Arginine vasopressin receptor 1A

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AVPR1A
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases AVPR1A, AVPR V1a, AVPR1, V1aR, arginine vasopressin receptor 1A
External IDs OMIM: 600821 MGI: 1859216 HomoloGene: 568 GeneCards: 552
RNA expression pattern
PBB GE AVPR1A 206250 x at tn.png

PBB GE AVPR1A 206251 s at tn.png

PBB GE AVPR1A 206252 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_000706

NM_016847

RefSeq (protein)

NP_000697.1

NP_058543.2

Location (UCSC) Chr 12: 63.14 – 63.15 Mb Chr 10: 122.45 – 122.45 Mb
PubMed search [1] [2]
Wikidata
View/Edit Human View/Edit Mouse

Arginine vasopressin receptor 1A (officially called AVPR1A) is one of the three major receptor types for arginine vasopressin (AVPR1B and AVPR2 being the others), and is present throughout the brain, as well as in the periphery in the liver, kidney, and vasculature.[1]

Arginine vasopressin receptor 1A is also known as:

  • V1a vasopressin receptor
  • antidiuretic hormone receptor 1A
  • SCCL vasopressin subtype 1a receptor
  • V1-vascular vasopressin receptor AVPR1A
  • vascular/hepatic-type arginine vasopressin receptor

Structure and function[edit]

Human AVPR1A cDNA is 1472 bp long and encodes a 418 amino-acid long polypeptide which shares 72%, 36%, 37%, and 45% sequence identity with rat Avpr1a, human AVPR2, rat Avpr2, and human oxytocin receptor (OXTR), respectively. AVPR1A is a G-protein coupled receptor (GPCR) with 7 transmembrane domains that couples to Gaq/11 GTP binding proteins, which along with Gbl, activate phospholipase C activity.[1][2] Clinically, the V1A receptor is related to vasoconstriction compared to the V1B receptor that is more related to ACTH release or the V2 receptor that is linked to the diuretic function of ADH.

Ligand binding[edit]

In the N-terminal juxtamembrane segment of the AVPR1A, the glutamate residue at position 54 (E54) and the arginine residue at position 46 (R46) are critical for binding with AVP and AVP agonists, with E54 likely to interact with AVP and R46 to contribute to a conformational switch.[3]

Competitors of [125I]Tyr-Phaa-specific binding to AVPR1A include:[2]

  • Linear V1a antagonist phenylacetyl-D-Tyr(Et)-Phe-Gln-Asn-Lys-Pro-Arg-NH2 (Ki = 1.2 ± 0.2 nM)
  • Relcovaptan (SR-49059) (Ki = 1.3 ± 0.2 nM)
  • AVP (Ki = 1.8 ± 0.4 nM)
  • Linear V1a antagonist phenylacetyl-D-Tyr(Et)-Phe-Val-Asn-Lys-Pro-Tyr-NH2 (Ki = 3.0 ± 0.5 nM)
  • V2 antagonist d(CH2)5-[D-Ile2, Ile4, Ala-NH2]AVP (Ki = 68 ± 17 nM)
  • Oxytocin (Ki = 129 ± 22 nM)

The AVPR1A is endocytosed by binding to beta arrestin, which dissociates rapidly from AVPR1A to allow it to return to the plasma membrane; however, upon activation, AVPR1A can heterodimerize with AVPR2 to increase beta-arrestin-mediated endocytosis (and intracellular accumulation) of AVPR1A, since AVPR2 is far less likely to dissociate from beta-arrestin.[4]

Role in behavior[edit]

The activity / genetic variants of the AVPR1A gene might be related to generosity and altruistic behavior.[5] NatureNews has referred to AVPR1A as the "ruthlessness gene".[6]

Prairie vs. montane voles[edit]

The injection of oxytocin (OXT) vs. oxytocin antagonist (OTA) at birth has sexually dimorphic effects in prairie voles later on in life in various areas of the brain.[7]

Males treated with OXT showed increases in Avpr1a in the ventral palladium, lateral septum, and cingulate cortex, while females showed decreases; males treated with an OTA showed decreases in AVPR1A in the bed nucleus of the stria terminalis, medial preoptic area of the hypothalamus, and lateral septum.[7]

Although the Avpr1a coding region is 99% identical between prairie and montane voles, and binding and second messenger activity does not differ, patterns of distribution of Avpr1a differ drastically.[8]

Mice[edit]

Male knockout mice in Avpr1a have reduced anxiety-like behavior and greatly impaired social recognition abilities, without any defects in spatial and nonsocial olfactory learning and memory tasks, as measured by the elevated plus maze, light/dark box, Morris water maze, forced swim, baseline acoustic startle and prepulse inhibition (PPI), and olfactory habituation tests.[9] Some studies have shown Avpr1a knockout mice to have deficits in their circadian rhythms[10][11] and olfaction.[10]

Avpr1a’s role in social recognition is particularly important in the lateral septum, as using viral vectors to replace inactivated Avpr1a expression rescues social recognition and increases anxiety-related behavior.[12] However, conflicting results have been found in another study.[10] Also, unlike vasopressin 1b receptor and oxytcoin knockout mice, Avpr1a KO mice have a normal Bruce effect (appropriate failure of pregnancy in presence of novel male).[13]

Although activation of Avpr1a is a major mediator of anxiogenesis in males, it is not in females.[14]

Rats[edit]

Avpr1a transcripts are diurnally expressed 12 hours out of phase from vasopressin expression in vasopressin and vasoactive intestinal polypeptide neurons of the suprachiasmatic nucleus in both vasopressin-normal Sprague-Dawley rats, as well as vasopressin-deficient Brattleboro rats.[15]

Rats with reduced Avpr1a in the bed nucleus of the stria terminalis have increased incidences of the isolation potentiated startle, a measure of isolation-induced anxiety.[16]

Interestingly, subchronic phencyclidine (PCP) treatment (which induces schizophrenic symptoms) reduces Avpr1a density in many brain regions, implying there might be a role for AVPR1A in schizophrenia.[17]

Avpr1a is present in the lateral septum, neocortical layer IV, hippocampal formation, amygdalostriatal area, bed nucleus of the stria terminalis, suprachiasmatic nucleus, ventral tegmental area, substantia nigra, superior colliculus, dorsal raphe, nucleus of the solitary tract, spinal cord, and inferior olive, while mRNA transcripts for Avpr1a are found in the olfactory bulb, hippocampal formation, lateral septum, suprachiasmatic nucleus, paraventricular nucleus, anterior hypothalamic area, arcuate nucleus, lateral habenula, ventral tegmental area, substantia nigra (pars compacta), superior colliculus, raphe nuclei, locus coeruleus, inferior olive, choroid plexus, endothelial cells, area postrema and nucleus of the solitary tract.[1]

Humans[edit]

Although vasopressin cell and fibre distribution patterns are highly conserved across species (with centrally projecting systems being sexually dimorphic), the vasopressin receptor AVPR1A distribution differs both between and within species; vasopressin production occurs in the hypothalamus, bed nucleus of the stria terminalis, and the medial amygdala (projecting to the lateral septum and ventral pallidum), while vasopressin binding sites in humans are in the lateral septum, thalamus, basal amygdaloid nucleus, and brainstem, but not cortex.[18]

Human AVPR1A is situated on chromosome 12q14-15, and the promoter region does not have repeat sequences homologous to those found in prairie voles. Three polymorphic repetitive sequences have been found in humans in the 5’ flanking region: RS3, RS1, and a (GT)25 dinucleotide repeat.

A 2015 study found a correlation between AVPR1A expression and predisposition to extra-pair mating in women but not in men.[19]

Polymorphisms[edit]

RS3[edit]

The AVPR1A repeat polymorphism RS3 is a complex (CT)4-TT-(CT)8-(GT)24 repeat that is 3625 bp upstream of the transcription start site.

Homozygosity in allele 334 of RS3 is associated in men (but not women) with problems with pair-bonding behavior, measured by traits such as partner bonding, perceived marital problems, marital status, as well as spousal perception of marital quality.[20]

In a study of 203 male and female university students, participants with short (308-325 bp) vs. long (327-342) versions of RS3 were less generous, as measured by lower scores on both money allocations in the dictator game, as well as by self-report with the Bardi-Schwartz Universalism and Benevolence Value-expressive Behavior Scales; although the precise functional significance of longer AVPR1A RS3 repeats is not known, they are associated with higher AVPR1A postmortem hippocampal mRNA levels.[5]

Relative to all other alleles, the 334 allele of RS3 shows overactivation of left amygdala (in response to fearful face stimuli), with longer variants of RS3 additionally associated with stronger amygdala activation.[18]

RS1[edit]

The AVPR1A repeat polymorphism RS1 is a (GATA)14 tetranucleotide repeat that is 553 bp upstream from the transcription start site. Allele 320 in RS1 is associated with increased novelty seeking and decreased harm avoidance; additionally, relative to all other alleles, the 320 allele of RS1 showed significantly less activity in the left amygdala, with shorter variants showing a trend of stronger activity.[18]

Other microsatellites[edit]

The AGAT polymorphism is associated with age of first intercourse in females, with those homozygous for long repeats more likely to have sex before age 15 than any other genotype.[21] However, there is no evidence of preferential transmission of AVPR1A microsatellite repeats to hypersexual or uninhibited people-seeking.[22]

Polymorphisms in AVPR1A have also been shown to be associated with social interaction skills, and have been linked to such diverse traits as dancing and musical ability, altruism and autism.[23][24][25][26]

Chimpanzees populations have individuals with single (only (GT)25 microsatellite) and duplicated (the (GT)25 microsatellite as well as the RS3) alleles, with allele frequencies of 0.795 and 0.205, respectively.[10]

References[edit]

  1. ^ a b c Caldwell HK, Lee HJ, Macbeth AH, Young WS (Jan 2008). "Vasopressin: behavioral roles of an "original" neuropeptide". Progress in Neurobiology 84 (1): 1–24. doi:10.1016/j.pneurobio.2007.10.007. PMC 2292122. PMID 18053631. 
  2. ^ a b Thibonnier M, Auzan C, Madhun Z, Wilkins P, Berti-Mattera L, Clauser E (Feb 1994). "Molecular cloning, sequencing, and functional expression of a cDNA encoding the human V1a vasopressin receptor". The Journal of Biological Chemistry 269 (5): 3304–10. PMID 8106369. 
  3. ^ Hawtin SR, Wesley VJ, Simms J, Argent CC, Latif K, Wheatley M (Nov 2005). "The N-terminal juxtamembrane segment of the V1a vasopressin receptor provides two independent epitopes required for high-affinity agonist binding and signaling". Molecular Endocrinology 19 (11): 2871–81. doi:10.1210/me.2005-0148. PMID 15994199. 
  4. ^ Terrillon S, Barberis C, Bouvier M (Feb 2004). "Heterodimerization of V1a and V2 vasopressin receptors determines the interaction with beta-arrestin and their trafficking patterns". Proceedings of the National Academy of Sciences of the United States of America 101 (6): 1548–53. doi:10.1073/pnas.0305322101. PMC 341772. PMID 14757828. 
  5. ^ a b Knafo A, Israel S, Darvasi A, Bachner-Melman R, Uzefovsky F, Cohen L, Feldman E, Lerer E, Laiba E, Raz Y, Nemanov L, Gritsenko I, Dina C, Agam G, Dean B, Bornstein G, Ebstein RP (Apr 2008). "Individual differences in allocation of funds in the dictator game associated with length of the arginine vasopressin 1a receptor RS3 promoter region and correlation between RS3 length and hippocampal mRNA". Genes, Brain, and Behavior 7 (3): 266–75. doi:10.1111/j.1601-183X.2007.00341.x. PMID 17696996. 
  6. ^ Hopkin, Michael (April 2008). "'Ruthlessness gene' discovered". Nature@News. doi:10.1038/news.2008.738. Dictatorial behaviour may be partly genetic, study suggests 
  7. ^ a b Bales KL, Plotsky PM, Young LJ, Lim MM, Grotte N, Ferrer E, Carter CS (Jan 2007). "Neonatal oxytocin manipulations have long-lasting, sexually dimorphic effects on vasopressin receptors". Neuroscience 144 (1): 38–45. doi:10.1016/j.neuroscience.2006.09.009. PMC 1774559. PMID 17055176. 
  8. ^ Nair HP, Young LJ (Apr 2006). "Vasopressin and pair-bond formation: genes to brain to behavior". Physiology 21 (2): 146–52. doi:10.1152/physiol.00049.2005. PMID 16565480. 
  9. ^ Bielsky IF, Hu SB, Szegda KL, Westphal H, Young LJ (Mar 2004). "Profound impairment in social recognition and reduction in anxiety-like behavior in vasopressin V1a receptor knockout mice". Neuropsychopharmacology 29 (3): 483–93. doi:10.1038/sj.npp.1300360. PMID 14647484. 
  10. ^ a b c d Wersinger SR, Caldwell HK, Martinez L, Gold P, Hu SB, Young WS (Aug 2007). "Vasopressin 1a receptor knockout mice have a subtle olfactory deficit but normal aggression". Genes, Brain, and Behavior 6 (6): 540–51. doi:10.1111/j.1601-183X.2006.00281.x. PMID 17083331. 
  11. ^ Li JD, Burton KJ, Zhang C, Hu SB, Zhou QY (Mar 2009). "Vasopressin receptor V1a regulates circadian rhythms of locomotor activity and expression of clock-controlled genes in the suprachiasmatic nuclei". American Journal of Physiology. Regulatory, Integrative and Comparative Physiology 296 (3): R824–30. doi:10.1152/ajpregu.90463.2008. PMID 19052319. 
  12. ^ Bielsky IF, Hu SB, Ren X, Terwilliger EF, Young LJ (Aug 2005). "The V1a vasopressin receptor is necessary and sufficient for normal social recognition: a gene replacement study". Neuron 47 (4): 503–13. doi:10.1016/j.neuron.2005.06.031. PMID 16102534. 
  13. ^ Wersinger SR, Temple JL, Caldwell HK, Young WS (Jan 2008). "Inactivation of the oxytocin and the vasopressin (Avp) 1b receptor genes, but not the Avp 1a receptor gene, differentially impairs the Bruce effect in laboratory mice (Mus musculus)". Endocrinology 149 (1): 116–21. doi:10.1210/en.2007-1056. PMC 2194605. PMID 17947352. 
  14. ^ Bielsky IF, Hu SB, Young LJ (Oct 2005). "Sexual dimorphism in the vasopressin system: lack of an altered behavioral phenotype in female V1a receptor knockout mice". Behavioural Brain Research 164 (1): 132–6. doi:10.1016/j.bbr.2005.06.005. PMID 16046007. 
  15. ^ Young WS, Kovács K, Lolait SJ (Aug 1993). "The diurnal rhythm in vasopressin V1a receptor expression in the suprachiasmatic nucleus is not dependent on vasopressin". Endocrinology 133 (2): 585–90. doi:10.1210/en.133.2.585. PMID 8344200. 
  16. ^ Nair HP, Gutman AR, Davis M, Young LJ (Dec 2005). "Central oxytocin, vasopressin, and corticotropin-releasing factor receptor densities in the basal forebrain predict isolation potentiated startle in rats". The Journal of Neuroscience 25 (49): 11479–88. doi:10.1523/JNEUROSCI.2524-05.2005. PMID 16339041. 
  17. ^ Tanaka K, Suzuki M, Sumiyoshi T, Murata M, Tsunoda M, Kurachi M (Dec 2003). "Subchronic phencyclidine administration alters central vasopressin receptor binding and social interaction in the rat". Brain Research 992 (2): 239–45. doi:10.1016/j.brainres.2003.08.050. PMID 14625062. 
  18. ^ a b c Meyer-Lindenberg A, Kolachana B, Gold B, Olsh A, Nicodemus KK, Mattay V, Dean M, Weinberger DR (Oct 2009). "Genetic variants in AVPR1A linked to autism predict amygdala activation and personality traits in healthy humans". Molecular Psychiatry 14 (10): 968–75. doi:10.1038/mp.2008.54. PMC 2754603. PMID 18490926. 
  19. ^ Zietsch, Brendan P.; Westberg, Lars; Santtila, Pekka; Jern, Patrick (2015). "Genetic analysis of human extrapair mating: heritability, between-sex correlation, and receptor genes for vasopressin and oxytocin". Evolution & Human Behavior 36 (2): 130–136. doi:10.1016/j.evolhumbehav.2014.10.001. 
  20. ^ Walum H, Westberg L, Henningsson S, Neiderhiser JM, Reiss D, Igl W, Ganiban JM, Spotts EL, Pedersen NL, Eriksson E, Lichtenstein P (Sep 2008). "Genetic variation in the vasopressin receptor 1a gene (AVPR1A) associates with pair-bonding behavior in humans". Proceedings of the National Academy of Sciences of the United States of America 105 (37): 14153–6. doi:10.1073/pnas.0803081105. PMC 2533683. PMID 18765804. 
  21. ^ Prichard ZM, Mackinnon AJ, Jorm AF, Easteal S (Nov 2007). "AVPR1A and OXTR polymorphisms are associated with sexual and reproductive behavioral phenotypes in humans. Mutation in brief no. 981. Online". Human Mutation 28 (11): 1150. doi:10.1002/humu.9510. PMID 17939166. 
  22. ^ Geller B, Tillman R, Badner JA, Cook EH (Dec 2005). "Are the arginine vasopressin V1a receptor microsatellites related to hypersexuality in children with a prepubertal and early adolescent bipolar disorder phenotype?". Bipolar Disorders 7 (6): 610–6. doi:10.1111/j.1399-5618.2005.00259.x. PMID 16403186. 
  23. ^ Bachner-Melman R, Dina C, Zohar AH, Constantini N, Lerer E, Hoch S, Sella S, Nemanov L, Gritsenko I, Lichtenberg P, Granot R, Ebstein RP (Sep 2005). "AVPR1a and SLC6A4 gene polymorphisms are associated with creative dance performance". PLoS Genetics 1 (3): e42. doi:10.1371/journal.pgen.0010042. PMC 1239939. PMID 16205790.  open access publication - free to read
  24. ^ Yirmiya N, Rosenberg C, Levi S, Salomon S, Shulman C, Nemanov L, Dina C, Ebstein RP (May 2006). "Association between the arginine vasopressin 1a receptor (AVPR1a) gene and autism in a family-based study: mediation by socialization skills". Molecular Psychiatry 11 (5): 488–94. doi:10.1038/sj.mp.4001812. PMID 16520824. 
  25. ^ Israel S, Lerer E, Shalev I, Uzefovsky F, Reibold M, Bachner-Melman R, Granot R, Bornstein G, Knafo A, Yirmiya N, Ebstein RP (2008). "Molecular genetic studies of the arginine vasopressin 1a receptor (AVPR1a) and the oxytocin receptor (OXTR) in human behaviour: from autism to altruism with some notes in between". Progress in Brain Research 170: 435–49. doi:10.1016/S0079-6123(08)00434-2. PMID 18655900. 
  26. ^ Ukkola LT, Onkamo P, Raijas P, Karma K, Järvelä I (2009). Reif A, ed. "Musical aptitude is associated with AVPR1A-haplotypes". PloS One 4 (5): e5534. doi:10.1371/journal.pone.0005534. PMC 2678260. PMID 19461995.  open access publication - free to read

Further reading[edit]

  • Thibonnier M, Coles P, Thibonnier A, Shoham M (2002). "Molecular pharmacology and modeling of vasopressin receptors". Progress in Brain Research 139: 179–96. doi:10.1016/S0079-6123(02)39016-2. PMID 12436935. 
  • Cross SH, Charlton JA, Nan X, Bird AP (Mar 1994). "Purification of CpG islands using a methylated DNA binding column". Nature Genetics 6 (3): 236–44. doi:10.1038/ng0394-236. PMID 8012384. 
  • Hirasawa A, Shibata K, Kotosai K, Tsujimoto G (Aug 1994). "Cloning, functional expression and tissue distribution of human cDNA for the vascular-type vasopressin receptor". Biochemical and Biophysical Research Communications 203 (1): 72–9. doi:10.1006/bbrc.1994.2150. PMID 8074728. 
  • Thibonnier M, Auzan C, Madhun Z, Wilkins P, Berti-Mattera L, Clauser E (Feb 1994). "Molecular cloning, sequencing, and functional expression of a cDNA encoding the human V1a vasopressin receptor". The Journal of Biological Chemistry 269 (5): 3304–10. PMID 8106369. 
  • Young WS, Kovács K, Lolait SJ (Aug 1993). "The diurnal rhythm in vasopressin V1a receptor expression in the suprachiasmatic nucleus is not dependent on vasopressin". Endocrinology 133 (2): 585–90. doi:10.1210/en.133.2.585. PMID 8344200. 
  • Thibonnier M, Graves MK, Wagner MS, Auzan C, Clauser E, Willard HF (Feb 1996). "Structure, sequence, expression, and chromosomal localization of the human V1a vasopressin receptor gene". Genomics 31 (3): 327–34. doi:10.1006/geno.1996.0055. PMID 8838314. 
  • North WG, Fay MJ, Longo K, Du J (1998). "Functional vasopressin V1 type receptors are present in variant as well as classical forms of small-cell carcinoma". Peptides 18 (7): 985–93. doi:10.1016/S0196-9781(97)00072-7. PMID 9357056. 
  • North WG, Fay MJ, Longo KA, Du J (May 1998). "Expression of all known vasopressin receptor subtypes by small cell tumors implies a multifaceted role for this neuropeptide". Cancer Research 58 (9): 1866–71. PMID 9581826. 
  • North WG, Fay MJ, Du J (1999). "MCF-7 breast cancer cells express normal forms of all vasopressin receptors plus an abnormal V2R". Peptides 20 (7): 837–42. doi:10.1016/S0196-9781(99)00070-4. PMID 10477084. 
  • Tahara A, Tsukada J, Ishii N, Tomura Y, Wada K, Kusayama T, Yatsu T, Uchida W, Tanaka A (Jul 1999). "Comparison of vasopressin binding sites in human uterine and vascular smooth muscle cells". European Journal of Pharmacology 378 (1): 137–42. doi:10.1016/S0014-2999(99)00403-3. PMID 10478574. 
  • Thibonnier M, Graves MK, Wagner MS, Chatelain N, Soubrier F, Corvol P, Willard HF, Jeunemaitre X (Apr 2000). "Study of V(1)-vascular vasopressin receptor gene microsatellite polymorphisms in human essential hypertension". Journal of Molecular and Cellular Cardiology 32 (4): 557–64. doi:10.1006/jmcc.2000.1108. PMID 10756113. 
  • Berrada K, Plesnicher CL, Luo X, Thibonnier M (Sep 2000). "Dynamic interaction of human vasopressin/oxytocin receptor subtypes with G protein-coupled receptor kinases and protein kinase C after agonist stimulation". The Journal of Biological Chemistry 275 (35): 27229–37. doi:10.1074/jbc.M002288200. PMID 10858434. 
  • Kim SJ, Young LJ, Gonen D, Veenstra-VanderWeele J, Courchesne R, Courchesne E, Lord C, Leventhal BL, Cook EH, Insel TR (2002). "Transmission disequilibrium testing of arginine vasopressin receptor 1A (AVPR1A) polymorphisms in autism". Molecular Psychiatry 7 (5): 503–7. doi:10.1038/sj.mp.4001125. PMID 12082568. 
  • Tahtaoui C, Balestre MN, Klotz P, Rognan D, Barberis C, Mouillac B, Hibert M (Oct 2003). "Identification of the binding sites of the SR49059 nonpeptide antagonist into the V1a vasopressin receptor using sulfydryl-reactive ligands and cysteine mutants as chemical sensors". The Journal of Biological Chemistry 278 (41): 40010–9. doi:10.1074/jbc.M301128200. PMID 12869559. 
  • Hawtin SR, Wesley VJ, Simms J, Parslow RA, Miles A, McEwan K, Keen M, Wheatley M (Dec 2003). "An arginyl in the N-terminus of the V1a vasopressin receptor is part of the conformational switch controlling activation by agonist". European Journal of Biochemistry / FEBS 270 (23): 4681–8. doi:10.1046/j.1432-1033.2003.03865.x. PMID 14622255. 
  • Terrillon S, Barberis C, Bouvier M (Feb 2004). "Heterodimerization of V1a and V2 vasopressin receptors determines the interaction with beta-arrestin and their trafficking patterns". Proceedings of the National Academy of Sciences of the United States of America 101 (6): 1548–53. doi:10.1073/pnas.0305322101. PMC 341772. PMID 14757828. 
  • Wassink TH, Piven J, Vieland VJ, Pietila J, Goedken RJ, Folstein SE, Sheffield VC (Oct 2004). "Examination of AVPR1a as an autism susceptibility gene". Molecular Psychiatry 9 (10): 968–72. doi:10.1038/sj.mp.4001503. PMID 15098001. 

External links[edit]