Skip to main content

Advertisement

SpringerLink
Log in

Identifying specific prefrontal neurons that contribute to autism-associated abnormalities in physiology and social behavior

  • Article
  • Published:
Molecular Psychiatry Submit manuscript

Abstract

Functional imaging and gene expression studies both implicate the medial prefrontal cortex (mPFC), particularly deep-layer projection neurons, as a potential locus for autism pathology. Here, we explored how specific deep-layer prefrontal neurons contribute to abnormal physiology and behavior in mouse models of autism. First, we find that across three etiologically distinct models—in utero valproic acid (VPA) exposure, CNTNAP2 knockout and FMR1 knockout—layer 5 subcortically projecting (SC) neurons consistently exhibit reduced input resistance and action potential firing. To explore how altered SC neuron physiology might impact behavior, we took advantage of the fact that in deep layers of the mPFC, dopamine D2 receptors (D2Rs) are mainly expressed by SC neurons, and used D2-Cre mice to label D2R+ neurons for calcium imaging or optogenetics. We found that social exploration preferentially recruits mPFC D2R+ cells, but that this recruitment is attenuated in VPA-exposed mice. Stimulating mPFC D2R+ neurons disrupts normal social interaction. Conversely, inhibiting these cells enhances social behavior in VPA-exposed mice. Importantly, this effect was not reproduced by nonspecifically inhibiting mPFC neurons in VPA-exposed mice, or by inhibiting D2R+ neurons in wild-type mice. These findings suggest that multiple forms of autism may alter the physiology of specific deep-layer prefrontal neurons that project to subcortical targets. Furthermore, a highly overlapping population—prefrontal D2R+ neurons—plays an important role in both normal and abnormal social behavior, such that targeting these cells can elicit potentially therapeutic effects.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Centers for Disease Control and Prevention. Prevalence of autism spectrum disorders–Autism and Developmental Disabilities Monitoring Network, 14 sites, United States, 2008. Morb Mortal Wkly Rep 2012; 61: 1–19.

    Google Scholar 

  2. Baron-Cohen S, Ring H, Moriarty J, Schmitz B, Costa D, Ell P. Recognition of mental state terms. Clinical findings in children with autism and a functional neuroimaging study of normal adults. Br J Psychiatry 1994; 165: 640–649.

    Article  CAS  Google Scholar 

  3. Castelli F, Frith C, Happé F, Frith U. Autism, Asperger syndrome and brain mechanisms for the attribution of mental states to animated shapes. Brain 2002; 125: 1839–1849.

    Article  Google Scholar 

  4. Bachevalier J, Mishkin M. Visual recognition impairment follows ventromedial but not dorsolateral prefrontal lesions in monkeys. Behav Brain Res 1986; 20: 249–261.

    Article  CAS  Google Scholar 

  5. Morgan MA, Romanski LM, LeDoux JE. Extinction of emotional learning: contribution of medial prefrontal cortex. Neurosci Lett 1993; 163: 109–113.

    Article  CAS  Google Scholar 

  6. Yizhar O, Fenno LE, Prigge M, Schneider F, Davidson TJ, O’Shea DJ et al. Neocortical excitation/inhibition balance in information processing and social dysfunction. Nature 2011; 477: 1–8.

    Article  Google Scholar 

  7. Willsey AJ, Sanders SJ, Li M, Dong S, Tebbenkamp AT, Muhle RA et al. Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism. Cell 2013; 155: 997–1007.

    Article  CAS  Google Scholar 

  8. Happé F, Ehlers S, Fletcher P, Frith U, Johansson M, Gillberg C et al. ‘Theory of mind’ in the brain. Evidence from a PET scan study of Asperger syndrome. Neuroreport 1996; 8: 197–201.

    Article  Google Scholar 

  9. Pierce K, Haist F, Sedaghat F, Courchesne E. The brain response to personally familiar faces in autism: findings of fusiform activity and beyond. Brain 2004; 127: 2703–2716.

    Article  Google Scholar 

  10. Cheon KA, Kim YS, Oh SH, Park SY, Yoon HW, Herrington J et al. Involvement of the anterior thalamic radiation in boys with high functioning autism spectrum disorders: a Diffusion Tensor Imaging study. Brain Res 2011; 1417: 77–86.

    Article  CAS  Google Scholar 

  11. Nair A, Treiber JM, Shukla DK, Shih P, Müller R-A. Impaired thalamocortical connectivity in autism spectrum disorder: a study of functional and anatomical connectivity. Brain 2013; 136: 1942–1955.

    Article  Google Scholar 

  12. Testa-Silva G, Loebel A, Giugliano M, de Kock CPJ, Mansvelder HD, Meredith RM. Hyperconnectivity and slow synapses during early development of medial prefrontal cortex in a mouse model for mental retardation and autism. Cereb Cortex 2012; 22: 1333–1342.

    Article  Google Scholar 

  13. Rinaldi T, Perrodin C, Markram H, Cauli B, Pierre U. Hyper-connectivity and hyper-plasticity in the medial prefrontal cortex in the valproic acid animal model of autism. Front Neural Circuits 2008; 2: 4.

    Article  Google Scholar 

  14. Kalmbach BE, Johnston D, Brager DH. Cell-type specific channelopathies in the prefrontal cortex of the fmr1-/y mouse model of Fragile X syndrome. eNeuro 2015; 2, ENEURO.0114-15.2015.

  15. Qiu S, Anderson CT, Levitt P, Shepherd GMG. Circuit-specific intracortical hyperconnectivity in mice with deletion of the autism-associated Met receptor tyrosine kinase. J Neurosci 2011; 31: 5855–5864.

    Article  CAS  Google Scholar 

  16. Gee S, Ellwood I, Patel T, Luongo F, Deisseroth K, Sohal VS. Synaptic activity unmasks dopamine D2 receptor modulation of a specific class of layer V pyramidal neurons in prefrontal cortex. J Neurosci 2012; 32: 4959–4971.

    Article  CAS  Google Scholar 

  17. Lee AT, Gee SM, Vogt D, Patel T, Rubenstein JL, Sohal VS. Pyramidal neurons in prefrontal cortex receive subtype-specific forms of excitation and inhibition. Neuron 2014; 81: 61–68.

    Article  CAS  Google Scholar 

  18. Dembrow NC, Chitwood RA, Johnston D. Projection-specific neuromodulation of medial prefrontal cortex neurons. J Neurosci 2010; 30: 16922–16937.

    Article  CAS  Google Scholar 

  19. Seong HJ, Carter AG. D1 receptor modulation of action potential firing in a subpopulation of layer 5 pyramidal neurons in the prefrontal cortex. J. Neurosci 2012; 32: 10516–10521.

    Article  CAS  Google Scholar 

  20. Moore SJ, Turnpenny P, Quinn A, Glover S, Lloyd DJ, Montgomery T et al. A clinical study of 57 children with fetal anticonvulsant syndromes. J Med Genet 2000; 37: 489–497.

    Article  CAS  Google Scholar 

  21. Christensen J, Grønborg TK, Sørensen MJ, Schendel D, Parner ET, Pedersen LH et al. Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. JAMA 2013; 309: 1696–1703.

    Article  CAS  Google Scholar 

  22. Schneider T, Przewłocki R. Behavioral alterations in rats prenatally exposed to valproic acid: animal model of autism. Neuropsychopharmacology 2005; 30: 80–89.

    Article  CAS  Google Scholar 

  23. Strauss KA, Puffenberger EG, Huentelman MJ, Gottlieb S, Dobrin SE, Parod JM et al. Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2. N Engl J Med 2006; 354: 1370–1377.

    Article  CAS  Google Scholar 

  24. Verkerk A, Pieretti M, Sutcliffe J, Fu Y. Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 1991; 65: 905–914.

    Article  CAS  Google Scholar 

  25. Peñagarikano O, Abrahams BSS, Herman EII, Winden KDD, Gdalyahu A, Dong H et al. Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits. Cell 2011; 147: 235–246.

    Article  Google Scholar 

  26. The Dutch-Belgian Fragile X Consortium. Fmr1 knockout mice: a model to study fragile X mental retardation. Cell 1994; 78: 23–33.

    Google Scholar 

  27. Spencer CM, Alekseyenko O, Serysheva E, Yuva-Paylor LA, Paylor R. Altered anxiety-related and social behaviors in the Fmr1 knockout mouse model of fragile X syndrome. Genes Brain Behav 2005; 4: 420–430.

    Article  CAS  Google Scholar 

  28. Murdoch JD, Gupta AR, Sanders SJ, Walker MF, Keaney J, Fernandez TV et al. No evidence for association of autism with rare heterozygous point mutations in contactin-associated protein-like 2 (CNTNAP2), or in other contactin-associated proteins or contactins. PLoS Genet 2015; 11: e1004852.

    Article  Google Scholar 

  29. Gogolla N, Leblanc JJ, Quast KB, Südhof T, Fagiolini M, Hensch TK. Common circuit defect of excitatory-inhibitory balance in mouse models of autism. J Neurodev Disord 2009; 1: 172–181.

    Article  Google Scholar 

  30. Gunaydin LA, Grosenick L, Finkelstein JC, Kauvar IV, Fenno LE, Adhikari A et al. Natural neural projection dynamics underlying social behavior. Cell 2014; 157: 1535–1551.

    Article  CAS  Google Scholar 

  31. Yona G, Meitav N, Kahn I, Shoham S. Realistic numerical and analytical modeling of light scattering in brain tissue for optogenetic applications. eNeuro 2016; 3, ENEURO.0059-15.2015.

  32. Rinaldi T, Silberberg G, Markram H. Hyperconnectivity of local neocortical microcircuitry induced by prenatal exposure to valproic acid. Cereb Cortex 2008; 18: 763–770.

    Article  Google Scholar 

  33. Zhang Y, Bonnan A, Bony G, Ferezou I, Pietropaolo S, Ginger M et al. Dendritic channelopathies contribute to neocortical and sensory hyperexcitability in Fmr1−/y mice. Nat Neurosci 2014; 17: 1701–1709.

    Article  CAS  Google Scholar 

  34. Shah MM. Hyperpolarization-activated cyclic nucleotide-gated channel currents in neurons. Cold Spring Harb Protoc 2016; 2016, pdb.top087346.

  35. Yi F, Yi F, Danko T, Botelho SC, Patzke C, Pak C et al. Autism-associated SHANK3 haploinsufficiency causes I h channelopathy in human neurons. Science 2016; 352: 2669.

    Article  Google Scholar 

  36. Adelsberger H, Garaschuk O, Konnerth A. Cortical calcium waves in resting newborn mice. Nat Neurosci 2005; 8: 988–990.

    Article  CAS  Google Scholar 

  37. Cui G, Jun SB, Jin X, Pham MD, Vogel SS, Lovinger DM et al. Concurrent activation of striatal direct and indirect pathways during action initiation. Nature 2013; 494: 238–242.

    Article  CAS  Google Scholar 

  38. Cui G, Jun SB, Jin X, Luo G, Pham MD, Lovinger DM et al. Deep brain optical measurements of cell type-specific neural activity in behaving mice. Nat Protoc 2014; 9: 1213–1228.

    Article  CAS  Google Scholar 

  39. Chen T-W, Wardill TJ, Sun Y, Pulver SR, Renninger SL, Baohan A et al. Ultrasensitive fluorescent proteins for imaging neuronal activity. Nature 2013; 499: 295–300.

    Article  CAS  Google Scholar 

  40. Karlsson MP, Tervo DGR, Karpova AY. Network resets in medial prefrontal cortex mark the onset of behavioral uncertainty. Science 2012; 338: 135–139.

    Article  CAS  Google Scholar 

  41. Hyman JM, Ma L, Balaguer-Ballester E, Durstewitz D, Seamans JK. Contextual encoding by ensembles of medial prefrontal cortex neurons. Proc Natl Acad Sci USA 2012; 109: 5086–5091.

    Article  CAS  Google Scholar 

  42. Ma L, Hyman JM, Durstewitz D, Phillips AG, Seamans JK. A quantitative analysis of context-dependent remapping of medial frontal cortex neurons and ensembles. J Neurosci 2016; 36: 8258–8272.

    Article  CAS  Google Scholar 

  43. Tritsch NX, Sabatini BL. Dopaminergic modulation of synaptic transmission in cortex and striatum. Neuron 2012; 76: 33–50.

    Article  CAS  Google Scholar 

  44. Adhikari A, Lerner TN, Finkelstein J, Pak S, Jennings JH, Davidson TJ et al. Basomedial amygdala mediates top-down control of anxiety and fear. Nature 2015; 527: 179–185.

    Article  CAS  Google Scholar 

  45. Krettek JE, Price JL. The cortical projections of the mediodorsal nucleus and adjacent thalamic nuclei in the rat. J Comp Neurol 1977; 171: 157–191.

    Article  CAS  Google Scholar 

  46. Groenewegen HJ. Organization of the afferent connections of the mediodorsal thalamic nucleus in the rat, related to the mediodorsal-prefrontal topography. Neuroscience 1988; 24: 379–431.

    Article  CAS  Google Scholar 

  47. Ray JP, Price JL. The organization of the thalamocortical connections of the mediodorsal thalamic nucleus in the rat, related to the ventral forebrain-prefrontal cortex topography. J Comp Neurol 1992; 323: 167–197.

    Article  CAS  Google Scholar 

  48. Ray JP, Price JL. The organization of projections from the mediodorsal nucleus of the thalamus to orbital and medial prefrontal cortex in macaque monkeys. J Comp Neurol 1993; 31: 1–31.

    Article  Google Scholar 

  49. Goldman-Rakic PS, Porrino LJ. The primate mediodorsal (MD) nucleus and its projection to the frontal lobe. J Comp Neurol 1985; 242: 535–560.

    Article  CAS  Google Scholar 

  50. Conde F, Audinat E, Maire-Lepoivre E, Crepel F. Afferent connections of the medial frontal cortex of the rat. A study using retrograde transport of fluorescent dyes. I. Thalamic afferents. Brain Res Bull 1990; 24: 341–354.

    Article  CAS  Google Scholar 

  51. Parnaudeau S, Taylor K, Bolkan SS, Ward RD, Balsam PD, Kellendonk C. Mediodorsal thalamus hypofunction impairs flexible goal-directed behavior. Biol Psychiatry 2015; 77: 445–453.

    Article  Google Scholar 

  52. Parnaudeau S, O’Neill P-K, Bolkan SS, Ward RD, Abbas AI, Roth BL et al. Inhibition of mediodorsal thalamus disrupts thalamofrontal connectivity and cognition. Neuron 2013; 77: 1151–1162.

    Article  CAS  Google Scholar 

  53. Bellebaum C, Daum I, Koch B, Schwarz M, Hoffmann KP. The role of the human thalamus in processing corollary discharge. Brain 2005; 128: 1139–1154.

    Article  CAS  Google Scholar 

  54. Crapse TB, Sommer MA. Corollary discharge across the animal kingdom. Nat Rev Neurosci 2008; 9: 587–600.

    Article  CAS  Google Scholar 

  55. Baxter MG. Mediodorsal thalamus and cognition in non-human primates. Front Syst Neurosci 2013; 7: 38.

    Article  Google Scholar 

  56. Browning PGF, Chakraborty S, Mitchell AS. Evidence for mediodorsal thalamus and prefrontal cortex interactions during cognition in macaques. Cereb Cortex 2015; 25: 4519–4534.

    Article  Google Scholar 

  57. Golden EC, Graff-Radford J, Jones DT, Benarroch EE. Mediodorsal nucleus and its multiple cognitive functions. Neurology 2016; 87: 2161–2168.

    Article  Google Scholar 

  58. Tsatsanis KD, Rourke BP, Klin A, Volkmar FR, Cicchetti D, Schultz RT. Reduced thalamic volume in high-functioning individuals with autism. Biol Psychiatry 2003; 53: 121–129.

    Article  Google Scholar 

  59. Tamura R, Kitamura H, Endo T, Hasegawa N, Someya T. Reduced thalamic volume observed across different subgroups of autism spectrum disorders. Psychiatry Res 2010; 184: 186–188.

    Article  Google Scholar 

  60. Tan GCY, Doke TF, Ashburner J, Wood NW, Frackowiak RSJ. Normal variation in fronto-occipital circuitry and cerebellar structure with an autism-associated polymorphism of CNTNAP2. Neuroimage 2010; 53: 1030–1042.

    Article  CAS  Google Scholar 

  61. Rubenstein JLR, Merzenich MM. Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav 2003; 2: 255–267.

    Article  CAS  Google Scholar 

  62. Nelson SB, Valakh V. Excitatory/inhibitory balance and circuit homeostasis in autism spectrum disorders. Neuron 2015; 87: 684–698.

    Article  CAS  Google Scholar 

  63. Gibson JR, Bartley AF, Hays Sa, Huber KM. Imbalance of neocortical excitation and inhibition and altered UP states reflect network hyperexcitability in the mouse model of fragile X syndrome. J Neurophysiol 2008; 100: 2615–2626.

    Article  Google Scholar 

  64. Dani VS, Chang Q, Maffei A, Turrigiano GG, Jaenisch R, Nelson SB. Reduced cortical activity due to a shift in the balance between excitation and inhibition in a mouse model of Rett syndrome. Proc Natl Acad Sci USA 2005; 102: 12560–12565.

    Article  CAS  Google Scholar 

  65. Brager DH, Akhavan AR, Johnston D. Impaired dendritic expression and plasticity of h-channels in the fmr1-/y mouse model of Fragile X syndrome. Cell Rep 2012; 1: 225–233.

    Article  CAS  Google Scholar 

  66. Tyzio R, Nardou R, Ferrari DC, Tsintsadze T, Shahrokhi A, Eftekhari S et al. Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring. Science 2014; 343: 675–679.

    Article  CAS  Google Scholar 

  67. Luongo FJ, Horn ME, Sohal VS. Putative microcircuit-level substrates for attention are disrupted in mouse models of autism. Biol Psychiatry 2016; 79: 667–675.

    Article  Google Scholar 

Download references

Acknowledgments

We thank Cooper Grossman and Sahana Kribakiran for genotyping assistance. We acknowledge funding from the following sources: R00 MH085946 (NIMH), R01 MH100292 (NIMH), DP2 MH100011 (NIH/OD), 339018 Director’s Award (SFARI), R25 NS070680-02S1 (NINDS), K12 HD072222-01A1 (NICHD), K08 NS094643 (NINDS), Child Neurology Foundation PERF award UCSF Springer Memorial Fund Pilot Award for Junior Investigators, K01 MH097841 (NIMH), 206734 Pilot Award (SFARI), and R93-A8624 (Lundbeck Foundation).

Author information

Author notes

  1. Current address: Departments of Neurology and Pediatrics, Dell Medical School, and Department of Neuroscience and Center for Learning and Memory at The University of Texas at Austin, Austin, TX, USA.

  2. These three authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, Weill Institute for Neurosciences, Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, CA, USA

    A C Brumback

  2. Department of Psychiatry, Weill Institute for Neurosciences, Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, CA, USA

    A C Brumback, I T Ellwood, C Kjaerby, J Iafrati, S Robinson, A T Lee, T Patel, S Nagaraj, F Davatolhagh & V S Sohal

Authors
  1. A C Brumback
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. I T Ellwood
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C Kjaerby
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J Iafrati
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S Robinson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A T Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. T Patel
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. S Nagaraj
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. F Davatolhagh
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. V S Sohal
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

ACB designed the project, performed electrophysiology, histology, photometry, optogenetics and behavioral experiments, interpreted all data and wrote the paper; IE designed, performed and analyzed photometry experiments; CK designed and performed photometry and optogenetics experiments; JI performed histology experiments; SR performed electrophysiology experiments; AL performed histology experiments; TP performed optogenetic manipulations during behavioral assays; SN analyzed photometry data and performed histology experiments; FD performed behavioral assays; VSS designed the project, interpreted data and wrote the paper.

Corresponding author

Correspondence to V S Sohal.

Ethics declarations

Conflict of Interest

The authors declare no conflict of interest.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Brumback, A.C., Ellwood, I.T., Kjaerby, C. et al. Identifying specific prefrontal neurons that contribute to autism-associated abnormalities in physiology and social behavior. Mol Psychiatry 23, 2078–2089 (2018). https://doi.org/10.1038/mp.2017.213

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2017.213

  • Springer Nature Limited

This article is cited by

Search

Navigation