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Influence of Gestational Chlorpyrifos Exposure on ASD-like Behaviors in an fmr1-KO Rat Model

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Abstract

Based on previous reports, exposure to pesticides could be linked to the prevalence increase of autism spectrum disorders (ASD). Gestational exposure to chlorpyrifos (CPF) has been associated with ASD diagnosis in humans and ASD-like behaviors in rodents. However, ASD severity degree results from the complex relationship between genetic background and environmental factors. Thus, animals with a genetic vulnerability and prenatally exposed to CPF could have a more severe ASD-like phenotype. Fragile X syndrome is one of the most common monogenic causes of ASD, characterized by a mutation in the X chromosome which alters the expression of the fragile X mental retardation protein (FMRP). Based on this, some fmr1 knockout (KO) rodent models have been developed to study the physiological and genetic basis of ASD. Both fmr1-KO and wild-type male rats (F2 generation) were used in the present study. F1 pregnant females were randomly exposed to 1 mg/kg/mL/day of CPF (s.c.) from GD12.5–15.5 or vehicle. Different behavioral, developmental, and molecular variables were analyzed in F2 males. KO rats were heavier, emitted altered USVs, were socially inefficient, reacted more to a novel stimulus, were hyperactive when exploring a new context, but hypoactive when exploring anxiety-inducing environments, and had an upregulated hippocampal expression of the grin2c gene. When exposed to low doses of CPF during gestation, these KO rats showed decreased climbing capacity, dysfunctional social interaction, and increased hippocampal expression for kcc1 and 5ht2c genes. Gestational CPF exposure increased the ASD-like phenotype in those animals with a genetic vulnerability, although its effect was less generalized than expected. It is the first time that this additive effect of CPF exposure and the fmr1-KO genetic vulnerability model is explored concerning social traits or any other behavior.

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Data Availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

AI:

Anxiety index

ANOVA:

Analysis of the variance

APOE:

Apolipoprotein E

ASD:

Autism spectrum disorders

CA:

Closed arm

CPF:

Chlorpyrifos

FSX:

X fragile syndrome

GD:

Gestational day

KO:

Knockout

NOR:

Novel object recognition

OA:

Open arm

OP:

Organophosphate

PM:

Plus maze

PND:

Postnatal day

RT-qPCR:

Retro-transcription-quantitative polymerase chain reaction

S1:

Stranger 1

S2:

Stranger 2

SI:

Social index

SNI:

Social novelty index

USV:

Ultrasound vocalization

WT:

Wild-type

3-CT:

3 Chambers test

References

  1. Lord C, Elsabbagh M, Baird G, Veenstra-Vanderweele J (2018) Autism spectrum disorder. Lancet 392(10146):508–520. https://doi.org/10.1016/S0140-6736(18)31129-2

    Article  PubMed  PubMed Central  Google Scholar 

  2. Christ SE, Holt DD, White DA, Green L (2007) Inhibitory control in children with autism spectrum disorder. J Autism Dev Disord 37(6):1155–1165. https://doi.org/10.1007/s10803-006-0259-y

    Article  PubMed  Google Scholar 

  3. Whyatt C, Craig C (2013) Sensory-motor problems in autism. Front Integr Neurosci 7 https://doi.org/10.3389/fnint201300051

  4. Vasa RA, Mazurek MO (2015) An update on anxiety in youth with autism spectrum disorders. Curr Opin Psychiatry 28(2):83–90. https://doi.org/10.1097/YCO0000000000000133

    Article  PubMed  PubMed Central  Google Scholar 

  5. Choi L, An JY (2021) Genetic architecture of autism spectrum disorder: lessons from large-scale genomic studies. Neurosci Biobehav Rev 128:244–257. https://doi.org/10.1016/J.NEUBIOREV.2021.06.028

    Article  CAS  PubMed  Google Scholar 

  6. Chaste P, Leboyer M (2012) Autism risk factors: genes environment and gene-environment interactions. Dialogues Clin Neurosci 2012,14(3) 281. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3513682/

  7. Karimi P, Kamali E, Mousavi SM, Karahmadi M (2017) Environmental factors influencing the risk of autism In. J Res Med Sci 22(1) Isfahan University of Medical Sciences (IUMS) https://doi.org/10.4103/1735–1995200272

  8. Tessari L, Angriman M, Díaz-Román A, Zhang J, Conca A, Cortese S (2020) Association between exposure to pesticides and ADHD or autism spectrum disorder: a systematic review of the literature. J Atten Disord https://doi.org/10.1177/1087054720940402

  9. Biosca-Brull J, Pérez-Fernández C, Mora S, Carrillo B, Pinos H, Conejo NM, Collado P, Arias JL, Martín-Sánchez F, Sánchez-Santed F, Colomina MT (2021) Relationship between autism spectrum disorder and pesticides: a systematic review of human and preclinical models. Int J Environ Res Public Health 18(10):5190. https://doi.org/10.3390/IJERPH18105190

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Morales-Navas M, Castaño-Castaño S, Pérez-Fernández C, Sánchez-Gil A, Colomina MT, Leinekugel X, Sánchez-Santed F (2020) Similarities between the effects of prenatal chlorpyrifos and valproic acid on ultrasonic vocalization in infant Wistar rats. Int J Environ Res Public Health 17(17):6376. https://doi.org/10.3390/IJERPH17176376

    Article  CAS  PubMed Central  Google Scholar 

  11. Eaton DL, Daroff RB, Autrup H, Bridges J, Buffler P, Costa LG, Coyle J, McKhann G, Mobley WC, Nadel L, Neubert D, Schulte-Hermann R, Spencer PS (2008) Review of the toxicology of chlorpyrifos with an emphasis on human exposure and neurodevelopment. Crit Rev Toxicol 38(sup2):1–125. https://doi.org/10.1080/10408440802272158

    Article  CAS  PubMed  Google Scholar 

  12. Lan A, Stein D, Portillo M, Toiber D, Kofman O (2019) Impaired innate and conditioned social behavior in adult C57Bl6/J mice prenatally exposed to chlorpyrifos. Behav Brain Funct 15(1):2. https://doi.org/101186/s12993-019-0153-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lan A, Kalimian M, Amram B, Kofman O (2017) Prenatal chlorpyrifos leads to autism-like deficits in C57Bl6/J mice. Environ Health 16(1):43. https://doi.org/10.1186/s12940-017-0251-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Abreu AC, Navas MM, Fernández CP, Sánchez-Santed F, Fernández I (2021) NMR-based metabolomics approach to explore brain metabolic changes induced by prenatal exposure to autism-inducing chemicals. ACS Chem Biol 16(4):753–765. https://doi.org/10.1021/ACSCHEMBIO.1C00053

    Article  CAS  PubMed  Google Scholar 

  15. De Felice A, Scattoni ML, Ricceri L, Calamandrei G (2015) Prenatal exposure to a common organophosphate insecticide delays motor development in a mouse model of idiopathic autism. PLoS One 10(3):e0121663. https://doi.org/10.1371/journal.pone.0121663

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. De Felice A, Anita G, Calamandrei G, Minghetti L (2016) Prenatal exposure to the organophosphate insecticide chlorpyrifos enhances brain oxidative stress and prostaglandin E2 synthesis in a mouse model of idiopathic autism. J Neuroinflammation 13(1):149. https://doi.org/10.1186/s12974-016-0617-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Basaure P, Guardia-Escote L, Biosca-Brull J, Blanco J, Cabré M, Peris-Sampedro F, Sánchez-Santed F, Domingo JL, Colomina MT (2019) Exposure to chlorpyrifos at different ages triggers APOE genotype-specific responses in social behavior body weight and hypothalamic gene expression. Environ Res 178:108684. https://doi.org/10.1016/J.ENVRES.2019.108684

    Article  CAS  PubMed  Google Scholar 

  18. Mullen BR, Khialeeva E, Hoffman DB, Ghiani CA, Carpenter EM (2013) Decreased reelin expression and organophosphate pesticide exposure alters mouse behaviour and brain morphology. ASN Neuro 5(1):AN20120060. https://doi.org/10.1042/AN20120060

    Article  CAS  Google Scholar 

  19. Fyke W, Velinov M (2021) FMR1 and autism an intriguing connection revisited. Genes 12(8). https://doi.org/10.3390/GENES12081218

  20. Ellenbroek B, Youn J (2016) Rodent models in neuroscience research: Is it a rat race? DMM Dis Models Mech 9(10):1079–1087. https://doi.org/10.1242/dmm.026120

    Article  CAS  Google Scholar 

  21. Siegel-Ramsay JE, LRomaniuk L, Whalley HC, Roberts N, Holly Branigan H, Stanfield AC, Lawrie SM, Dauvermann MR (2021) Glutamate and functional connectivity - support for the excitatory-inhibitory imbalance hypothesis in autism spectrum disorders. Psychiatry Res Neuroimaging 313 https://doi.org/10.1016/JPSCYCHRESNS2021111302

  22. Perez-Fernandez C, Morales-Navas M, Guardia-Escote L, Garrido-Cárdenas JA, Colomina MT, Giménez E, Sánchez-Santed F (2020) Long-term effects of low doses of Chlorpyrifos exposure at the preweaning developmental stage: a locomotor pharmacological brain gene expression and gut microbiome analysis. Food Chem Toxicol 135 https://doi.org/10.1016/jfct2019110865

  23. Perez-Fernandez C, Morales-Navas M, Guardia-Escote L, Colomina MT, Giménez E, Sánchez-Santed F (2020) Postnatal exposure to low doses of chlorpyrifos induces long-term effects on 5C-SRTT learning and performance cholinergic and GABAergic systems and BDNF expression. Exp Neurol 202:113356. https://doi.org/10.1016/jexpneurol2020113356

    Article  Google Scholar 

  24. Venerosi A, Ricceri L, Scattoni ML, Calamandrei G (2009) Prenatal chlorpyrifos exposure alters motor behavior and ultrasonic vocalization in CD-1 mouse pups. Environ Health Glob Access Sci Source 8(1):12. https://doi.org/10.1186/1476-069X-8-12

    Article  CAS  Google Scholar 

  25. Perez-Fernandez C, Morales-Navas M, Guardia-Escote L, Colomina MT, Giménez E, Sánchez-Santed F (2021) Pesticides and aging: preweaning exposure to chlorpyrifos induces a general hypomotricity state in late-adult rats. NeuroToxicol 86:69–77. https://doi.org/10.1016/JNEURO202107002

    Article  CAS  Google Scholar 

  26. Liu ZH, Chuang DM, Smith CB (2011) Lithium ameliorates phenotypic deficits in a mouse model of fragile X syndrome. Int J Neuropsychopharmacol 14(5):618–630. https://doi.org/10.1017/S1461145710000520

    Article  CAS  PubMed  Google Scholar 

  27. Leboucher A, Bermudez-Martin P, Mouska X, Amri E-Z, Pisani DF, Davidovic L (2019) Fmr1-deficiency impacts body composition skeleton and bone microstructure in a mouse model of fragile X syndrome. Front Endocrinol 10:678. https://doi.org/10.3389/fendo201900678

    Article  Google Scholar 

  28. Qin M, Xia Z, Huang T, Smith CB (2011) Effects of chronic immobilization stress on anxiety-like behavior and basolateral amygdala morphology in fmr1 knockout mice. Neurosci 194:282. https://doi.org/10.1016/JNEUROSCIENCE201106047

    Article  CAS  Google Scholar 

  29. Dölen G, Osterweil E, Rao BSS, Smith GB, Auerbach BD, Chattarji S, Bear MF (2007) Correction of fragile X syndrome in mice. Neuron 56(6):955. https://doi.org/10.1016/J.NEURON.2007.12.001

    Article  PubMed  PubMed Central  Google Scholar 

  30. de Vries BBA, Fryns JP, Butler MG, Canziani F, Wesby-van Swaay E, van Hemel JO, Oostra BA, Halley DJJ, Niermeijer MF (1993) Clinical and molecular studies in fragile X patients with a Prader-Willi-like phenotype. J Med Genet 30(9):761–766. https://doi.org/10.1136/jmg.30.9.761

    Article  PubMed  PubMed Central  Google Scholar 

  31. Schrander-Stumpel C, Gerver W‐J, Engelen J, Mulder H, Fryns J‐P (1994) Prader-Willi-like phenotype in fragile X syndrome. Clin Genet 45(4):175–180. https://doi.org/10.1111/j1399-00041994tb04018x

    Article  CAS  PubMed  Google Scholar 

  32. McLennan Y, Polussa J, Tassone F, Hagerman R (2011) Fragile X Syndrome. Curr Genomics 12(3):216–224. https://doi.org/10.2174/138920211795677886

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Moon J, Beaudin AE, Verosky S, Driscoll LL, Weiskopf M, Levitsky DA, Crnic LS, Strupp BJ (2006) Attentional dysfunction impulsivity and resistance to change in a mouse model of fragile X syndrome. Behav Neurosci 120(6):1367–1379. https://doi.org/10.1037/0735-704412061367

    Article  CAS  PubMed  Google Scholar 

  34. Bausch AE, Ehinger R, Straubinger J, Zerfass P, Nann Y, Lukowski R (2018) Loss of sodium-activated potassium channel slack and FMRP differentially affect social behavior in mice. Neuroscience 384:361–374. https://doi.org/10.1016/j.neuroscience.2018.05.040

    Article  CAS  PubMed  Google Scholar 

  35. Roy S, Zhao Y, Allensworth M, Farook MF, LeDoux MS, Reiter LT, Heck DH (2011) Comprehensive motor testing in fmr1-KO mice exposes temporal defects in oromotor coordination. Behav Neurosci 125(6):962–969. https://doi.org/10.1037/a0025920

    Article  PubMed  PubMed Central  Google Scholar 

  36. Schiavi S, Carbone E, Melancia F, Buzzelli V, Manduca A, Campolongo P, Pallottini V, Trezza V (2020) Perinatal supplementation with omega-3 fatty acids corrects the aberrant social and cognitive traits observed in a genetic model of autism based on FMR1 deletion in rats. Nutr Neurosci https://doi.org/10.1080/1028415X20201819107

  37. Tian Y, Yang C, Shang S, Cai Y, Deng X, Zhang J, Shao F, Zhu D, Liu Y, Chen G, Liang J, Sun Q, Qiu Z, Zhang C (2017) Loss of FMRP impaired hippocampal long-term plasticity and spatial learning in rats. Front Mol Neurosci 10 https://doi.org/10.3389/fnmol201700269

  38. Asiminas A, Jackson AD, Louros SR, Till SM, Spano T, Dando O, Bear MF, Chattarji S, Hardingham GE, Osterweil EK, Wyllie DJA, Wood ER, Kind PC (2019) Sustained correction of associative learning deficits after brief early treatment in a rat model of fragile X syndrome. Sci Transl Med 11(494). https://doi.org/10.1126/scitranslmed.aao0498

  39. Saxena K, Webster J, Hallas-Potts A, Mackenzie R, Spooner PA, Thomson D, Kind P, Chatterji S, Morris RGM (2018) Experiential contributions to social dominance in a rat model of fragile-X syndrome. Proc R Soc B Biol Sci 285:1880. https://doi.org/10.1098/rspb20180294

    Article  Google Scholar 

  40. Thomas AM, Bui N, Perkins JR, Yuva-Paylor LA, Paylor R (2012) Group i metabotropic glutamate receptor antagonists alter select behaviors in a mouse model for fragile X syndrome. Psychopharmacology 219(1):47–58. https://doi.org/10.1007/s00213-011-2375-4

    Article  CAS  PubMed  Google Scholar 

  41. Baker KB, Wray SP, Ritter R, Mason S, Lanthorn TH, Savelieva KV (2010) Male and female Fmr1 knockout mice on C57 albino background exhibit spatial learning and memory impairments. Genes Brain Behav 9(6):562–574. https://doi.org/10.1111/J.1601-183X.2010.00585.X

    Article  CAS  PubMed  Google Scholar 

  42. Renoux AJ, Sala-Hamrick KJ, Carducci NM, Frazer M, Halsey KE, Sutton MA, Dolan DF, Murphy GG, Todd PK (2014) Impaired sensorimotor gating in Fmr1 knock out and fragile X premutation model mice. Behav Brain Res 267:42–45. https://doi.org/10.1016/jbbr201403013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. de Vrij FMS, Levenga J, van der Linde HC, Koekkoek SK, De Zeeuw CI, Nelson DL, Oostra BA, Willemsen R (2008) Rescue of behavioral phenotype and neuronal protrusion morphology in Fmr1 KO mice. Neurobiol Dis 31(1):127–132. https://doi.org/10.1016/j.nbd.2008.04.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Spencer CM, Serysheva E, Yuva-Paylor LA, Oostra BA, Nelson DL, Paylor R (2006) Exaggerated behavioral phenotypes in Fmr1/Fxr2 double knockout mice reveal a functional genetic interaction between fragile X-related proteins. Human Mol Genet 15(12):1984–1994. https://doi.org/10.1093/hmg/ddl121

    Article  CAS  Google Scholar 

  45. Kokash J, Alderson EM, Reinhard SM, Crawford CA, Binder DK, Ethell IM, Razak KA (2019) Genetic reduction of MMP-9 in the Fmr1 KO mouse partially rescues prepulse inhibition of acoustic startle response. Brain Res 1719:24–29. https://doi.org/10.1016/jbrainres201905029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Perez-Fernandez C, Morales-Navas M, Aguilera-Sáez LM, Abreu AC, Guardia-Escote L, Fernández I, Garrido-Cárdenas JA, Colomina MT, Giménez E, Sánchez-Santed F (2020) Medium and long-term effects of low doses of chlorpyrifos during the postnatal preweaning developmental stage on sociability dominance gut microbiota and plasma metabolites. Environ Res 184:109341. https://doi.org/10.1016/jenvres2020109341

    Article  CAS  PubMed  Google Scholar 

  47. Rotschafer SE, Trujillo MS, Dansie LE, Ethell IM, Razak KA (2012) Minocycline treatment reverses ultrasonic vocalization production deficit in a mouse model of fragile X Syndrome. Brain Res 1439:7–14. https://doi.org/10.1016/jbrainres201112041

    Article  CAS  PubMed  Google Scholar 

  48. Toledo MA, Wen TH, Binder DK, Ethell IM, Razak KA (2019) Reversal of ultrasonic vocalization deficits in a mouse model of fragile X syndrome with minocycline treatment or genetic reduction of MMP-9. Behav Brain Res 372:112068. https://doi.org/10.1016/jbbr2019112068

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Lai JKY, Sobala-Drozdowski M, Zhou L, Doering LC, Faure PA, Foster JA (2014) Temporal and spectral differences in the ultrasonic vocalizations of fragile X knock out mice during postnatal development. Behav Brain Res 259:119–130. https://doi.org/10.1016/jbbr201310049

    Article  PubMed  Google Scholar 

  50. Belagodu AP, Johnson AM, Galvez R (2016) Characterization of ultrasonic vocalizations of fragile X mice. Behav Brain Res 310:76–83. https://doi.org/10.1016/j.bbr.2016.04.016

    Article  PubMed  Google Scholar 

  51. Nolan SO, Hodges SL, Lugo JN (2020) High-throughput analysis of vocalizations reveals sex-specific changes in Fmr1 mutant pups. Genes Brain Behav 19(2) https://doi.org/10.1111/gbb12611

  52. Hodges SL, Nolan SO, Reynolds CD, Lugo JN (2017) Spectral and temporal properties of calls reveal deficits in ultrasonic vocalizations of adult Fmr1 knockout mice. Behav Brain Res 332:50–58. https://doi.org/10.1016/jbbr201705052

    Article  PubMed  PubMed Central  Google Scholar 

  53. Pietropaolo S, Guilleminot A, Martin B, D’Amato FR, Crusio WE (2011) Genetic-background modulation of core and variable autistic-like symptoms in Fmr1 knock-out mice. PLoS One 6(2) https://doi.org/10.1371/journalpone0017073

  54. Saldarriaga W, Lein P, Teshima LYG, Isaza C, Rosa L, Polyak A, Hagerman R, Girirajan S, Silva M, Tassone F (2016) Phenobarbital use and neurological problems in FMR1 premutation carriers. Neurotoxicology 53:141. https://doi.org/10.1016/JNEURO201601008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Costa L, Sardone LM, Bonaccorso CM, D’Antoni S, Spatuzza M, Gulisano W, Tropea MR, Puzzo D, Leopoldo M, Lacivita E, Catania MV, Ciranna L (2018) Activation of serotonin 5-HT7 receptors modulates hippocampal synaptic plasticity by stimulation of adenylate cyclases and rescues learning and behavior in a mouse model of fragile X syndrome. Front Mol Neurosci 0:353. https://doi.org/10.3389/FNMOL.2018.00353

    Article  Google Scholar 

  56. Prieto M, Folci A, Poupon G, Schiavi S, Buzzelli V, Pronot M, François U, Pousinha P, Lattuada N, Abelanet S, Castagnola S, Chafai M, Khayachi A, Gwizdek C, Brau F, Deval E, Francolini M, Bardoni B, Humeau Y, Martin S (2021) Missense mutation of Fmr1 results in impaired AMPAR-mediated plasticity and socio-cognitive deficits in mice. Nat Commun 12(1):1–15. https://doi.org/10.1038/s41467-021-21820-1

    Article  CAS  Google Scholar 

  57. Lieb-Lundell C (2016) Three faces of fragile X. Physical Therapy 96(11):1782–1790. https://doi.org/10.2522/PTJ20140430

    Article  PubMed  Google Scholar 

  58. Garrido D, Petrova D, Watson LR, Garcia-Retamero R, Carballo G (2017) Language and motor skills in siblings of children with autism spectrum disorder: a meta-analytic review. Autism Res 10(11):1737–1750. https://doi.org/10.1002/AUR.1829

    Article  PubMed  Google Scholar 

  59. Hayashi ML, Rao BSS, Seo J-S, Choi H-S, Dolan BM, Choi S-Y, Chattarji S, Tonegawa S (2007) Inhibition of p21-activated kinase rescues symptoms of fragile X syndrome in mice. Proc Natl Acad Sci U S A 104(27):11489. https://doi.org/10.1073/PNAS0705003104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Uutela M, Lindholm J, Louhivuori V, Wei H, Louhivuori LM, Pertovaara A, Åkerman K, Castrén E, Castrén ML (2012) Reduction of BDNF expression in Fmr1 knockout mice worsens cognitive deficits but improves hyperactivity and sensorimotor deficits. Genes Brain Behav 11(5):513–523. https://doi.org/10.1111/J1601-183X201200784X

    Article  CAS  PubMed  Google Scholar 

  61. Uutela M, Lindholm J, Rantamäki T, Umemori J, Hunter K, Võikar V, Castrén ML (2014) Distinctive behavioral and cellular responses to fluoxetine in the mouse model for fragile X syndrome. Front Cell Neurosci 8 https://doi.org/10.3389/FNCEL201400150

  62. Dansie LE, Phommahaxay K, Okusanya AG, Uwadia J, Huang M, Rotschafer SE, Razak KA, Ethell DW, Ethell IM (2013) Long-lasting effects of minocycline on behavior in young but not adult fragile X mice. Neuroscience 246:186–198. https://doi.org/10.1016/J.NEUROSCIENCE.2013.04.058

    Article  CAS  PubMed  Google Scholar 

  63. Oddi D, Subashi E, Middei S, Bellocchio L, Lemaire-Mayo V, Guzmán M, Crusio WE, D’Amato FR, Pietropaolo S (2015) Early social enrichment rescues adult behavioral and brain abnormalities in a mouse model of fragile X syndrome. Neuropsychopharmacology 40(5):1113. https://doi.org/10.1038/NPP2014291

    Article  PubMed  PubMed Central  Google Scholar 

  64. Qiu G, Chen S, Guo J, Wu J, Yi YH (2016) Alpha-asarone improves striatal cholinergic function and locomotor hyperactivity in Fmr1 knockout mice. Behav Brain Res 312:212–218. https://doi.org/10.1016/JBBR201606024

    Article  CAS  PubMed  Google Scholar 

  65. Schaefer TL, Davenport MH, Grainger LM, Robinson CK, Earnheart AT, Stegman MS, Lang AL, Ashworth AA, Molinaro G, Huber KM, Erickson CA (2017) Acamprosate in a mouse model of fragile X syndrome: modulation of spontaneous cortical activity ERK1/2 activation locomotor behavior and anxiety. J Neurodevelopmental Disord 9(1) https://doi.org/10.1186/S11689-017-9184-Y

  66. Chatterjee M, Kurup PK, Lundbye CJ, Hugger Toft AK, Kwon J, Benedict J, Kamceva M, Banke TG, Lombroso PJ (2018) STEP inhibition reverses behavioral electrophysiologic and synaptic abnormalities in Fmr1 KO mice. Neuropharmacology 128:43–53. https://doi.org/10.1016/J.NEUROPHARM.2017.09.026

    Article  CAS  PubMed  Google Scholar 

  67. Pirbhoy PS, Rais M, Lovelace JW, Woodard W, Razak KA, Binder DK, Ethell IM (2020) Acute pharmacological inhibition of matrix metalloproteinase-9 activity during development restores perineuronal net formation and normalizes auditory processing in Fmr1 KO mice. J Neurochem 155(5):538–558. https://doi.org/10.1111/JNC15037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Kozono NO, Kamura A, Honda S, Matsumoto M, Mihara T (2020) Gamma power abnormalities in a Fmr1-targeted transgenic rat model of fragile X syndrome. Sci Rep 10(1) https://doi.org/10.1038/S41598-020-75893-X

  69. Wong H, Hooper AWM, Niibori Y, Lee SJ, Hategan LA, Zhang LZ, Karumuthil-Melethil S, Sally M, Till SM, Peter C, Kind PC, Olivier Danos O, Bruder JT, Hampson DR (2020) Sexually dimorphic patterns in electroencephalography power spectrum and autism-related behaviors in a rat model of fragile X syndrome. Neurobiol Dis 146 https://doi.org/10.1016/JNBD2020105118

  70. Fish EW, Krouse MC, Stringfield SJ, Diberto JF, Robinson JE, Malanga CJ (2013) Changes in sensitivity of reward and motor behavior to dopaminergic glutamatergic and cholinergic drugs in a mouse model of fragile X syndrome. PloS One 8(10). https://doi.org/10.1371/JOURNAL.PONE.0077896

  71. Yu Y, Lin Y, Takasaki Y, Wang C, Kimura H, Xing J, Ishizuka K, Toyama M, Kushima I, Mori D, Arioka Y, Uno Y, Shiino T, Nakamura Y, Okada T, Morikawa M, Ikeda M, Iwata N, Okahisa Y, Ozaki N (2018) Rare loss of function mutations in N-methyl-d-aspartate glutamate receptors and their contributions to schizophrenia susceptibility Translational. Psychiatry 8(1):12. https://doi.org/10.1038/S41398-017-0061-Y

    Article  Google Scholar 

  72. Dölen G, Bear MF (2008) Role for metabotropic glutamate receptor 5 (mGluR5) in the pathogenesis of fragile X syndrome. J Physiol 586(6):1503–1508. https://doi.org/10.1113/JPHYSIOL.2008.150722

    Article  PubMed  Google Scholar 

  73. Yau S-Y, Bettio L, Chiu J, Chiu C, Christie BR (2019) Fragile-X syndrome is associated with NMDA receptor hypofunction and reduced dendritic complexity in mature dentate granule cells. Front Mol Neurosci 11 https://doi.org/10.3389/FNMOL201800495

  74. Banke TG, Barria A (2020) Transient enhanced GluA2 expression in young hippocampal neurons of a fragile X mouse model. Front Synaptic Neurosci 12. https://doi.org/10.3389/FNSYN.2020.588295

  75. Bostrom CA, Majaess N-M, Morch K, White E, Eadie BD, Christie BR (2015) Rescue of NMDAR-dependent synaptic plasticity in Fmr1 knock-out mice. Cereb Cortex 25(1):271–279. https://doi.org/10.1093/CERCOR/BHT237

    Article  CAS  PubMed  Google Scholar 

  76. Vieira M, Yong XLH, Roche KW, Anggono V (2020) Regulation of NMDA glutamate receptor functions by the GluN2 subunits. J Neurochem 154(2):121–143. https://doi.org/10.1111/JNC14970

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Wold EA, Wild CT, Cunningham KA, Zhou J (2019) Targeting the 5-HT2C receptor in biological context and the current state of 5-HT2C receptor ligand development. Curr Topics Med Chem 19(16):1381. https://doi.org/10.2174/1568026619666190709101449

    Article  CAS  Google Scholar 

  78. Prophitt J, Armstrong J, Chen Y, Canal C (2019) Assessment of brain serotonin receptors in an Fmr1 knockout mouse model of fragile X syndrome. FASEB J 33(S1):6671–6671. https://doi.org/10.1096/FASEBJ2019331_SUPPLEMENT6671

    Article  Google Scholar 

  79. Saraf T, Chen Y, Armstrong JL, Prophitt J, Canal C (2021) Evaluation of Serotonin 5-HT1A 5-HT2A and 5-HT2C receptors and the serotonin transporter in an Fmr1 knockout mouse model of fragile X syndrome. FASEB J 35(S1) https://doi.org/10.1096/FASEBJ202135S103781

  80. Garneau AP, Slimani S, Tremblay LE, Fiola MJ, Marcoux AA, Isenring P (2019) K+-Cl- cotransporter 1 (KCC1): A housekeeping membrane protein that plays key supplemental roles in hematopoietic and cancer cells. J Hematol Oncol 12(1). https://doi.org/10.1186/S13045-019-0766-X

  81. Wang C, Shimizu-Okabe C, Watanabe K, Okabe A, Matsuzaki H, Ogawa T, Mori N, Fukuda A, Sato K (2002) Developmental changes in KCC1 KCC2 and NKCC1 mRNA expressions in the rat brain. Dev Brain Res 139(1):59–66. https://doi.org/10.1016/S0165-3806(02)00536-9

    Article  CAS  Google Scholar 

  82. Lydiard RB (2003) The role of GABA in anxiety disorders. J Clin Psychiatry 2003 64(suppl 3).

  83. Hettema JM, An SS, Neale MC, Bukszar J, van den Oord EJC, Kendler G, KS, Chen X, (2006) Association between glutamic acid decarboxylase genes and anxiety disorders major depression and neuroticism. Mol Psychiatry 11(8):752–762. https://doi.org/10.1038/sjmp4001845

    Article  CAS  PubMed  Google Scholar 

  84. Engin E, Liu J, Rudolph U (2012) α2-containing GABAA receptors: a target for the development of novel treatment strategies for CNS disorders. Pharmacol Ther 136(2):142. https://doi.org/10.1016/J.PHARMTHERA.2012.08.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Myslivecek J, Farar V, Valuskova P (2017) M(4) muscarinic receptors and locomotor activity regulation. Physiol Res 66(Suppl 4):S443–S455. https://doi.org/10.33549/PHYSIOLRES933796

    Article  CAS  PubMed  Google Scholar 

  86. Koshimizu H, Leiter LM, Miyakawa T (2012) M 4 muscarinic receptor knockout mice display abnormal social behavior and decreased prepulse inhibition. Mol Brain 5(1):1–10. https://doi.org/10.1186/1756-6606-5-10

    Article  CAS  Google Scholar 

  87. Unal G, Bekci H, Cumaoglu A, Yerer MB, Aricioglu F (2020) Alpha 7 nicotinic receptor agonist and positive allosteric modulators improved social and molecular deficits of MK-801 model of schizophrenia in rats. Pharmacol Biochem Behav 193:172916. https://doi.org/10.1016/JPBB2020172916

    Article  CAS  PubMed  Google Scholar 

  88. Halberstadt AL, Powell SB, Geyer MA (2013) Role of the 5-HT2A receptor in the locomotor hyperactivity produced by phenylalkylamine hallucinogens in mice. Neuropharmacology 70:218. https://doi.org/10.1016/JNEUROPHARM201301014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Halberstadt AL, van der Heijden I, Ruderman MA, Risbrough VB, Gingrich JA, Geyer MA, Powell SB (2009) 5-HT2A and 5-HT2C receptors exert opposing effects on locomotor activity in mice. Neuropsychopharmacology 34(8):1958–1967. https://doi.org/10.1038/npp200929

    Article  CAS  PubMed  Google Scholar 

  90. Platzer K, Yuan H, Schütz H, Winschel A, Chen W, Hu C, Kusumoto H, Heyne HO, Helbig KL, Tang S, Willing MC, Tinkle BT, Adams DJ, Depienne C, Keren B, Mignot C, Frengen E, Strømme P, Biskup S, Lemke JR (2017) GRIN2B encephalopathy: novel findings on phenotype variant clustering functional consequences and treatment aspects. J Med Genet 54(7):460–470. https://doi.org/10.1136/JMEDGENET-2016-104509

    Article  CAS  PubMed  Google Scholar 

  91. Narita K, Murata T, Matsuoka S (2016) The ventromedial hypothalamus oxytocin induces locomotor behavior regulated by estrogen. Physiol Behav 164:107–112. https://doi.org/10.1016/JPHYSBEH201605047

    Article  CAS  PubMed  Google Scholar 

  92. Raam T, McAvoy KM, Besnard A, Veenema AH, Sahay A (2017) Hippocampal oxytocin receptors are necessary for discrimination of social stimuli Nature. Communications 8(1):1–14. https://doi.org/10.1038/s41467-017-02173-0

    Article  CAS  Google Scholar 

  93. Chamoun M, Groleau M, Bhat M (2016) Dose-dependent effect of donepezil administration on long-term enhancement of visually evoked potentials and cholinergic receptor overexpression in rat visual cortex. J Phys Paris 110(1–2):65–74. https://doi.org/10.1016/J.JPHYSPARIS.2016.11.010

    Article  Google Scholar 

  94. Lips KS, Lührmann A, Tschernig T, Stoeger T, Alessandrini F, Grau V, Haberberger RV, Koepsell H, Pabst R, Kummer W (2007) Down-regulation of the non-neuronal acetylcholine synthesis and release machinery in acute allergic airway inflammation of rat and mouse. Life Sci 80(24–25):2263–2269. https://doi.org/10.1016/jlfs200701026

    Article  CAS  PubMed  Google Scholar 

  95. Jameson RR, Seidler FJ, Slotkin TA (2007) Nonenzymatic functions of acetylcholinesterase splice variants in the developmental neurotoxicity of organophosphates: chlorpyrifos, chlorpyrifos oxon, and diazinon. Environ Health Perspect 115(1):65–70. https://doi.org/10.1289/ehp9487

    Article  CAS  PubMed  Google Scholar 

  96. Fujimura J, Nagano M, Suzuki H (2005) Differential expression of GABAA receptor subunits in the distinct nuclei of the rat amygdala. Mol Brain Res 138(1):17–23. https://doi.org/10.1016/j.molbrainres.2005.03.013

    Article  CAS  PubMed  Google Scholar 

  97. Jaenisch N, Witte OW, Frahm C (2010) Downregulation of potassium chloride cotransporter KCC2 after transient focal cerebral ischemia. Stroke 41(3):e151-9. https://doi.org/10.1161/STROKEAHA109570424

    Article  CAS  PubMed  Google Scholar 

  98. Cho H-M, Lee H-A, Kim HY, Lee D-Y, Kim IK (2013) Recruitment of specificity protein 1 by CpG hypomethylation upregulates Na+-K+-2Cl− cotransporter 1 in hypertensive rats. J Hypertens 31(7):1406–1413. https://doi.org/10.1097/HJH.0b013e3283610fed

    Article  CAS  PubMed  Google Scholar 

  99. Kindlundh-Högberg AMS, Svenningsson P, Schiöth HB (2006) Quantitative mapping shows that serotonin rather than dopamine receptor mRNA expressions are affected after repeated intermittent administration of MDMA in rat brain. Neuropharmacology 51(4):838–847. https://doi.org/10.1016/jneuropharm200605026

    Article  PubMed  Google Scholar 

  100. Lau JC, Kroes RA, Moskal JR, Linsenmeier RA (2013) Diabetes changes expression of genes related to glutamate neurotransmission and transport in the Long-Evans rat retina. Mol vision 19:1538–1553

    CAS  Google Scholar 

  101. Pershina EV, Mikheeva IB, Kamaltdinova ER, Arkhipov VI (2018) Expression of mGlu receptor genes in the hippocampus after intoxication with trimethyltin. J Mol Neurosci 67(2):258–264. https://doi.org/10.1007/S12031-018-1233-9

    Article  PubMed  Google Scholar 

  102. Hamilton SM, Green JR, Veeraragavan S et al (2014) Fmr1 and Nlgn3 knockout rats: novel tools for investigating autism spectrum disorders. Behav Neurosci 128(2):103–109. https://doi.org/10.1037/A0035988

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We are grateful to Ainhoa Sánchez Gil for its initial help with the F0 mating/breeding protocol

Funding

This study was supported by the Grant PID2020-113812RB-C32, MCIN/AEI/ https://doi.org/10.13039/501100011033.

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Authors and Affiliations

  1. Department of Psychology and Health Research Center (CEINSA), Laboratory of Psychobiology, University of Almería CeiA3, Carretera de Sacramento s/n, La Cañada de San Urbano, 04120, Almería, Spain

    Cristian Perez-Fernandez, Miguel Morales-Navas & Fernando Sánchez-Santed

  2. Biomolecular Mass Spectrometry and Proteomics Group, Faculty of Science, Utrecht University, 3584 CS, Utrecht, The Netherlands

    María Matamala Montoya

  3. Research in Neurobehavior and Health (NEUROLAB), Universitat Rovira I Virgili, 43007, Tarragona, Spain

    Laia Guardia-Escote, María Cabré & María Teresa Colomina

  4. Department of Psychology and Research Center for Behavior Assessment (CRAMC), Universitat Rovira I Virgili, Campus Sescelades, 43007, Tarragona, Spain

    Laia Guardia-Escote & María Teresa Colomina

  5. Department of Biochemistry and Biotechnology, Universitat Rovira I Virgili, 43007, Tarragona, Spain

    María Cabré

  6. Department of Biology and Geology, University of Almería, Ctra. Sacramento, s/n, 04120, Almería, Spain

    Estela Giménez

Authors
  1. Cristian Perez-Fernandez
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  2. María Matamala Montoya
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  3. Miguel Morales-Navas
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  4. Laia Guardia-Escote
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  5. María Cabré
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  6. María Teresa Colomina
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  7. Estela Giménez
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  8. Fernando Sánchez-Santed
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Contributions

P-F C made the original conceptualization of the experimental design, completed the animals’ maintenance, behavioral tasks, initial statistical analyses, figures design, and the first version of the manuscript. MM M made most of the gene expression analyzed. M–N M helped with the original conceptualization of the study design, behavioral experiments, and sacrifices. G-E L, C M, and G E completed the genotyping protocol (including optimization of the PCR settings) and helped with the gene expression analyses. CM T and S–S F had the original conceptualization of this set of experiments, completed continuous supervision of the work, get the economical and material resources, and review this manuscript until its last version. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Fernando Sánchez-Santed.

Ethics declarations

Ethics Approval and Consent to Participate

The present study is part of the project ES040130002260 and was conducted following the Spanish Royal Decree 53/2013, the European Community Directive (2010/63/EU) for animal research and complies with the ARRIVE guidelines for animal research. The Animal Research Committee of the University of Almeria approved the experiments described here.

Competing Interests

The authors declare no competing interests.

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Perez-Fernandez, C., Matamala Montoya, M., Morales-Navas, M. et al. Influence of Gestational Chlorpyrifos Exposure on ASD-like Behaviors in an fmr1-KO Rat Model. Mol Neurobiol 59, 5835–5855 (2022). https://doi.org/10.1007/s12035-022-02933-0

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