Virally Mediated Increased Neurotensin 1 Receptor in the Nucleus Accumbens Decreases Behavioral Effects of Mesolimbic System Activation

Cáceda, Ricardo; Kinkead, Becky; Owens, Michael J.; Nemeroff, Charles B.

doi:10.1523/jneurosci.4282-05.2005

Cited by 26 publications

(29 citation statements)

References 59 publications

(73 reference statements)

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“…NTSR1 encodes the receptor for the neuropeptide neurotensin. A murine ntsr1 knockout showed alternations in sleep and affective behaviors (18,19).…”

Section: Resultsmentioning

confidence: 99%

Rare variants in neuronal excitability genes influence risk for bipolar disorder

Ament

Szelinger

Glusman

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

163

135

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We sequenced the genomes of 200 individuals from 41 families multiply affected with bipolar disorder (BD) to identify contributions of rare variants to genetic risk. We initially focused on 3,087 candidate genes with known synaptic functions or prior evidence from genomewide association studies. BD pedigrees had an increased burden of rare variants in genes encoding neuronal ion channels, including subunits of GABA A receptors and voltage-gated calcium channels. Four uncommon coding and regulatory variants also showed significant association, including a missense variant in GABRA6. Targeted sequencing of 26 of these candidate genes in an additional 3,014 cases and 1,717 controls confirmed rare variant associations in ANK3, CACNA1B, CACNA1C, CACNA1D, CACNG2, CAMK2A, and NGF. Variants in promoters and 5′ and 3′ UTRs contributed more strongly than coding variants to risk for BD, both in pedigrees and in the case-control cohort. The genes and pathways identified in this study regulate diverse aspects of neuronal excitability. We conclude that rare variants in neuronal excitability genes contribute to risk for BD. by episodes of mania and depression (1). Episodes of mania are marked by elevated or alternatively irritable mood, grandiosity, racing thoughts, rapid speech, diminished need for sleep, and risk-taking behavior. Depression includes sadness, low energy and motivation, decreased ability to experience pleasure, insomnia, and appetite changes. Psychosis with hallucinations and delusions can occur in either state. BD affects 1-2% of the US population, and if untreated, up to 15% of patients die from suicide. Twin and family studies suggest that heritable causes explain 60-80% of lifetime risk for BD (2), with an approximate eightfold relative risk in the siblings of BD probands (3). Several common genetic markers have shown significant and replicable associations in genome-wide association studies (GWASs), including a region near a voltage-gated calcium channel, CACNA1C, and another near a synaptic scaffolding gene, ANK3 (4). Additive effects of common loci detectable on commercially available genomic arrays may be used to predict about 25% of the risk for BD (5), but typically the function and exact location of the causative variants linked to these loci is unknown.Rare variants may explain additional risk for BD. It is possible that one or a few rare variants of large effect dramatically increase disease risk, resulting in an inheritance model resembling monogenic inheritance in a given family. However, four exomesequencing and whole-genome sequencing (WGS) studies of BD pedigrees have detected few, if any, plausible variants of large effect (6-9). An alternative oligogenic model posits that different combinations of several uncommon or rare variants of moderate effect cluster in affected individuals and collectively cause disease.To test the hypothesis that rare variants contribute to risk for BD, we sequenced the genomes of 200 individuals from 41 multiply affected BD pedigrees of European ancestry. We seque...

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“…NTSR1 encodes the receptor for the neuropeptide neurotensin. A murine ntsr1 knockout showed alternations in sleep and affective behaviors (18,19).…”

Section: Resultsmentioning

confidence: 99%

Rare variants in neuronal excitability genes influence risk for bipolar disorder

Ament

Szelinger

Glusman

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

163

135

View full text Add to dashboard Cite

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“…HEK293T cells were transfected with the pLL3.7 plasmid and packaging vectors using Lipo-fectamine 2000 (Caceda et al, 2005). The second-generation human immunodeficiency virus (HIV)-based lentiviral packing vectors used were pCMV-dR8.91 and pVSV-G (generously provided by Dr. R. Caceda, Emory University, Atlanta, GA).…”

Section: Animals Mice Carrying Conditional Hif-1␣ Floxed Alleles (Himentioning

confidence: 99%

The Transcriptional Activator Hypoxia Inducible Factor 2 (HIF-2/EPAS-1) Regulates the Oxygen-Dependent Expression of Erythropoietin in Cortical Astrocytes

Chávez¹,

Baranova²,

Lin³

et al. 2006

J. Neurosci.

218

194

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In the ischemic or hypoxic brain, astrocytes appear to be one of the main sources of erythropoietin (EPO). In this study, we investigated the differential contribution of hypoxia inducible factor (HIF) isoforms to the regulation of hypoxic EPO expression in cultured astrocytes. In addition, using an in vitro model of oxygen-glucose deprivation (OGD), we studied the role of HIF-1␣ and HIF-2␣ in the generation of paracrine protective signals by astrocytes that modulate the survival of neurons exposed to OGD. Expression of HIF-1␣ or HIF-2␣ was abrogated by infecting astrocytes with lentiviral particles encoding small interference RNA specific for HIF-1␣ or HIF-2␣ (siHIF-1␣ or siHIF-2␣). Astrocytes infected with siHIF-1␣ showed abrogated hypoxic induction of vascular endothelial growth factor (VEGF) and lactate dehydrogenase (LDH) but normal EPO induction. In contrast, reduction of HIF-2␣ expression by siHIF-2␣ led to a drastic decrease of EPO hypoxic expression, but it did not affect LDH or VEGF upregulation. To further test whether HIF-2 is sufficient to drive EPO upregulation, we expressed oxygen-insensitive mutant forms of HIF-1␣ (mtHIF-1␣) (P402A/P577A) and HIF-2␣ (mtHIF-2␣) (P405A/P530A). Expression of mtHIF-2␣ but not mtHIF-1␣ in normoxic astrocytes resulted in a significant upregulation of EPO mRNA and protein. Accordingly, HIF-2␣ but not HIF-1␣ was found to be associated with the EPO hypoxia-response element by a chromatin immunoprecipitation assay. Interestingly, conditioned medium from astrocytes challenged by sublethal OGD improved neuronal survival to OGD; however, this effect was abolished during the downregulation of astrocytic HIF-2␣ using siHIF-2␣. These results indicate that HIF-2␣ mediates the transcriptional activation of EPO expression in astrocytes, and this pathway may promote astrocytic paracrinedependent neuronal survival during ischemia.

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“…resembling the action of clozapine (151). There are reports that typical and atypical antipsychotic drugs differentially alter NT neurotransmission in nigrostriatal and mesolimbic regions affecting the side effect liability and efficacy, respectively (140).…”

Section: Biochemical Womb Of Schizophreniamentioning

confidence: 99%

The biochemical womb of schizophrenia: A review

Gaur

Sharma

et al. 2008

Indian J Clin Biochem

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Virally Mediated Increased Neurotensin 1 Receptor in the Nucleus Accumbens Decreases Behavioral Effects of Mesolimbic System Activation

Cited by 26 publications

References 59 publications

Rare variants in neuronal excitability genes influence risk for bipolar disorder

Rare variants in neuronal excitability genes influence risk for bipolar disorder

The Transcriptional Activator Hypoxia Inducible Factor 2 (HIF-2/EPAS-1) Regulates the Oxygen-Dependent Expression of Erythropoietin in Cortical Astrocytes

The biochemical womb of schizophrenia: A review

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