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Molecular Autism
Published in: Molecular Autism 1/2018

Open Access 01-12-2018 | Research

17-β estradiol increases parvalbumin levels in Pvalb heterozygous mice and attenuates behavioral phenotypes with relevance to autism core symptoms

Authors: Federica Filice, Emanuel Lauber, Karl Jakob Vörckel, Markus Wöhr, Beat Schwaller

Published in: Molecular Autism | Issue 1/2018

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Abstract

Background

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by two core symptoms: impaired social interaction and communication, and restricted, repetitive behaviors and interests. The pathophysiology of ASD is not yet fully understood, due to a plethora of genetic and environmental risk factors that might be associated with or causal for ASD. Recent findings suggest that one putative convergent pathway for some forms of ASD might be the downregulation of the calcium-binding protein parvalbumin (PV). PV-deficient mice (PV−/−, PV+/−), as well as Shank1−/−, Shank3−/−, and VPA mice, which show behavioral deficits relevant to all human ASD core symptoms, are all characterized by lower PV expression levels.

Methods

Based on the hypothesis that PV expression might be increased by 17-β estradiol (E2), PV+/− mice were treated with E2 from postnatal days 5–15 and ASD-related behavior was tested between postnatal days 25 and 31.

Results

PV expression levels were significantly increased after E2 treatment and, concomitantly, sociability deficits in PV+/− mice in the direct reciprocal social interaction and the 3-chamber social approach assay, as well as repetitive behaviors, were attenuated. E2 treatment of PV+/+ mice did not increase PV levels and had detrimental effects on sociability and repetitive behavior. In PV−/− mice, E2 obviously did not affect PV levels; tested behaviors were not different from the ones in vehicle-treated PV−/− mice.

Conclusion

Our results suggest that the E2-linked amelioration of ASD-like behaviors is specifically occurring in PV+/− mice, indicating that PV upregulation is required for the E2-mediated rescue of ASD-relevant behavioral impairments.
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Literature
1.
de la Torre-Ubieta L, Won H, Stein JL, Geschwind DH. Advancing the understanding of autism disease mechanisms through genetics. Nat Med. 2016;22(4):345–61.CrossRefPubMedPubMedCentral
2.
Ergaz Z, Weinstein-Fudim L, Ornoy A. Genetic and non-genetic animal models for autism spectrum disorders (ASD). Reprod Toxicol. 2016;64:116–40.CrossRefPubMed
3.
Politte LC, McDougle CJ. Atypical antipsychotics in the treatment of children and adolescents with pervasive developmental disorders. Psychopharmacology. 2014;231(6):1023–36.CrossRefPubMed
4.
Sahin M, Sur M. Genes, circuits, and precision therapies for autism and related neurodevelopmental disorders. Science. 2015;350(6263).
5.
Filice F, Vörckel KJ, Sungur AO, Wöhr M, Schwaller B. Reduction in parvalbumin expression not loss of the parvalbumin-expressing GABA interneuron subpopulation in genetic parvalbumin and shank mouse models of autism. Mol Brain. 2016;9:10.CrossRefPubMedPubMedCentral
6.
Lauber E, Filice F, Schwaller B. Prenatal valproate exposure differentially affects parvalbumin-expressing neurons and related circuits in the cortex and striatum of mice. Front Mol Neurosci. 2016;9:150.CrossRefPubMedPubMedCentral
7.
Wöhr M, Orduz D, Gregory P, Moreno H, Khan U, Vorckel KJ, Wolfer DP, Welzl H, Gall D, Schiffmann SN, et al. Lack of parvalbumin in mice leads to behavioral deficits relevant to all human autism core symptoms and related neural morphofunctional abnormalities. Transl Psychiatry. 2015;5:e525.CrossRefPubMedPubMedCentral
8.
Hashemi E, Ariza J, Rogers H, Noctor SC, Martinez-Cerdeno V. The number of parvalbumin-expressing interneurons is decreased in the medial prefrontal cortex in autism. Cereb Cortex. 2017;27(3):1931-43.
9.
10.
Parikshak NN, Swarup V, Belgard TG, Irimia M, Ramaswami G, Gandal MJ, Hartl C, Leppa V, Ubieta LT, Huang J, et al. Genome-wide changes in lncRNA, splicing, and regional gene expression patterns in autism. Nature. 2016;540(7633):423–7.CrossRefPubMed
11.
Blurton-Jones M, Tuszynski MH. Estrogen receptor-beta colocalizes extensively with parvalbumin-labeled inhibitory neurons in the cortex, amygdala, basal forebrain, and hippocampal formation of intact and ovariectomized adult rats. J Comp Neurol. 2002;452(3):276–87.CrossRefPubMed
12.
Ross NR, Porter LL. Effects of dopamine and estrogen upon cortical neurons that express parvalbumin in vitro. Brain Res Dev Brain Res. 2002;137(1):23–34.CrossRefPubMed
13.
Sotonyi P, Gao Q, Bechmann I, Horvath TL. Estrogen promotes parvalbumin expression in arcuate nucleus POMC neurons. Reprod Sci. 2010;17(12):1077–80.CrossRefPubMed
14.
Fujimoto N, Igarashi K, Kanno J, Honda H, Inoue T. Identification of estrogen-responsive genes in the GH3 cell line by cDNA microarray analysis. J Steroid Biochem Mol Biol. 2004;91(3):121–9.CrossRefPubMed
15.
Corvino V, Di Maria V, Marchese E, Lattanzi W, Biamonte F, Michetti F, Geloso MC. Estrogen administration modulates hippocampal GABAergic subpopulations in the hippocampus of trimethyltin-treated rats. Front Cell Neurosci. 2015;9:433.CrossRefPubMedPubMedCentral
16.
17.
Wöhr M, Scattoni ML. Behavioural methods used in rodent models of autism spectrum disorders: current standards and new developments. Behav Brain Res. 2013;251:5–17.CrossRefPubMed
18.
Gorski RA. Perinatal effects of sex steroids on brain development and function. Prog Brain Res. 1973;39:149–63.CrossRefPubMed
19.
Alcantara S, Ferrer I, Soriano E. Postnatal development of parvalbumin and calbindin D28K immunoreactivities in the cerebral cortex of the rat. Anat Embryol. 1993;188:63–73.CrossRefPubMed
20.
del Rio JA, de Lecea L, Ferrer I, Soriano E. The development of parvalbumin-immunoreactivity in the neocortex of the mouse. Brain Res Dev Brain Res. 1994;81(2):247–59.CrossRefPubMed
21.
Gandal MJ, Nesbitt AM, McCurdy RM, Alter MD. Measuring the maturity of the fast-spiking interneuron transcriptional program in autism, schizophrenia, and bipolar disorder. PLoS One. 2012;7(8):e41215.CrossRefPubMedPubMedCentral
22.
Macrì S, Biamonte F, Romano E, Marino R, Keller F, Laviola G. Perseverative responding and neuroanatomical alterations in adult heterozygous reeler mice are mitigated by neonatal estrogen administration. Psychoneuroendocrinology. 2010;35(9):1374–87.CrossRefPubMed
23.
Hoffman EJ, Turner KJ, Fernandez JM, Cifuentes D, Ghosh M, Ijaz S, Jain RA, Kubo F, Bill BR, Baier H, et al. Estrogens suppress a behavioral phenotype in zebrafish mutants of the autism risk gene, CNTNAP2. Neuron. 2016;89(4):725–33.CrossRefPubMedPubMedCentral
24.
Schwaller B, Dick J, Dhoot G, Carroll S, Vrbova G, Nicotera P, Pette D, Wyss A, Bluethmann H, Hunziker W, et al. Prolonged contraction-relaxation cycle of fast-twitch muscles in parvalbumin knockout mice. Am J Physiol (Cell Physiol). 1999;276(2 Pt 1):C395–403.CrossRef
25.
Moreno H, Burghardt NS, Vela-Duarte D, Masciotti J, Hua F, Fenton AA, Schwaller B, Small SA. The absence of the calcium-buffering protein calbindin is associated with faster age-related decline in hippocampal metabolism. Hippocampus. 2012;22(5):1107–20.CrossRefPubMed
26.
Aiello TP, Whitaker-Azmitia PM. Sexual differentiation and the neuroendocrine hypothesis of autism. Anat Rec (Hoboken). 2011;294(10):1663–70.CrossRef
27.
Patisaul HB, Fortino AE, Polston EK. Neonatal genistein or bisphenol-A exposure alters sexual differentiation of the AVPV. Neurotoxicol Teratol. 2006;28(1):111–8.CrossRefPubMed
28.
Sungur AO, Vorckel KJ, Schwarting RK, Wöhr M. Repetitive behaviors in the Shank1 knockout mouse model for autism spectrum disorder: developmental aspects and effects of social context. J Neurosci Methods. 2014;234:92–100.CrossRefPubMed
29.
Yang M, Silverman JL, Crawley JN. Automated three-chambered social approach task for mice. Curr Protoc Neurosci. 2011;56:8.26.1–8.26.16.
30.
Thomas A, Burant A, Bui N, Graham D, Yuva-Paylor LA, Paylor R. Marble burying reflects a repetitive and perseverative behavior more than novelty-induced anxiety. Psychopharmacology. 2009;204(2):361–73.CrossRefPubMedPubMedCentral
31.
Caillard O, Moreno H, Schwaller B, Llano I, Celio MR, Marty A. Role of the calcium-binding protein parvalbumin in short-term synaptic plasticity. Proc Natl Acad Sci U S A. 2000;97(24):13372–7.CrossRefPubMedPubMedCentral
32.
Schwaller B, Tetko IV, Tandon P, Silveira DC, Vreugdenhil M, Henzi T, Potier MC, Celio MR, Villa AE. Parvalbumin deficiency affects network properties resulting in increased susceptibility to epileptic seizures. Mol Cell Neurosci. 2004;25(4):650–63.CrossRefPubMed
33.
Silverman JL, Turner SM, Barkan CL, Tolu SS, Saxena R, Hung AY, Sheng M, Crawley JN. Sociability and motor functions in Shank1 mutant mice. Brain Res. 2011;1380:120–37.CrossRefPubMed
34.
Wang X, McCoy PA, Rodriguiz RM, Pan Y, Je HS, Roberts AC, Kim CJ, Berrios J, Colvin JS, Bousquet-Moore D, et al. Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3. Hum Mol Genet. 2011;20(15):3093–108.CrossRefPubMedPubMedCentral
35.
Won H, Lee HR, Gee HY, Mah W, Kim JI, Lee J, Ha S, Chung C, Jung ES, Cho YS, et al. Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function. Nature. 2012;486(7402):261–5.CrossRefPubMed
36.
Filice F, Schwaller B. Parvalbumin and autism: different causes, same effect? Oncotarget. 2017;8(5):7222–3.CrossRefPubMed
37.
Sungur AO, Schwarting RK, Wöhr M. Early communication deficits in the Shank1 knockout mouse model for autism spectrum disorder: developmental aspects and effects of social context. Autism Res. 2016;9(6):696–709.CrossRefPubMed
38.
Wöhr M, Roullet FI, Hung AY, Sheng M, Crawley JN. Communication impairments in mice lacking Shank1: reduced levels of ultrasonic vocalizations and scent marking behavior. PLoS One. 2011;6(6):e20631.CrossRefPubMedPubMedCentral
39.
Peca J, Feliciano C, Ting JT, Wang W, Wells MF, Venkatraman TN, Lascola CD, Fu Z, Feng G. Shank3 mutant mice display autistic-like behaviours and striatal dysfunction. Nature. 2011;472(7344):437–42.CrossRefPubMedPubMedCentral
40.
41.
Peixoto RT, Wang W, Croney DM, Kozorovitskiy Y, Sabatini BL. Early hyperactivity and precocious maturation of corticostriatal circuits in Shank3B(−/−) mice. Nat Neurosci. 2016;19(5):716–24.CrossRefPubMedPubMedCentral
42.
43.
Bell RW, Nitschke W, Gorry TH, Zachman TA. Infantile stimulation and ultrasonic signaling: a possible mediator of early handling phenomena. Dev Psychobiol. 1971;4(2):181–91.CrossRefPubMed
44.
45.
Pare WP, Glavin GB. Restraint stress in biomedical research: a review. Neurosci Biobehav Rev. 1986;10(3):339–70.CrossRefPubMed
46.
Boivin JR, Piekarski DJ, Wahlberg JK, Wilbrecht L. Age, sex, and gonadal hormones differently influence anxiety- and depression-related behavior during puberty in mice. Psychoneuroendocrinology. 2017;85:78–87.CrossRefPubMed
47.
Piekarski DJ, Boivin JR, Wilbrecht L. Ovarian hormones organize the maturation of inhibitory neurotransmission in the frontal cortex at puberty onset in female mice. Curr Biol. 2017;27(12):1735–45. e1733CrossRefPubMed
48.
Reilly MP, Weeks CD, Topper VY, Thompson LM, Crews D, Gore AC. The effects of prenatal PCBs on adult social behavior in rats. Horm Behav. 2015;73:47–55.CrossRefPubMedPubMedCentral
49.
50.
Wu MV, Manoli DS, Fraser EJ, Coats JK, Tollkuhn J, Honda S, Harada N, Shah NM. Estrogen masculinizes neural pathways and sex-specific behaviors. Cell. 2009;139(1):61–72.CrossRefPubMedPubMedCentral
51.
52.
Schwaller B. The use of transgenic mouse models to reveal the functions of Ca2+ buffer proteins in excitable cells. Biochim Biophys Acta. 2012;1820(8):1294–303.CrossRefPubMed
53.
Rubenstein JL, Merzenich MM. Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav. 2003;2(5):255–67.CrossRefPubMed
54.
Xiong Y, Liu X, Han L, Yan J. The ongoing balance of cortical excitation and inhibition during early development. Neurosci Biobehav Rev. 2011;35(10):2114–6.CrossRefPubMed
55.
Gogolla N, Takesian AE, Feng G, Fagiolini M, Hensch TK. Sensory integration in mouse insular cortex reflects GABA circuit maturation. Neuron. 2014;83(4):894–905.CrossRefPubMedPubMedCentral
56.
Krishnan K, Wang BS, Lu J, Wang L, Maffei A, Cang J, Huang ZJ. MeCP2 regulates the. MD: modeling autism by SHANK gene mutations in mice. Neuron. 2013;78(1):8–27.CrossRef
57.
Berkowicz SR, Featherby TJ, Qu Z, Giousoh A, Borg NA, Heng JI, Whisstock JC, Bird PI. Brinp1(−/−) mice exhibit autism-like behaviour, altered memory, hyperactivity and increased parvalbumin-positive cortical interneuron density. Molecular Autism. 2016;7:22.CrossRefPubMedPubMedCentral
58.
59.
Yoo J, Bakes J, Bradley C, Collingridge GL, Kaang BK. Shank mutant mice as an animal model of autism. Philos Trans R Soc Lond Ser B Biol Sci. 2014;369(1633):20130143.CrossRef
Metadata
Title
17-β estradiol increases parvalbumin levels in Pvalb heterozygous mice and attenuates behavioral phenotypes with relevance to autism core symptoms
Authors
Federica Filice
Emanuel Lauber
Karl Jakob Vörckel
Markus Wöhr
Beat Schwaller
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Molecular Autism / Issue 1/2018
Electronic ISSN: 2040-2392
DOI
https://doi.org/10.1186/s13229-018-0199-3

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