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Dennis L. Murphy - US grants
Affiliations: | NIMH/NIH | National Institute of Health, Bethesda, MD, United States |
Area:
OCD, serotonin transporterWebsite:
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High-probability grants
According to our matching algorithm, Dennis L. Murphy is the likely recipient of the following grants.Years | Recipients | Code | Title / Keywords | Matching score |
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2006 — 2012 | Murphy, Dennis L | Z01Activity Code Description: Undocumented code - click on the grant title for more information. ZIAActivity Code Description: Undocumented code - click on the grant title for more information. |
The Genetics of Obsessive Compulsive Disorder @ National Institute of Mental Health OCD is a severe, heritable condition with a lifetime prevalence of about two percent of world populations. The mode of inheritance is incompletely understood but is likely complex, involving multiple genetic loci of small to moderate effect. Our laboratory has played a leading role in studies of OCD and of its genetics for over 15 years, and was one of the founding sites of a multi-center genome-wide study of OCD, the results of which have begun to be reported in the groups publications noted below. In addition, a series of association studies that have identified and evaluated candidate genes in OCD and related disorders is continuing. Several major OCD genetic research results from our Lab in the last year (2008-2009) can be highlighted: 1). In our Labs continuing and collaborative investigations of the role of serotonin and its major genes in OCD and related disorders, we sequenced the promoter region of SLC6A4 to search for additional common possibly functional variants. We discovered that a common single nucleotide polymorphism (SNP), rs25532, strongly modulated SERT expression in several cultured cell lines and in human post-mortem brain cortex. When this SNP and other SLC6A4 SNPs were included in haplotype (i.e., combination) analyses, our group discovered a highly significant association in a large OCD case-control sample (Wendland et al., 2008). In keeping with the hypothesis of increased SERT functioning in OCD, a haplotype containing the higher-expressing variant at each locus was found to be significantly more common in OCD probands than in controls (Wendland et al., 2009). The strong relationship of SLC6A4 variants to different SRI treatment responses in humans represents additional illustrations of gene-based influences on serotonergic pharmacologic responses, i.e., a new SERT-based pharmacogenomics. (2). There is recent evidence from treatment and genetic studies that suggests that another neurotransmitter system besides serotonin may contribute to OCD. This is the brain glutamate system. As with the serotonin system, a brain transporter, the neuronal glutamate transporter, is major regulator of glutamate availability. This glutamate transporter is encoded by the gene SLC1A1. Recent evidence from gene linkage analyses and follow-up candidate gene studies suggested the potential involvement of SLC1A1 in the development of OCD. For these reasons, we undertook a large case-control study that included over 300 OCD probands and over 650 matched controls collected by our Lab. In addition, publicly-accessible SLC1A1 expression and genotype data were evaluated to gain further insights into SLC1A1 function. Six SNPs in or near SLC1A1 were genotyped. We found that gene expression of SLC1A1 is heritable in human cell lines (Wendland et al., 2008). We identified three SNPs in or near SLC1A1 that correlated with gene expression levels. Additionally, two of these SNPs also predicted expression levels in human post-mortem brain tissue, and one SNP was found to have functional consequences in reporter gene studies (Wendland et al., 2009). Two haplotypes at three SNPs, rs3087879, rs301430, and rs7858819, were significantly associated with OCD after multiple testing corrections and contained two of the SNPs associated with expression levels. In addition, another SNP correlating with SLC1A1 gene expression, rs3933331, was associated with an OCD hoarding sub-phenotype as assessed by two independent, validated rating scales for hoarding. Thus, our case-control data corroborate previous smaller family-based studies that, taken together, indicate that SLC1A1, like SLC6A4, is a susceptibility gene for OCD. The expression and genotype database-mining approach that we used provides a new and useful complementary approach to strengthen future candidate gene studies in neuropsychiatric and other disorders which represent a large public health burden. In fact, seven of these disorders, including OCD, were listed in the 2001 World Health Organizations report on the leading causes of years of extended disability among adults. 3). In additional studies of the genetics of OCD, we focused on a gene suggested to be a candidate gene for OCD based on an animal model of some OCD-related compulsive behaviors. Although heritability studies in OCD have shown a 7 times increased risk for first-degree relatives, and twin studies have revealed higher concordance amongst monozygotic twins (85%) compared to dizygotic twins (50%), the identification of the underlying risk-conferring genetic variation by means of classic genetic association studies has proven to be difficult. Recently, it was shown that mice deficient in the postsynaptic synapse-associated protein Sapap3 develop an OCD-like phenotype, which included compulsive grooming and increased anxiety-like behaviors. Interestingly, the phenotype of Sapap3 gene knock-out mice can be rescued by administering SRIs, the most effective group of therapeutic agents for OCD. We hypothesized that variants in the similar human gene, SAPAP3, could contribute to disorders in the OCD spectrum. To test this, we resequenced SAPAP3 in OCD and related disorders in a case-control study, investigating the complete coding region and flanking intronic sequences of SAPAP3 using standard capillary sequencing. We detected seven novel non-synonymous variants. SAPAP3 variants were present in 4.2% of diagnosed OCD and related disorder patients, but only in 1.1% of controls. Thus, we observed a significant case-control association in our moderately sized sample (Zuchner et al., 2009). The majority of changes were missense mutations, while one variant was an in-frame insertion of five amino acids. Modeling analysis of these missense variants identified several variants with likely functional consequences. It is thus possible that a combination of relatively rare susceptibility variants may prove contributory to OCD, as suggested for some other disorders including autism as well as for OCD itself in our prior study of the SLC6A4 uncommon variant, Ileu425Val (Wendland et al., 2008). The combination of the Sapap3 mouse model with compulsive behaviors and our recent, first case-control study of the SAPAP3 gene in humans with OCD demonstrates a role for SAPAP3 in OCD and compulsive behaviors. In fact, a follow-up study recently reported by our colleagues in our collaborative study of siblings who were both affected by OCD found that four of six SNPs investigated in SAPAP3 were nominally associated with specifically-studied grooming disorders, with high genotypic relative risks of 1.6-3.3. All three haplotypes that were identified were nominally associated with at least one grooming disorder. This study thus brings an even sharper focus on OCD subtypes or sub-populations that may be more closely related to specific single genes. Other studies by our group of OCD-related common and uncommon gene variants and also of other OCD subtypes such as hoarding are noted in our list of 2008-2009 publications, below. Also of note is that our group continues to share our 15+ year collection of DNA and phenotype data with collaborators in the Obsessive-Compulsive Disorder Collaborative Genetics Study (OCGS) and the Obsessive-Compulsive Foundation (OCF) groups, as well as other intramural and extramural individual collaborators, thus enhancing the global search for underlying contributions to OCD and related disorders that are of major public health concerns. Twelve papers that were published in the last year that are listed below resulted from these collaborative studies. Other papers that were published that have helped to refine the phenotype for OCD genetic studies are also listed. |
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2007 — 2012 | Murphy, Dennis L | Z01Activity Code Description: Undocumented code - click on the grant title for more information. ZIAActivity Code Description: Undocumented code - click on the grant title for more information. |
Genetic Animal Models For the Study of Serotonin Function and Behavior @ National Institute of Mental Health As recently reviewed, SERT-deficient Slc6a4 +/- and -/- mice have gene-proportionate increases in extracellular fluid serotonin (5-HT) concentrations. i.e., 3- or 6-fold excesses respectively over +/+ mice (Murphy et al., 2008;Murphy &Lesch 2008;Fox et al., 2007). At the same time, the Slc6a4 -/- mice have a marked deficit of intracellular, releasable 5-HT. These mice also have significantly increased 5-HT synthesis and turnover across all five brain regions investigated in Slc6a4 -/- mice, and this increase is significantly greater in female Slc6a4 -/- mice. Expression of the organic cation transporters, OCT1 and OCT3, which are low affinity transporters of monoamines, is increased--indicative of some partial but inefficient attempts at compensation via heterologous transporters. Slc6a4 +/- mice manifest decreased 5-HT clearance and elevated extracellular fluid 5-HT but nonetheless have unchanged tissue 5-HT concentrations in the brain and periphery and unchanged brain 5-HT synthesis and turnover. Thus, a single copy of Slc6a4 is adequate to maintain overall 5-HT tissue homeostasis. The resulting data are: (1). Continuing advances have been made in our studies of the serotonin syndrome. Most commonly, this syndrome occurs as a side effect in humans treated with certain antidepressant and anti-anxiety drugs. Importantly, its occurrence contributes to reduced therapeutic efficacy or a requirement to interrupt treatment in some individuals. Our earlier studies exploring this behavioral and temperature-related syndrome in SERT-deficient mice had discovered that genetic vulnerability to a markedly exaggerated serotonin syndrome was present when these mice were exposed to the metabolic precursor of serotonin, 5-HTP, or to other serotonergic drugs such as the monoamine oxidase inhibiting (MAOI) antidepressant, tranylcypromine. Tranylcypromine is a clinically available antidepressant drug, and 5-HTP is readily available on more than 100 internet sites and sold over-the-counter as a dietary supplement. Spontaneous mild serotonin-syndrome behaviors were also observed in untreated Slc6a4 -/- mice (Fox et al., 2007;Fox et al., 2008). To better define the mechanisms underlying the serotonin syndrome, brain levels of serotonin and its metabolites were measured. In parallel with the greater behavioral changes, SERT -/- mice had 5 to 12-fold increases in serotonin, with smaller 2 to 5-fold increases in SERT +/+ and +/- mice following 5-HTP treatment (Fox et al., 2008). Exaggerated changes in temperature were also found in SERT -/- mice. Different serotonin receptor mechanisms were discovered to be involved with temperature responses by studies with different selective serotonin antagonists. In SERT +/+ and +/- mice, the 5-HT1A auto receptor was primarily involved. However, in SERT -/- mice, the 5-HT7 receptor was the primary mediator of these temperature changes (Fox et al., 2008). As roles for 5-HT7 receptors in anxiety and depression were recently established and contributions of 5-HT1A receptors to therapeutic responses to serotonergic drugs have been well-established, the current findings have implications for understanding the high anxiety-like and depressive-like phenotype of SERT-deficient mice relevant to the treatment of human anxiety and affective disorders. In another series of studies based on case reports implicating the clinically-used atypical opioid, tramadol and another opioid that is an abused substance, meperidine, in the development of the human serotonin syndrome, we examined tramadol and meperidine as possible causative drugs in our SERT genetic mouse model. Comparisons were also made with SERT mice treated with morphine, an opioid not implicated in the serotonin syndrome in humans. We found that tramadol and meperidine, but not morphine, induced serotonin syndrome behaviors in mice, and that this response was exaggerated in SERT -/- and +/- mice (Fox et al., 2009). The exaggerated response to tramadol in SERT -/- mice was blocked by pretreatment with a serotonin receptor 5-HT1A antagonist. Further, we found that morphine-, meperidine- and tramadol-induced analgesia was markedly decreased in SERT -/- mice. These studies suggest that caution seems warranted in prescribing or not warning patients receiving SRIs or MAOIs that dangerous side-effects may occur during concurrent use of tramadol and similar agents. These findings in this mouse genetic model raise the possibility that humans with lower-expressing SLC6A4 SS genotypes or other SERT variants that lead to 50-80% decreases in SERT binding sites or transport function may be at higher risk to develop serotonin syndrome neurotoxicity. This is based on highly congruent data from imaging, neuroendocrine and other studies that have compared SERT-deficient mice to humans with SERT gene variants. Of special note, it is likely that relatively mild serotonin syndrome occurrence may contribute to early discontinuation of SRIs and other side effects during SRI treatment that are strongly associated with the lower-expressing SLC6A4 SS genotypes and S alleles as well as other newly discovered lower-expressing variants in this gene, as described in our other report, MH000336-30 LCS. (2). Another behavioral abnormality in SERT-deficient mice is reduced head twitch responses to serotonergic agents. This response is considered a pharmacologic proxy for hallucinogenic-like behaviors, as most of the drugs that induce this response in rodents are hallucinogens in humans, and these responses can be blocked by anti-psychotic drugs. In exploring mechanisms underlying this response, we found this year that reducing excess brain serotonin in SERT-deficient mice by using a serotonin synthesis inhibitor restored the deficient head twitch state in SERT -/- mice to levels of SERT control +/+ mice (Basselin et al., 2009). These findings provide a more comprehensive understanding of mechanisms in this genetic mouse model that eventually may provide insights into human disorders with genetic contributions that include hallucinogenic phenomena such as schizophrenia and bipolar disorders as well as the consequences of certain types of substance abuse disorders, all of major public health concern. (3). SERT-deficient mice were also compared to mice with gene-based deficiencies in other neurotransmitters, those for dopamine and norepinephrine, as well as to mice with other genetic deficiencies that interact with SERT, such as the integrin alphaIIbeta3 gene, as well as other types of environmental stimuli. Differences in brain, platelet and gut responses to multiple agents were observed. These findings serve as further illustrations of earlier data accumulated by our Lab that support the use of these mice as vulnerability models for humans with SERT gene variants with regard to gene-environment and gene-gene interactions that contribute to human diseases. (4). In other new studies of SERT-deficient mice, these mice were examined for possible autism-related traits, as some studies have identified associations of SLC6A4 polymorphisms as well as plasma serotonin levels with the occurrence of autism. In a three-chambered choice task, male SERT-deficient mice displayed significantly reduced social interaction behaviors with other mice compared to SERT +/+ mice (Moy et al., 2009). Thus, together with increased anxiety-like behaviors plus increased startle responses and increased behavioral and physiological responses to various types of stress, these mice show a series of features highly relevant to symptoms in several neuropsychiatric disorders of important public health concern. |
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2013 | Murphy, Dennis L | ZIAActivity Code Description: Undocumented code - click on the grant title for more information. |
Genetic Mouse Models For the Study of Serotonin Function and Behavior @ National Institute of Mental Health As recently reviewed by us, SERT-deficient +/- and -/- mice have gene-proportionate increases in extracellular fluid serotonin concentrations, i.e., 5- or 7-fold excesses respectively over wildtype +/+ mice. At the same time, SERT -/- mice have a marked deficit of intracellular, releasable serotonin. Continuing advances have been made in our studies of serotonin-related toxic reactions, including the serotonin syndrome. Most commonly, this toxicity occurs as a side effect in humans treated with certain antidepressant and anti-anxiety drugs. Importantly, its milder forms contribute to reduced therapeutic efficacy or a requirement to interrupt treatment in some individuals treated with SRIs. Our earlier studies exploring this behavioral and temperature-related syndrome in SERT-deficient mice revealed a genetic vulnerability to a markedly exaggerated serotonin syndrome when these mice were exposed to the metabolic precursor of serotonin, 5-HTP, or to other serotonergic drugs such as the monoamine oxidase-inhibiting (MAO-I) antidepressant tranylcypromine. In addition to the serotonin syndrome behavioral changes, exaggerated alterations in temperature responses were also found in SERT- and MAO-deficient mice. We are now further extending these studies to include dopamine transporter (DAT) knockout mice to further explicate the unusual behavioral feature, some resembling compulsive, stereotyped behaviors related to human obsessive-compulsive disorder (OCD). These findings in these mouse genetic models suggest the likelihood that humans with lower-expressing SLC6A4 SS, SLg and LgLg genotypes, or other SERT or MAO or DAT variants that may lead to 50-80% decreases in binding sites or transport function, may be at higher risk to develop behavioral neurotoxicity. Of special note, it is likely that relatively mild serotonin syndrome occurrence may contribute to early discontinuation of SRIs and other side effects during SRI treatment of neuropsychiatric patients that are strongly associated with the lower-expressing SLC6A4, SLC6A3 or SLC1A1 genotypes. Given this transgenic mouse data and human SLC6A4 and MAO polymorphism data, we have formed an international collaborative effort - Genes Involved in Serotonin Toxicity or GISETTO - in which we are examining functional variants in the multiple serotonin (SLC6A4, MAOA) and drug metabolizing gene groups (e.g., CYP2D6) in hospitalized individuals developing serotonin toxicity and other serotonin-related toxicities, both retrospectively and prospectively, in collaboration with our Newcastle, AZ colleagues. Understanding these genetic mechanisms will improve serotonergic drug safety and efficacy by identifying patients whose response to drugs might be genetically compromised, and thereby might be at risk of adverse and potentially life threatening drug reactions. SERT and MAO provide intriguing examples of likely mouse-human congruence in genetic vulnerability to serotonin toxicity. Functional variants exist in additional genes that can also be postulated to confer vulnerability to serotonin neurotoxicity, for example, serotonin receptor genes. This past year, we extended our studies of transporter systems by generating both conditional EAAC3 knockout and transgenic overexpressing mice. Comprehensive behavioral and other studies were initiated this year. A report about these mice was published in abstract from this year (Moya PR et al., 2013). Overall, the data accumulated by our Lab, as referenced below and previously, support the use of different genetically modified mice as vulnerability models for humans with SERT, MAO, EAAC3 and other gene variants with regard to gene-gene and gene-environment interactions that contribute to human diseases and the pharmacologic treatment of multiple psychiatric disorders. Citations numbers of other papers that have referenced our scientific reports number over 35,000 as of August, 2013. The protocol number for this report is LCS 04. |
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2013 — 2014 | Murphy, Dennis L | ZIAActivity Code Description: Undocumented code - click on the grant title for more information. |
The Genetics of Obsessive Compulsive Disorder and Related Ocd Spectrum Disorders @ National Institute of Mental Health OCD is a severe, heritable condition with a lifetime prevalence of about two percent in world populations. First-degree family members and OCD probands are at a ten-fold higher risk of developing OCD and related disorders. The mode of inheritance is incompletely understood but is likely complex, involving multiple genetic loci of small to moderate effect. Our laboratory has played a leading role in studies of OCD and of its genetics for over 25 years, and was one of the founding sites of multi-center genome-wide project for studies of OCD, partial results of which have recently been reported in the group's publications noted below. In addition, a series of association studies that has identified and evaluated several genes in OCD and related disorders is continuing. In our Lab's collaborative investigations, we have also worked to clarify the fundamental phenotypical features of OCD and related disorders, sometimes designated 'OCD spectrum disorders', in reports published in 2012-2013. We currently have a multifaceted array of compulsive phenotypical features that cut across traditional diagnostic designations (DSM-IV and DSM-5). In continuing efforts, our group and our collaborators have been using latent class modeling to go beyond factor and cluster analyses in order to parse OCD and related disorders by considering underlying features and comorbid disorders (e.g., affective/bipolar disorders) and life stresses. Examples of some sub-disorders that can contribute to OCD but can be found without classic OCD features include our recent and prior studies of Tourette's disorder and hoarding as well as of comorbid affective disorders, including bipolar disorder. Bipolar disorder is also the subject of direct and molecular genetic studies in continuing collaborative investigations with the Bipolar Genetics Consortium group. Studies are ongoing of the role of serotonin, the SLC6A4 gene and other major serotonin genes plus SLC1A1 in OCD and related disorders such as Tourette disorder (in which 50% of patients meet diagnostic criteria for OCD). A manuscript was published this year about the multiple common and rare SLC6A4 variants found to be associated with Tourette's Disorder including the 5HTTLPR, rs25531, rs25532 and SERT I425V variants (Moya et al., 2013). The relationship of SLC6A4 variants to different SRI treatment responses in humans represents an additional illustration of gene-based influences on serotonergic pharmacologic responses, i.e., a new SERT-based pharmacogenomics, directly relevant to the treatment of human neuropsychiatric disorders such as OCD and depression as well as to other serotonin-related human diseases as we have recently reviewed. Recent evidence from treatment and genetic studies suggest that another neurotransmitter system may contribute to OCD. As with SERT in the serotonin system, the neuronal glutamate transporter is a major regulator of glutamate availability. This glutamate transporter, EAAC3, is encoded by the gene SLC1A1 located within the chromosomal region 9p24. Recent evidence from 9p24 gene linkage analyses and candidate gene studies has suggested probable involvement of SLC1A1 in the development of OCD. Our large case-control study of SLC1A1 included a total of over 950 OCD probands and controls collected by our Lab were published this year. In addition, SLC1A1 expression and data were recently evaluated to gain further insights into SLC1A1 function. We found that gene expression of SLC1A1 is heritable in human cell lines. We identified three SNPs in or near SLC1A1 that correlated with gene expression levels. Additionally, two of these SNPs also predicted expression levels in human post-mortem brain tissue, and one SNP was found to have functional consequences in reporter gene studies. We are currently continuing further lab-based studies of this gene using transgenic techniques in mice and Dr. Moya from our Lab has created conditional Slc1a1 mice, one set of which has this gene deleted and another set which preferentially overexpresses this gene in the forebrain. The rational for creating these two opposite functional Slc1a1 mice was based on the equivocal findings from the human SLC1A1 studies regarding whether this gene might be hypofunctional or hyperfunctional in OCD. These investigations, taken together, indicate that SLC1A1, like SLC6A4, is a susceptibility gene for OCD. The expression and database-mining approach that we used provides a new and useful complementary model approach to strengthen future GWAS and candidate rare functional gene studies in neuropsychiatric and other disorders which represent a large public health burden. In fact, seven neuropsychiatric disorders, including OCD, were listed in the 2001 World Health Organizations report as among the leading causes of years of extended disability among adults. Thus these studies are expected to have a considerable public health impact. In additional studies of the genetics of OCD, we focused on candidate genes for OCD based on animal models of some OCD-related compulsive behaviors. These studies thus bring an even sharper focus on OCD subtypes or sub-populations that may be more closely related to specific single genes. Also of note is that our group continues to share our 25+ year collection of DNA and phenotype data with collaborators in the Obsessive-Compulsive Disorder Collaborative Genetics Study (OCGS) and the Obsessive-Compulsive Foundation (OCF) groups, as well as with other intramural and extramural individual collaborators, thus enhancing the global search for underlying contributions to OCD and related disorders that are of major public health concerns. Many papers that were published in the last year that are listed below resulted from these collaborative studies. The collaborative study to which our Lab contributed DNA and phenotype data based at Massachusetts General Hospital yielded a case-control genome association study involving 7022 individuals published in 2012. One of the top signals obtained was in DLGAP1, coding a post-synaptic density (PSD) protein with high similarity to another PSD gene, DLGAP3 (SAPAP3) which we found to have rare variants enriched in OCD patients versus controls, as reported in a 2011 paper from our group and colleagues. The OCF collaborational GWAS was conceived to compliment the earlier OCGS family-based genome linkage study of 299 OCD-affected sibling pairs together with other family members and now constitutes more than 1100 individuals. The OCGS studies generated 20 publications to date, the most recent last year. This study conducted fine mapping followed by SNP association studies of two regions identified in the initial linkage analysis. Associations were identified in or near a set of associated homeobox genes including MEIS2. Two of these form a heterodemeric complex. All three are involved in neurodevelopment and the heterodemeric complex is specifically known to affect development of the striatum, a brain region previously implicated in OCD via human brain imaging studies. Citations numbers of other papers that have referenced our scientific reports number over 35,000 as of August, 2013. The protocol number for this Annual Report is 96-M-0124 and the NCT number is NCT00001548. |
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2014 | Murphy, Dennis L | ZIAActivity Code Description: Undocumented code - click on the grant title for more information. |
Genetic Mouse Models For the Study of Serotonin, Dopamine and Glutamate Function and Behavior @ National Institute of Mental Health As recently reviewed by us, SERT-deficient +/- and -/- mice have gene-proportionate increases in extracellular fluid serotonin concentrations, i.e., 5- or 7-fold excesses respectively over wildtype +/+ mice. At the same time, SERT -/- mice have a marked deficit of intracellular, releasable serotonin. To investigate a rare variant in the serotonin transporter, I425V, strongly associated with obsessive-compulsive disorder and more recently, Tourettes Disorder in our own studies published over the last several years and most recently last year, a mouse model was created in C57B6 mice with this gene alteration. Preliminary results of initial investigations were reported at the ACNP meeting in 2013 (Ramamoorthy, Murphy DL, et al.) and will also be reported at the Society for Neuroscience meeting on November, 2014 Continuing advances have been made in our studies of serotonin-related toxic reactions, including the serotonin syndrome. Most commonly, this toxicity occurs as a side effect in humans treated with certain antidepressant and anti-anxiety drugs. Importantly, its milder forms contribute to reduced therapeutic efficacy or a requirement to interrupt treatment in some individuals treated with SRIs. Our earlier studies exploring this behavioral and temperature-related syndrome in SERT-deficient mice revealed a genetic vulnerability to a markedly exaggerated serotonin syndrome when these mice were exposed to the metabolic precursor of serotonin, 5-HTP, or to other serotonergic drugs such as the monoamine oxidase-inhibiting (MAO-I) antidepressant, tranylcypromine. In addition to the serotonin syndrome behavioral changes, exaggerated alterations in temperature responses were also found in SERT- and MAO-deficient mice. We have further extended these studies to include dopamine transporter (DAT) knockout mice to further explicate the unusual behavioral feature, some resembling compulsive, stereotyped behaviors related to human obsessive-compulsive disorder (OCD). We have also created both conditional EAAT3 over-expressing and conditional EAAT3 knockout mice, to investigate the functional consequences of altered expression of this important glutamate transporter. We are currently characterizing these mice at molecular, neurochemical and behavioral levels. In addition, A report about these mice was published in abstract form this year (Moya PR et al., 2013).In collaboration with Dr. Andrew Holmes at NIAAA we plan to characterize behavioral phenotypes that might arise from GAD65-Cre-mediated EAAT3 overexpression in interneurons that might shed light into the role of EAAT3 in neuropsychiatric disorders such as OCD. These findings in these mouse genetic models suggest the likelihood that humans with lower-expressing SLC6A4 SS, SLg and LgLg genotypes, or other SERT variants as well as SLC6A3 and SLC1A1 variants that may lead to 50-100% alterations in binding sites or transport function, may be at higher risk to develop neurodevelopmental disorders. Of special note, it is likely that relatively mild serotonin syndrome occurrence may contribute to early discontinuation of SRIs and other side effects during SRI treatment of neuropsychiatric patients that are strongly associated with the lower-expressing SLC6A4. Likewise variants in SLC6A3 and SLC1A1 genes have recently been found to be associated with multiple neuropsychiatric disorders such as ADHD and OCD. Our Laboratory has contributed to research on variants in these genes as noted in our other 2014 Annual Report ZIA MH000332-36 LCS. Given this transgenic mouse data and human SLC6A4, SLC6A3 and SLC1A1 polymorphism data, we have joined in multiple collaborative gene-hunting efforts to find and examine functional likely involved in neuropsychiatric disorders. Overall, the data accumulated by our Lab, as referenced below and previously in over 800 Pubmed references, support the use of different genetically modified mice as vulnerability models for humans with SERT, DAT, EAAT3 and other gene variants with regard to gene-gene and gene-environment interactions that contribute to human diseases and the pharmacologic treatment of multiple psychiatric disorders. We have published reviews of our work on these murine models in major journals (e.g., Murphy and Lesch, Nature Neuroscience, 2008). Citation numbers of other papers that have referenced our scientific reports number over 3500 as of August, 2014. The protocol number for this report is LCS 04. |
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