Biomedical subjects

Elizabeth A Thomas

Publications and source records attributed to Elizabeth A Thomas.

13 recordsLinked to original sources

PubMed2007

Chronic haloperidol treatment results in a decrease in the expression of myelin/oligodendrocyte-related genes in the mouse brain.

Schizophrenia is a complex psychiatric illness that manifests as a combination of positive symptoms, negative symptoms, and cognitive deficits. Antipsychotic drugs, such as haloperidol, attenuate dopamine receptor signaling in neurons and constitute the frontline treatment for the positive symptoms of schizophrenia. However, haloperidol treatment has also been reported to exacerbate preexisting negative symptoms/cognitive deficits and the severity of these deficits has been correlated with white matter pathology in schizophrenia. Indeed, several studies implicate oligodendrocyte function in the pathophysiology of schizophrenia, but it is unknown whether these effects are related to drug treatment. It is well established that haloperidol alters gene expression in neurons. However, its effect on oligodendrocytes is unknown. In this study, we investigate the effects of chronic haloperidol treatment on the expression of eight genes known to play critical roles in myelin/oligodendrocyte function. We treated male mice with haloperidol (2 mg/kg/day) for 30 days and measured gene expression changes by using in situ hybridization analysis and quantitative densitometry. Haloperidol caused a decrease in the expression of these genes in several white matter regions of the mouse CNS. In contrast, clozapine (10 mg/kg/day) had no effect on the expression of a subset of these genes. This has important implications for both disease pathology and the consideration of treatment options for patients.

Analysis of Variance↗

PubMed2006

Striatal specificity of gene expression dysregulation in Huntington's disease.

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by an expanded CAG repeat region in exon 1 of the HD gene. This mutation results in the presence of an abnormally long polyglutamine tract in the encoded protein, huntingtin (htt). A major question in this field is how the mutant htt protein, which is expressed ubiquitously throughout the brain and body, causes severe neuropathologic changes predominantly in the striatum. The mechanisms accounting for this specificity are unknown. The role of transcriptional dysregulation in the pathophysiology of HD has gained much attention in recent years, however, this theory has been unable to explain the specificity of dysfunction and degeneration in HD. Microarray studies have showed hundreds of gene expression changes in mouse models of HD and in post-mortem brain samples from HD subjects. Among the genes whose expression levels are preferentially altered are those that exhibit enriched expression in the striatum, which we have argued are the most relevant to disease pathology. These "striatal-enriched" genes are associated with several systems previously implicated in HD pathology, especially disturbances in transcriptional processes and calcium homeostasis. Large-scale changes in striatal gene expression in this manner would likely have particularly devastating effects to normal striatal function and could explain the specificity of striatal dysfunction and ultimate neurodegeneration observed in HD.

Calcium↗

PubMed2006

Clozapine specifically alters the arachidonic acid pathway in mice lacking apolipoprotein D.

Apolipoprotein D (apoD), a member of the lipocalin superfamily of lipid-binding proteins, exhibits abundant expression within the CNS of many species, including humans; however, its physiological role remains unclear. Treatment with atypical antipsychotic drugs, especially clozapine, results in elevation of apoD expression levels in rodent brain and in human plasma samples. In order to further explore the role of apoD in mechanisms of clozapine function, we have measured a panel of membrane fatty acids and membrane lipids in brain from drug-treated apoD knock-out mice. Mice received clozapine (10 mg/kg/day) in their drinking water for 28 days and forebrain samples were analyzed using high performance liquid chromatography and capillary gas chromatography. We identified significant differences in the levels of membrane fatty acids in response to clozapine treatment specifically in the brains of apoD knock-out mice, but not wild-type (wt) mice. The most striking observations were decreases in the levels of fatty acids related to metabolism of arachidonic acid (AA), which is a known binding partner for apoD. These include the precursor to arachidonic acid, linoleic acid (LA; 18:2n6c), arachidonic acid itself (20:4n6) and the elongation product of arachidonic acid, adrenic acid (22:4n6). We further report increases in LA, eicosadienoic acid and docosahexaenoic acid in apoD knock-out compared to wild-type mice. These findings implicate an important apoD/AA interaction, which may be necessary for clozapine function.

Animals↗

PubMed2006

Selective deficits in the expression of striatal-enriched mRNAs in Huntington's disease.

We have identified and cataloged 54 genes that exhibit predominant expression in the striatum. Our hypothesis is that such mRNA molecules are likely to encode proteins that are preferentially associated with particular physiological processes intrinsic to striatal neurons, and therefore might contribute to the regional specificity of neurodegeneration observed in striatal disorders such as Huntington's disease (HD). Expression of these genes was measured simultaneously in the striatum of HD R6/1 transgenic mice using Affymetrix oligonucleotide arrays. We found a decrease in expression of 81% of striatum-enriched genes in HD transgenic mice. Changes in expression of genes associated with G-protein signaling and calcium homeostasis were highlighted. The most striking decrement was observed for a newly identified subunit of the sodium channel, beta 4, with dramatic decreases in expression beginning at 8 weeks of age. A subset of striatal genes was tested by real-time PCR in caudate samples from human HD patients. Similar alterations in expression were observed in human HD and the R6/1 model for the striatal genes tested. Expression of 15 of the striatum-enriched genes was measured in 6-hydroxydopamine-lesioned rats to determine their dependence on dopamine innervation. No changes in expression were observed for any of these genes. These findings demonstrate that mutant huntingtin protein causes selective deficits in the expression of mRNAs responsible for striatum-specific physiology and these may contribute to the regional specificity of degeneration observed in HD.

Analysis of Variance↗

PubMed2006

Molecular profiling of antipsychotic drug function: convergent mechanisms in the pathology and treatment of psychiatric disorders.

Despite great progress in antipsychotic drug research, the molecular mechanisms by which these drugs work have remained elusive. High-throughput gene profiling methods have advanced this field by allowing the simultaneous investigation of hundreds to thousands of genes. However, different methodologies, choice of brain region, and drugs studied have made comparisons across different studies difficult. Because of the complexity of gene expression changes caused by drugs, teasing out the most relevant expression differences is a challenging task. One approach is to focus on gene expression changes that converge on the same systems that were previously deemed important to the pathology of psychiatric disorders. From the microarray studies performed on human postmortem brain samples from schizophrenics, the systems most implicated to be dysfunctional are synaptic machinery, oligodendrocyte/myelin function, and mitochondrial/ubiquitin metabolism. Drugs may act directly or indirectly to compensate for underlying pathological deficits in schizophrenia or via other mechanisms that converge on these pathways. Side effects, consisting of motor and metabolic dysfunction (which occur with typical and atypical drugs, respectively), also may be mediated by gene expression changes that have been reported in these studies. This article surveys both the convergent antipsychotic mechanisms and the genes that may be responsible for other effects elicited by antipsychotic drugs.

Animals↗

PubMed2005

Regulation of alpha-synuclein expression in limbic and motor brain regions of morphine-treated mice.

Chronic exposure to opiates produces dependence and addiction, which may result from neuroadaptations in the dopaminergic reward pathway and its target brain regions. The neuronal protein alpha-synuclein has been implicated in neuronal plasticity and proposed to serve as a negative regulator of dopamine neurotransmission. Thus, alpha-synuclein could mediate some effects of opiates in the brain. The present study investigated the influence of acute and chronic morphine administration on alpha-synuclein mRNA and protein expression in the brains of mice. Downregulation of alpha-synuclein mRNA was observed in the basolateral amygdala, dorsal striatum, nucleus accumbens, and ventral tegmental area of mice withdrawn from chronic morphine treatment. The changes were the most pronounced after longer periods of withdrawal (48 h). In contrast, levels of alpha-synuclein protein, as assessed by Western blotting, were significantly increased in the amygdala and striatum/accumbens (but not in the mesencephalon) of morphine-withdrawn mice. In both brain regions, levels of alpha-synuclein were elevated for as long as 2 weeks after treatment cessation. Because alpha-synuclein is a presynaptic protein, the detected opposite changes in its mRNA and protein levels are likely to take place in different populations of projection neurons whose somata are in different brain areas. Axonal localization of alpha-synuclein was confirmed by immunofluorescent labeling. An attempt to identify postsynaptic neurons innervated by alpha-synuclein-containing axon terminals revealed their selective apposition to calbindin D28K-negative projection neurons in the basolateral amygdala. The observed changes in alpha-synuclein levels are discussed in connection with their putative role in mediating suppression of dopaminergic neurotransmission during opiate withdrawal.

Analysis of Variance↗

PubMed2005

Association of plasma apolipoproteins D with RBC membrane arachidonic acid levels in schizophrenia.

Apolipoprotein D (apoD) is a member of the lipocalin superfamily of transporter proteins that bind small hydrophobic molecules, including arachidonic acid (AA). The ability of apoD to bind AA implicates it in pathways associated with membrane phospholipid signal transduction and metabolism. Recent findings of an increased expression of apoD in the mouse brain after clozapine treatment suggested a role for apoD in the pharmacological action of clozapine. Moreover, clozapine has been shown to increase membrane AA levels in RBC phospholipids from schizophrenic patients. ApoD levels have also been shown to be elevated in the CNS of subjects with chronic schizophrenia, a disorder associated with AA dysfunction. In this study, we examined whether plasma apoD levels are related to red blood cell membrane AA contents in the first-episode neuroleptic-naive schizophrenic (FENNS) patients. Plasma apoD levels as measured by enzyme-linked immunosorbent assay (ELISA) were not significantly different (F = 0.51, df = 2,86, p = 0.60) among healthy controls (n = 36), FENNS patients (n = 33) and patients with other psychiatric disorders (n = 19). However, plasma apoD levels were significantly correlated with RBC-AA (p = 0.0022) and docosapentaenoic acid (p = 0.0008) in FENNS patients. There are several known mechanisms that can lead to the type of membrane fatty acid defects that have been identified in schizophrenia. Whether plasma apoD alone is a major determinant of reduced RBC membrane AA levels in FENNS patients remains to be determined, although these preliminary data appear not to support this premise. Taken together with other in vitro studies, however, the present data support the view that an increased expression of apoD such as induced by atypical neuroleptic drug, may facilitate incorporation of AA into membrane phospholipids by its selective binding to AA.

Adult↗

PubMed2003

Increased levels of apolipoprotein E in the frontal cortex of subjects with schizophrenia.

BACKGROUND: It is unclear whether altered expression of a specific isoform of apolipoprotein E (apoE) is associated with the pathology of schizophrenia. METHODS: To address whether apoE may be involved in the pathology of schizophrenia, we measured the genotypic and allelic frequency of polymorphisms in its gene and transcriptional regulatory region in DNA from Brodmann's area (BA) 9 obtained postmortem from schizophrenic and control subjects as well as its levels in the same tissue using Western blot analysis. RESULTS: The genotypic or allelic frequencies of any polymorphism studied did not vary between diagnostic cohorts. There was a significant increase in the levels of apoE protein in BA 9 from the schizophrenic subjects (Mean +/- SEM: 270 +/- 8.3 vs. 238 +/- 7.1 ng apoE/mg protein, p =.008) and a decrease in tissue from an analogous cortical region from rats treated with haloperidol compared with vehicle-treated animals (50 +/- 6.4 vs. 116 +/- 9.2 ng apoE/mg protein; p =.0002). CONCLUSIONS: These data support the hypothesis that increased levels of apoE may be associated with the pathology of schizophrenia and that antipsychotic drugs decrease apoE levels as part of their therapeutic actions.

Adult↗

PubMed2003

Apolipoprotein D levels are elevated in prefrontal cortex of subjects with Alzheimer's disease: no relation to apolipoprotein E expression or genotype.

BACKGROUND: Apolipoprotein E (apoE) has been implicated in the pathology of AD ever since inheritance of the epsilon4 allele was shown to be an important risk factor for the development of AD. Apolipoprotein D (apoD) is elevated in association with several central nervous system disorders, including Alzheimer's disease (AD), and has been proposed to be an especially robust marker for brain regions specifically affected by particular neuropathologies. Progressive cognitive decline is the core clinical feature of AD and is associated with disturbances in the prefrontal cortex. METHODS: We measured apoD levels in prefrontal cortex samples obtained postmortem from 20 autopsy-confirmed AD subjects and 40 control subjects. RESULTS: Enzyme-linked immunosorbent assay analysis revealed a significant increase in apoD expression in AD subjects compared with control subjects (.218+/-.029 microg/mg protein vs.117+/-.011 microg/mg protein; p=0003). There was no significant difference in apoD expression between early-onset and late-onset Alzheimer's subjects. Apolipoprotein D expression levels were not correlated with apoE levels, nor were they correlated with inheritance of the APOE epsilon4 allele. CONCLUSIONS: These findings suggest that apoD may be related to the cognitive decline observed in AD patients and that apoD and apoE likely play different roles in the pathogenesis of AD.

Aged↗

PubMed2003

Apolipoprotein D modulates arachidonic acid signaling in cultured cells: implications for psychiatric disorders.

Deficiencies in arachidonic acid (AA) parameters have been reported in schizophrenic patients. AA is a primary binding ligand for apolipoprotein D (apoD), which is increased in response to antipsychotic drug treatment and elevated in subjects with schizophrenia and bipolar disorder. In this study, we investigated whether apoD might modulate AA signaling/mobilization in cultured embryonic kidney (HEK) 293T cells. Immunofluorescent labeling revealed both cytosolic and membrane-bound expression of apoD protein in apoD-transfected cells. In cells expressing apoD, phorbal 12-myristate 13-acetate-induced AA release was inhibited compared to controls and membrane levels of AA were elevated, as indicated by the amount of AA maximally incorporated into membrane phospholipids. In addition, exogenous apoD added directly to the incubation media prevented cellular uptake of free [3H]AA. These results suggest that apoD acts to stabilize membrane-associated AA by preventing release and sequestering free AA in the cell. These actions of apoD may be beneficial to psychiatric patients.

Animals↗

PubMed2002

Novel isoform of insulin receptor substrate p53/p58 is generated by alternative splicing in the CRIB/SH3-binding region.

Insulin receptor substrate p53/p58 (IRSp53) is involved in cytoskeletal dynamics and is a candidate disease sensor in polyglutamine expansion neurodegeneration. It is widely expressed throughout the body, but its levels are dramatically elevated in forebrain regions. IRSp53 functions as a signal transducing adaptor between activated Rho family GTPases and their effectors. There are four known alternatively spliced isoforms of IRSp53 that vary by the identity of the 3'-terminal exon. We report here that there is a fifth alternatively spliced isoform, IRSp53-B, which lacks 40 amino acids abutting the CRIB/SH3 (Cdc42/Rac-interactive binding/Src homology 3)-binding site. We speculate that the novel form has an altered function related to the mechanism of autoinactivation. IRSp53-B has an odd history in the mammalian lineage, which may complicate the use of rodent models to study cytoskeletal reorganization.

Alternative Splicing↗

PubMed2002

A new UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase mRNA exhibits predominant expression in the hypothalamus, thalamus and amygdala of mouse forebrain.

Protein glycosylation is a common and important process that can alter the stability, half-life, biological activity and receptor recognition of target molecules. We have identified a new putative mouse UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase family member, termed GalNAc-T10/ppGaNTase-T10 (gene symbol Galnt10), and determined its expression pattern in mouse CNS using in situ hybridization analysis. Results demonstrated predominant expression of Galnt10 in several distinct hypothalamic, thalamic and amygdaloid nuclei. The most abundant hybridization levels were observed in the paraventricular, ventromedial and arcuate nuclei of the hypothalamus, the anterodorsal and parafascicular nuclei of the thalamus and the central, basomedial and medial nuclei of the amygdala. Expression of Galnt10 was also detected in cerebral cortex, lateral septum, habenula and hippocampus. The localization of this putative glycosyltransferase in distinct regions within the CNS indicates the specificity for complex protein modifications and suggests that region-specific glycosylation represents an essential process in basic biological functions.

Amygdala↗

PubMedDate not supplied

The neurobiology of apolipoproteins in psychiatric disorders.

A genetic contribution to the transmission of psychiatric disorders has been established and it is now accepted that several genes confer susceptibility to schizophrenia, and similar disorders, giving rise to a complex polygenic mode of inheritance. With the high-throughput molecular profiling techniques available, apolipoproteins have emerged as being important factors in psychiatric disorders. This review will focus on three apolipoproteins that have recently been shown to be elevated in neuropsychiatric disorders: apoD, apoE, and apoL. Furthermore, the authors discuss the role of apoD in the pathology and pharmacotherapy of schizophrenia and bipolar disorder.

Animals↗