresponding to an empirical P value of.012) and represents a novel susceptibility locus for schizophrenia. In addition to providing evidence for linkage for chromosome 1, we also identified a proband with a uniparental disomy (UPD) of the entire chromosome 1. This is the first time a UPD has been described in a patient with schizophrenia, lending further support to involvement of chromosome 1 in schizophrenia susceptibility in the Afrikaners.

Chromosome Mapping↗

PubMed2004

Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia.

AKT-GSK3beta signaling is a target of lithium and as such has been implicated in the pathogenesis of mood disorders. Here, we provide evidence that this signaling pathway also has a role in schizophrenia. Specifically, we present convergent evidence for a decrease in AKT1 protein levels and levels of phosphorylation of GSK3beta at Ser9 in the peripheral lymphocytes and brains of individuals with schizophrenia; a significant association between schizophrenia and an AKT1 haplotype associated with lower AKT1 protein levels; and a greater sensitivity to the sensorimotor gating-disruptive effect of amphetamine, conferred by AKT1 deficiency. Our findings support the proposal that alterations in AKT1-GSK3beta signaling contribute to schizophrenia pathogenesis and identify AKT1 as a potential schizophrenia susceptibility gene. Consistent with this proposal, we also show that haloperidol induces a stepwise increase in regulatory phosphorylation of AKT1 in the brains of treated mice that could compensate for an impaired function of this signaling pathway in schizophrenia.

Antipsychotic Agents↗

PubMed2004

Phenotypic characterization and genealogical tracing in an Afrikaner schizophrenia database.

Founder populations hold tremendous promise for mapping genes for complex traits, as they offer less genetic and environmental heterogeneity and greater potential for genealogical research. Not all founder populations are equally valuable, however. The Afrikaner population meets several criteria that make it an ideal population for mapping complex traits, including founding by a small number of initial founders that likely allowed for a relatively restricted set of mutations and a large current population size that allows identification of a sufficient number of cases. Here, we examine the potential to conduct genealogical research in this population and present initial results indicating that accurate genealogical tracing for up to 17 generations is feasible. We also examine the clinical similarities of schizophrenia cases diagnosed in South Africa and those diagnosed in other, heterogeneous populations, specifically the US. We find that, with regard to basic sample descriptors and cardinal symptoms of disease, the two populations are equivalent. It is, therefore, likely that results from our genetic study of schizophrenia will be applicable to other populations. Based on the results presented here, the history and current size of the population, as well as our previous analysis addressing the extent of background linkage disequilibrium (LD) in the Afrikaners, we conclude that the Afrikaner population is likely an appropriate founder population to map genes for schizophrenia using both linkage and LD approaches.

Adult↗

PubMed2003

Methoxyestradiols mediate the antimitogenic effects of 17beta-estradiol: direct evidence from catechol-O-methyltransferase-knockout mice.

BACKGROUND: Studies using pharmacological agents suggest but do not prove that the antimitogenic effects of estradiol are caused by conversion of estradiol to hydroxyestradiols (mediated by CYP450s) followed by methylation of hydroxyestradiols to methoxyestradiols (mediated by catechol-O-methyltransferase, COMT). METHODS AND RESULTS: To test this hypothesis more rigorously, we used aortic smooth muscle cells (SMCs) from mice lacking COMT (COMT-KO). Wild-type (WT) but not COMT-KO SMCs efficiently converted 2-hydroxyestradiol to 2-methoxyestradiol. Both WT and COMT-KO SMCs expressed estrogen receptors. Estradiol and 2-hydroxyestradiol concentration-dependently inhibited serum-induced DNA synthesis, cell numbers, and collagen synthesis in WT but not COMT-KO SMCs. 2-Methoxyestradiol inhibited DNA synthesis, cell numbers, and collagen synthesis in both WT and COMT-KO SMCs. CONCLUSIONS: These data provide strong evidence that the vascular antimitogenic effects of estradiol are estrogen receptor-independent and involve the sequential conversion of estradiol to hydroxyestradiols and then to methoxyestradiols.

2-Methoxyestradiol↗

PubMed2003

D-amphetamine responses in catechol-O-methyltransferase (COMT) disrupted mice.

RATIONALE: We have earlier found that 1). COMT inhibitors did not enhance amphetamine-induced dopamine efflux into striatal extracellular, that 2). they did not increase dopamine levels in striatal tissue and that 3). they did not potentiate amphetamine-induced turning behavior of hemiparkinsonian rats. Further, when COMT knockout mice were challenged with l-dopa or a dopamine transporter (DAT) inhibitor, an accumulation of dopamine occurred and the neurochemical and locomotor effects of l-dopa and GBR 12909 were modified accordingly. OBJECTIVE: Since DAT inhibitors and amphetamine apparently have different mechanisms of action, we were interested to see how COMT knockout mice would react to d-amphetamine treatment. METHODS: We measured the effects of d-amphetamine on locomotor activity and on the levels of catecholamines and their metabolites in striatal microdialysis fluid and in striatal, hypothalamic and cortical brain regions of COMT gene disrupted mice. Striatal dopamine receptor binding was also determined. RESULTS. After d-amphetamine administration, the DOPAC content in homozygous mice was 3-fold in the striatum, 17- to 18-fold in the cortex and 7- to 8-fold in the hypothalamus higher than in wild-type control mice, and there were no indications of genotypexsex interactions. However, the lack of COMT did not potentiate d-amphetamine-induced dopamine levels in brain tissue or in striatal extracellular fluid. D-amphetamine-induced (10 mg/kg) hyperlocomotion was less suppressed in male COMT knockout mice than in their wild-type counterparts. Striatal dopamine D(1) and D(2) receptor levels in male mice were not altered by COMT gene disruption. CONCLUSIONS: Changes in COMT activity modulates dopamine metabolism but the behavioral effects of d-amphetamine in male mice only to a small extent, and this action does not seem to depend on the actual extracellular dopamine concentration. Nor is it mediated through compensatory changes in dopamine D(1) and D(2) receptor levels. In dopaminergic neurons, the contribution of intracellular COMT remains secondary in conditions when dopamine is released by d-amphetamine.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2003

Evidence for association of schizophrenia with genetic variation in the 8p21.3 gene, PPP3CC, encoding the calcineurin gamma subunit.

Schizophrenia is a severe psychiatric disorder characterized by a complex mode of inheritance. Forebrain-specific CNB knockout mice display a spectrum of behavioral abnormalities related to altered behaviors observed in schizophrenia patients. To examine whether calcineurin dysfunction is involved in schizophrenia etiology, we undertook studies of an initial subset of calcineurin-related genes, prioritizing ones that map to loci previously implicated in schizophrenia by linkage studies. Transmission disequilibrium studies in a large sample of affected families detected association of the PPP3CC gene, which encodes the calcineurin gamma catalytic subunit, with disease. Our results identify PPP3CC, located at 8p21.3, as a potential schizophrenia susceptibility gene and support the proposal that alterations in calcineurin signaling contribute to schizophrenia pathogenesis.

Adult↗

PubMed2003

Sequence variants of the brain-derived neurotrophic factor (BDNF) gene are strongly associated with obsessive-compulsive disorder.

We evaluated a possible association between the brain-derived neurotrophic factor (BDNF) gene and susceptibility to obsessive-compulsive disorder (OCD) by genotyping a number of single-nucleotide polymorphisms (SNPs) and one microsatellite marker from the extended BDNF locus in 164 triads with OCD. Extensive background linkage disequilibrium was observed at this locus. Single-locus transmission-distortion tests revealed significant evidence of association with the disease for all the BDNF gene markers tested, including a Val66Met variation affecting the sequence of the proBDNF protein. Analysis of multi-SNP haplotypes provided similar results. Haplotype transmission comparisons in this and previous studies point to a functionally distinct BDNF haplotype uniquely marked by the rare Met66 allele, which is undertransmitted and likely confers a protective effect in OCD and other psychiatric disorders.

Adolescent↗