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Increased GABAA receptor binding in amygdala after prenatal administration of valproic acid to rats

  • Freja Bertelsen (a1) (a2), Arne Møller (a1) (a2), Davide Folloni (a1) (a3), Kim Ryun Drasbek (a1), Jørgen Scheel-Krüger (a1) and Anne M. Landau (a2) (a4)...



Prenatal exposure to valproic acid (VPA) enhances the risk for later development of autism spectrum disorders (ASD). An altered gamma-aminobutyric acid (GABA) system may be a key factor in ASD. Here we investigated possible changes in the GABA system in rats exposed to a low dose of prenatal VPA.


We performed autoradiography with [3H]muscimol, (a GABAA receptor agonist), and [11C]Ro15-4513 (a partial agonist of the GABAA α1+5 receptor subtypes), in brain sections containing amygdala, thalamus and hippocampus of rats treated prenatally with 20 mg/kg VPA or saline from the 12th day of gestation.


Prenatal VPA significantly increased [11C]Ro15-4513 binding in the left amygdala compared with controls (p<0.05). This difference was not observed in the hippocampus, thalamus or right amygdala. No differences were observed in [3H]muscimol binding.


We observed an asymmetric increase in GABAA receptor binding. Disturbances in the GABAA receptor system have also been detected in human autism with [11C]Ro15-4513.


Corresponding author

Anne M. Landau, Department of Nuclear Medicine and PET Centre, Nørrebrogade 44, Building 10G, 8000 Aarhus, Denmark. Tel: +45 7846 3029; Fax: +45 7846 1662; E-mail:


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1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Washington, DC , 2013.
2. Bailey, A, Le Couteur, A, Gottesman, I, et al. Autism as a strongly genetic disorder: evidence from a British twin study. Psychol Med 1995;25:6377.
3. Christensen, J, Gronborg, TK, Sorensen, MJ, et al. Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. JAMA 2013;309:16961703.
4. Ben-Ari, Y, Gaiarsa, JL, Tyzio, R, Khazipov, R. GABA: a pioneer transmitter that excites immature neurons and generates primitive oscillations. Physiol Rev 2007;87:12151284.
5. Shao, Y, Cuccaro, ML, Hauser, ER, et al. Fine mapping of autistic disorder to chromosome 15q11-q13 by use of phenotypic subtypes. Am J Hum Genet 2003;72:539548.
6. Blatt, GJ, Fitzgerald, CM, Guptill, JT, Booker, AB, Kemper, TL, Bauman, ML. Density and distribution of hippocampal neurotransmitter receptors in autism: an autoradiographic study. J Autism Dev Disord 2001;31:537543.
7. Oblak, A, Gibbs, TT, Blatt, GJ. Decreased GABAA receptors and benzodiazepine binding sites in the anterior cingulate cortex in autism. Autism Res 2009;2:205219.
8. Oblak, AL, Gibbs, TT, Blatt, GJ. Reduced GABAA receptors and benzodiazepine binding sites in the posterior cingulate cortex and fusiform gyrus in autism. Brain Res 2011;1380:218228.
9. Mori, T, Mori, K, Fujii, E, et al. Evaluation of the GABAergic nervous system in autistic brain: (123)I-iomazenil SPECT study. Brain Dev 2012;34:648654.
10. Mendez, MA, Horder, J, Myers, J, et al. The brain GABA-benzodiazepine receptor alpha-5 subtype in autism spectrum disorder: a pilot [(11)C]Ro15-4513 positron emission tomography study. Neuropharmacology 2013;68:195201.
11. Dufour-Rainfray, D, Vourc’h, P, Tourlet, S, Guilloteau, D, Chalon, S, Andres, CR. Fetal exposure to teratogens: evidence of genes involved in autism. Neurosci Biobehav Rev 2011;35:12541265.
12. Schneider, T, Przewlocki, R. Behavioral alterations in rats prenatally exposed to valproic acid: animal model of autism. Neuropsychopharmacology 2005;30:8089.
13. Rodier, PM, Ingram, JL, Tisdale, B, Croog, VJ. Linking etiologies in humans and animal models: studies of autism. Reprod Toxicol 1997;11:417422.
14. Sabers, A, Bertelsen, FC, Scheel-Kruger, J, Nyengaard, JR, Moller, A. Long-term valproic acid exposure increases the number of neocortical neurons in the developing rat brain. A possible new animal model of autism. Neurosci Lett 2014;580:1216.
15. Paxinos, G, Charles, C. The rat brain stereotaxic coordinates, 6th edn. London: Academic Press, 2007.
16. Noguchi, J, Suzuki, K. Automated synthesis of the ultra high specific activity of [11C]Ro15-4513 and its application in an extremely low concentration region to an ARG study. Nucl Med Biol 2003;30:335343.
17. Verdurand, M, Fillman, SG, Weickert, CS, Zavitsanou, K, et al. Increases in [3H]muscimol and [3H]flumazenil binding in the dorsolateral prefrontal cortex in schizophrenia are linked to alpha4 and gamma2S mRNA levels respectively. PLoS One 2013;8:e52724.
18. Banerjee, A, Garcia-Oscos, F, Roychowdhury, S, et al. Impairment of cortical GABAergic synaptic transmission in an environmental rat model of autism. Int J Neuropsychopharmacol 2013;16:13091318.
19. Tyzio, R, Nardou, R, Ferrari, DC, et al. Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring. Science 2014;343:675679.
20. Bauman, M, Kemper, TL. Histoanatomic observations of the brain in early infantile autism. Neurology 1985;35:866874.
21. Schumann, CM, Amaral, DG. Stereological analysis of amygdala neuron number in autism. J Neurosci 2006;26:76747679.
22. Schumann, CM, Hamstra, J, Goodlin-Jones, BL, et al. The amygdala is enlarged in children but not adolescents with autism; the hippocampus is enlarged at all ages. J Neurosci 2004;24:63926401.
23. Gogolla, N, Leblanc, JJ, Quast, KB, Sudhof, TC, Fagiolini, M, Hensch, TK. Common circuit defect of excitatory-inhibitory balance in mouse models of autism. J Neurodev Disord 2009;1:172181.
24. Ichijo, H, Hamada, M, Takahashi, S, et al. Lateralization, maturation, and anteroposterior topography in the lateral habenula revealed by ZIF268/EGR1 immunoreactivity and labeling history of neuronal activity. Neurosci Res 2015;95:2737.
25. Herbert, MR, Ziegler, DA, Deutsch, CK, et al. Brain asymmetries in autism and developmental language disorder: a nested whole-brain analysis. Brain 2005;128(Pt 1):213226.
26. Amaral, DG, Bauman, MD, Schumann, CM. The amygdala and autism: implications from non-human primate studies. Genes Brain Behav 2003;2:295302.
27. Amaral, DG. The amygdala, social behavior, and danger detection. Ann N Y Acad Sci 2003;1000:337347.
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Acta Neuropsychiatrica
  • ISSN: 0924-2708
  • EISSN: 1601-5215
  • URL: /core/journals/acta-neuropsychiatrica
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