Abstract
Autism is a neurodevelopmental disorder characterized by disruptions in three core behavioral domains: deficits in social interaction, impairments in communication, and repetitive and stereotyped patterns of behavior or thought. There are currently no drugs available for the treatment of the core symptoms of ASD and drugs that target comorbid symptoms often have serious adverse side effects, suggesting an urgent need for new therapeutic strategies. The neurobiology of autism is complex, but converging evidence suggests that ASD involves disruptions in the inhibitory GABAergic neurotransmitter system. Specifically, people with autism have a reduction in parvalbumin (PV)-containing interneurons in the PFC, leading to the suggestion that restoring interneuron function in this region may be a novel therapeutic approach for ASD. Here we used a dual-reporter embryonic stem cell line to generate enriched populations of PV-positive interneurons, which were transplanted into the medial prefrontal cortex (mPFC) of the Poly I:C rodent model of autism. PV interneuron transplants were able to decrease pyramidal cell firing in the mPFC and alleviated deficits in social interaction and cognitive flexibility. Our results suggest that restoring PV interneuron function in the mPFC may be a novel and effective treatment strategy to reduce the core symptoms of autism.
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References
Association AP (2013) Diagnostic and Statistical Manual of Mental Disorders: Dsm-5: Amer Psychiatric Pub Incorporated.
Baio J (2014) Prevalence of autism spectrum disorder among children aged 8 years -- Austism and developmental disabilities monitoring network, 11 sites, United States 2010. In: Morbidity and Mortality Weekly Report (Moran JS, ed), pp 1-22. Atlanta, GA.
McPheeters ML, Warren Z, Sathe N, Bruzek JL, Krishnaswami S, Jerome RN, Veenstra-VanderWeele J. A systematic review of medical treatments for children with autism spectrum disorders. Pediatrics. 2011;127:e1312–e1321.
Coghlan S, Horder J, Inkster B, Mendez MA, Murphy DG, Nutt DJ. GABA system dysfunction in autism and related disorders: From synapse to symptoms. Neurosci Biobehav Rev. 2012;36:2044–55.
Ma DQ, Whitehead PL, Menold MM, Martin ER, Ashley-Koch AE, Mei H, Ritchie MD, DeLong GR, Abramson RK, Wright HH, Cuccaro ML, Hussman JP, Gilbert JR, Pericak-Vance MA. Identification of significant association and gene-gene interaction of GABA receptor subunit genes in autism. Am J Human Genet. 2005;77:377–88.
Delahanty RJ, Kang JQ, Brune CW, Kistner EO, Courchesne E, Cox NJ, Cook EH Jr., Macdonald RL, Sutcliffe JS. Maternal transmission of a rare GABRB3 signal peptide variant is associated with autism. Mol Psychiatry. 2011;16:86–96.
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;31:537–43.
Mori T, Mori K, Fujii E, Toda Y, Miyazaki M, Harada M, Hashimoto T, Kagami S. Evaluation of the GABAergic nervous system in autistic brain: 123I-iomazenil SPECT study. Brain Dev. 2012;34:648–54.
Fatemi SH, Halt AR, Stary JM, Kanodia R, Schulz SC, Realmuto GR. Glutamic acid decarboxylase 65 and 67 kDa proteins are reduced in autistic parietal and cerebellar cortices. Biol Psychiatry. 2002;52:805–10.
Harada M, Taki M, Nose A, Kubo H, Mori K, Nishitani H, Matsuda T. Non-invasive evaluation of the GABAergic/glutamatergic system in autistic patients observed by MEGA-editing proton MR spectroscopy using a clinical 3 tesla instrument. J Autism Dev Disord. 2011;41:447–54.
Gogolla N, LeBlanc JJ, Quast KB, Südhof TC, Fagiolini M, Hensch TK. Common circuit defect of excitatory-inhibitory balance in mouse models of autism. J Neurodev Disord. 2009;1:172–81.
Wohr M, Orduz D, Gregory P, Moreno H, Khan U, Vorckel KJ, Wolfer DP, Welzl H, Gall D, Schiffmann SN, Schwaller B. 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.
Hashemi E, Ariza J, Rogers H, Noctor SC, MartÃnez-Cerdeño V. The number of parvalbumin-expressing interneurons is decreased in the medial prefrontal cortex in autism. Cereb Cortex. 2016;27:1931–43.
Zikopoulos B, Barbas H. Altered neural connectivity in excitatory and inhibitory cortical circuits in autism. Front Human Neurosci. 2013;7:609.
Sohal VS, Zhang F, Yizhar O, Deisseroth K. Parvalbumin neurons and gamma rhythms enhance cortical circuit performance. Nature. 2009;459:698–702.
Yizhar O, Fenno LE, Prigge M, Schneider F, Davidson TJ, O/‘Shea DJ, Sohal VS, Goshen I, Finkelstein J, Paz JT, Stehfest K, Fudim R, Ramakrishnan C, Huguenard JR, Hegemann P, Deisseroth K. Neocortical excitation/inhibition balance in information processing and social dysfunction. Nature. 2011;477:171–8.
Gandal MJ, Edgar JC, Ehrlichman RS, Mehta M, Roberts TPL, Siegel SJ. Validating γ oscillations and delayed auditory responses as translational biomarkers of autism. Biol Psychiatry. 2010;68:1100–6.
Orekhova EV, Stroganova TA, Nygren G, Tsetlin MM, Posikera IN, Gillberg C, Elam M. Excess of high frequency electroencephalogram oscillations in boys with autism. Biol Psychiatry. 2007;62:1022–9.
Amaral DG, Schumann CM, Nordahl CW. Neuroanatomy of autism. Trends Neurosci. 2008;31:137–45.
Dichter GS, Felder JN, Bodfish JW. Autism is characterized by dorsal anterior cingulate hyperactivation during social target detection. Soc Cogn Affect Neurosci. 2009;4:215–26.
Gomot M, Belmonte MK, Bullmore ET, Bernard FA, Baron-Cohen S. Brain hyper-reactivity to auditory novel targets in children with high-functioning autism. Brain. 2008;131:2479–88.
Belmonte MK, Gomot M, Baron-Cohen S. Visual attention in autism families: ‘unaffected’ sibs share atypical frontal activation. J Child Psychol Psychiatry. 2010;51:259–76.
Cardin JA, Carlen M, Meletis K, Knoblich U, Zhang F, Deisseroth K, Tsai L-H, Moore CI. Driving fast-spiking cells induces gamma rhythm and controls sensory responses. Nature. 2009;459:663–7.
Wilson TW, Rojas DC, Reite ML, Teale PD, Rogers SJ. Children and adolescents with autism exhibit reduced MEG steady-state gamma responses. Biol Psychiatry. 2007;62:192–7.
Cho KK, Hoch R, Lee AT, Patel T, Rubenstein JL, Sohal VS. Gamma rhythms link prefrontal interneuron dysfunction with cognitive inflexibility in Dlx5/6+/− mice. Neuron. 2015;85:1332–43.
Tyson JA, Anderson SA. GABAergic interneuron transplants to study development and treat disease. Trends Neurosci. 2014;37:169–77.
Tyson JA, Goldberg EM, Maroof AM, Xu Q, Petros TJ, Anderson SA. Duration of culture and sonic hedgehog signaling differentially specify PV versus SST cortical interneuron fates from embryonic stem cells. Development. 2015;142:1267–78.
Donegan JJ, Tyson Jennifer A, Branch SY, Beckstead MJ, Anderson SA, Lodge DJ (2016) Stem cell derived interneuron transplants as a treatment for schizophrenia: preclinical validation in a rodent model. Mol Psychiatry. Mol Psychiatry. 2017;22:1492–1501
Atladóttir H, Thorsen P, Østergaard L, Schendel D, Lemcke S, Abdallah M, Parner E. Maternal infection requiring hospitalization during pregnancy and autism spectrum disorders. J Autism Dev Disord. 2010;40:1423–30.
Patterson PH. Maternal infection and immune involvement in autism. Trends Mol Med. 2011;17:389–94.
Perez SM, Lodge DJ. Hippocampal interneuron transplants reverse aberrant dopamine system function and behavior in a rodent model of schizophrenia. Mol Psychiatry. 2013;18:1193–8.
Lord C, Risi S, Lambrecht L, Cook EH Jr., Leventhal BL, DiLavore PC, Pickles A, Rutter M. The autism diagnostic observation schedule-generic: a standard measure of social and communication deficits associated with the spectrum of autism. J Autism Dev Disord. 2000;30:205–23.
Hofer, M. A., Shair, H. N. and Brunelli, S. A. 2002. Ultrasonic Vocalizations in Rat and Mouse Pups. Current Protocols in Neuroscience. 17:8.14:8.14.1–8.14.16.
Cecchi M, Khoshbouei H, Morilak DA. Modulatory effects of norepinephrine, acting on alpha1 receptors in the central nucleus of the amygdala, on behavioral and neuroendocrine responses to acute immobilization stress. Neuropharmacology. 2002;43:1139–47.
Lapiz MD, Morilak DA. Noradrenergic modulation of cognitive function in rat medial prefrontal cortex as measured by attentional set shifting capability. Neuroscience. 2006;137:1039–49.
Homayoun H, Moghaddam B. NMDA Receptor Hypofunction Produces Opposite Effects on Prefrontal Cortex Interneurons and Pyramidal Neurons. J Neurosci. 2007;27:11496–11500.
Paxinos G, Watson C. The rat brain in stereotaxic coordinates. 6 Edition. London, UK: Elsevier; 2006.
Hughes C, Russell J, Robbins TW. Evidence for executive dysfunction in autism. Neuropsychologia. 1994;32:477–92.
Ozonoff S, Cook I, Coon H, Dawson G, Joseph RM, Klin A, McMahon WM, Minshew N, Munson JA, Pennington BF, Rogers SJ, Spence MA, Tager-Flusberg H, Volkmar FR, Wrathall D. Performance on cambridge neuropsychological test automated battery subtests sensitive to frontal lobe function in people with autistic disorder: evidence from the collaborative programs of excellence in autism network. J Autism Dev Disord. 2004;34:139–50.
Grillon C, Ameli R, Charney DS, Krystal J, Braff D. Startle gating deficits occur across prepulse intensities in schizophrenic patients. Biol Psychiatry. 1992;32:939–43.
Kohl S, Wolters C, Gruendler TOJ, Vogeley K, Klosterkötter J, Kuhn J. Prepulse inhibition of the acoustic startle reflex in high functioning autism. PLoS ONE. 2014;9:e92372.
Takahashi H, Komatsu S, Nakahachi T, Ogino K, Kamio Y. Relationship of the acoustic startle response and its modulation to emotional and behavioral problems in typical development children and those with autism spectrum disorders. J Autism Dev Disord. 2016;46:534–43.
Nelson Sacha B, Valakh V. Excitatory/inhibitory balance and circuit homeostasis in autism spectrum disorders. Neuron. 2015;87:684–98.
Rubenstein JLR, Merzenich MM. Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav. 2003;2:255–67.
Patterson PH. Maternal infection and autism. Brain Behav Immun. 2012;26:393.
Lodge DJ, Grace AA. Gestational methylazoxymethanol acetate administration: a developmental disruption model of schizophrenia. Behav Brain Res. 2009;204:306–12.
Neill JC, Barnes S, Cook S, Grayson B, Idris NF, McLean SL, Snigdha S, Rajagopal L, Harte MK. Animal models of cognitive dysfunction and negative symptoms of schizophrenia: focus on NMDA receptor antagonism. Pharmacol Ther. 2010;128:419–32.
Brown AS. Exposure to prenatal infection and risk of schizophrenia. Front Psychiatry. 2011;2:63.
Brown AS, Derkits EJ. Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. Am J Psychiatry. 2010;167:261–80.
Eßlinger M, Wachholz S, Manitz M-P, Plümper J, Sommer R, Juckel G, Friebe A. Schizophrenia associated sensory gating deficits develop after adolescent microglia activation. Brain Behav Immun. 2016;58:99–106.
Fortier M-E, Luheshi GN, Boksa P. Effects of prenatal infection on prepulse inhibition in the rat depend on the nature of the infectious agent and the stage of pregnancy. Behav Brain Res. 2007;181:270–7.
Zhang Z, van Praag H. Maternal immune activation differentially impacts mature and adult-born hippocampal neurons in male mice. Brain Behav Immun. 2015;45:60–70.
Bikovsky L, Hadar R, Soto-Montenegro ML, Klein J, Weiner I, Desco M, Pascau J, Winter C, Hamani C. Deep brain stimulation improves behavior and modulates neural circuits in a rodent model of schizophrenia. Exp Neurol. 2016;283:142–50.
Hsiao Elaine Y, McBride Sara W, Hsien S, Sharon G, Hyde Embriette R, McCue T, Codelli Julian A, Chow J, Reisman Sarah E, Petrosino Joseph F, Patterson Paul H, Mazmanian Sarkis K. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell. 2013;155:1451–63.
Yee N, Schwarting RKW, Fuchs E, Wöhr M. Increased affective ultrasonic communication during fear learning in adult male rats exposed to maternal immune activation. J Psychiatr Res. 2012;46:1199–205.
Insel T, Cuthbert B, Garvey M, Heinssen R, Pine DS, Quinn K, Sanislow C, Wang P. Research Domain Criteria (RDoC): Toward a new classification framework for research on mental disorders. Am J Psychiatry. 2010;167:748–51.
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.
Ronovsky M, Berger S, Zambon A, Reisinger SN, Horvath O, Pollak A, Lindtner C, Berger A, Pollak DD. Maternal immune activation transgenerationally modulates maternal care and offspring depression-like behavior. Brain Behav Immun. 2017;63:127–36.
Schwendener S, Meyer U, Feldon J. Deficient maternal care resulting from immunological stress during pregnancy is associated with a sex-dependent enhancement of conditioned fear in the offspring. J Neurodev Disord. 2009;1:15–32.
Meyer U, Nyffeler M, Schwendener S, Knuesel I, Yee BK, Feldon J. Relative prenatal and postnatal maternal contributions to schizophrenia-related neurochemical dysfunction after in utero immune challenge. Neuropsychopharmacology. 2007;33:441–56.
Richetto J, Calabrese F, Meyer U, Riva MA. Prenatal versus postnatal maternal factors in the development of infection-induced working memory impairments in mice. Brain Behav Immun. 2013;33:190–200.
Barak B, Feng G. Neurobiology of social behavior abnormalities in autism and Williams syndrome. Nat Neurosci. 2016;19:647–55.
Smith SEP, Li J, Garbett K, Mirnics K, Patterson PH. Maternal immune activation alters fetal brain development through interleukin-6. J Neurosci. 2007;27:10695–702.
Corbett R, Fielding S, Cornfeldt M, Dunn RW. GABAmimetic agents display anxiolytic-like effects in the social interaction and elevated plus maze procedures. Psychopharmacol (Berl). 1991;104:312–6.
File SE, Seth P. A review of 25 years of the social interaction test. Eur J Pharmacol. 2003;463:35–53.
Selimbeyoglu A, Kim CK, Inoue M, Lee SY, Hong ASO, Kauvar I, Ramakrishnan C, Fenno LE, Davidson TJ, Wright M, Deisseroth K (2017) Modulation of prefrontal cortex excitation/inhibition balance rescues social behavior in CNTNAP2-deficient mice. Sci Transl Med 9. pii: eaah6733
Rosene DL, Hoesen GWV. Hippocampal efferents reach widespread areas of cerebral cortex and amygdala in the rhesus monkey. Science. 1977;198:315–7.
Gunaydin Lisa A, Grosenick L, Finkelstein Joel C, Kauvar Isaac V, Fenno Lief E, Adhikari A, Lammel S, Mirzabekov Julie J, Airan Raag D, Zalocusky Kelly A, Tye Kay M, Anikeeva P, Malenka Robert C, Deisseroth K. Natural neural projection dynamics underlying social behavior. Cell. 2014;157:1535–51.
Lodge DJ. The medial prefrontal and orbitofrontal cortices differentially regulate dopamine system function. Neuropsychopharmacology. 2011;36:1227–36.
Kehagia AA, Murray GK, Robbins TW. Learning and cognitive flexibility: frontostriatal function and monoaminergic modulation. Curr Opin Neurobiol. 2010;20:199–204.
Cavada C, Compañy T, Tejedor J, Cruz-Rizzolo RJ, Reinoso-Suárez F. The anatomical connections of the macaque monkey orbitofrontal cortex. A Rev Cereb Cortex. 2000;10:220–42.
Kringelbach ML. The human orbitofrontal cortex: Linking reward to hedonic experience. Nat Rev: Neurosci. 2005;6:691–702.
Arnsten AFT. Stress signalling pathways that impair prefrontal cortex structure and function. Nat Rev: Neurosci. 2009;10:410–22.
Lodge DJ, Grace AA. Hippocampal dysregulation of dopamine system function and the pathophysiology of schizophrenia. Trends Pharmacol Sci. 2011;32:507–13.
Birrell JM, Brown VJ. Medial frontal cortex mediates perceptual attentional set shifting in the rat. J Neurosci. 2000;20:4320–4.
Lv YT, Zhang Y, Liu M, Qiuwaxi JN, Ashwood P, Cho SC, Huan Y, Ge RC, Chen XW, Wang ZJ, Kim BJ, Hu X. Transplantation of human cord blood mononuclear cells and umbilical cord-derived mesenchymal stem cells in autism. J Transl Med. 2013;11:196.
Sharma A, Gokulchandran N, Sane H, Nagrajan A, Paranjape A, Kulkarni P, Shetty A, Mishra P, Kali M, Biju H, Badhe P. Autologous bone marrow mononuclear cell therapy for autism: an open label proof of concept study. Stem Cells Int. 2013;2013:623875.
Siniscalco D, Bradstreet JJ, Sych N, Antonucci N. Mesenchymal stem cells in treating autism: novel insights. World J Stem Cells. 2014;6:173–8.
Acknowledgements
We would like to thank Dr. Stewart Anderson and Dr. Jennifer Tyson for their generous gift of the J27 mouse embryonic stem cell line containing dual reporters.
Funding
This work was supported by the Owens Foundation and by R01 MH090067 from the NIH. Cell sorting was performed by the Flow Cytometry Shared Resource Facility, supported by UTHSCSA, NIH-NCI P30 CA054174-20 (CTRC at UTHSCSA) and UL1 TR001120 (CTSA grant).
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Donegan, J.J., Boley, A.M. & Lodge, D.J. Embryonic stem cell transplants as a therapeutic strategy in a rodent model of autism. Neuropsychopharmacol 43, 1789–1798 (2018). https://doi.org/10.1038/s41386-018-0021-0
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DOI: https://doi.org/10.1038/s41386-018-0021-0
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