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Thalamic miR-338-3p mediates auditory thalamocortical disruption and its late onset in models of 22q11.2 microdeletion

Nature Medicine volume 23, pages 39–48 (2017)Cite this article

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Abstract

Although 22q11.2 deletion syndrome (22q11DS) is associated with early-life behavioral abnormalities, affected individuals are also at high risk for the development of schizophrenia symptoms, including psychosis, later in life. Auditory thalamocortical (TC) projections recently emerged as a neural circuit that is specifically disrupted in mouse models of 22q11DS (hereafter referred to as 22q11DS mice), in which haploinsufficiency of the microRNA (miRNA)-processing-factor-encoding gene Dgcr8 results in the elevation of the dopamine receptor Drd2 in the auditory thalamus, an abnormal sensitivity of thalamocortical projections to antipsychotics, and an abnormal acoustic-startle response. Here we show that these auditory TC phenotypes have a delayed onset in 22q11DS mice and are associated with an age-dependent reduction of miR-338-3p, a miRNA that targets Drd2 and is enriched in the thalamus of both humans and mice. Replenishing depleted miR-338-3p in mature 22q11DS mice rescued the TC abnormalities, and deletion of Mir338 (which encodes miR-338-3p) or reduction of miR-338-3p expression mimicked the TC and behavioral deficits and eliminated the age dependence of these deficits. Therefore, miR-338-3p depletion is necessary and sufficient to disrupt auditory TC signaling in 22q11DS mice, and it may mediate the pathogenic mechanism of 22q11DS-related psychosis and control its late onset.

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Figure 1: Adult onset of sensitivity to antipsychotics and of synaptic transmission disruption in auditory TC projections in mouse models of 22q11DS.
Figure 2: Identification of Drd2-targeting miR-338-3p in the auditory thalamus.
Figure 3: Replenishment of miR-338-3p in the auditory thalamus rescues deficits in synaptic transmission and presynaptic neurotransmitter release at TC projections in 22q11DS mouse models.
Figure 4: The depletion of mir-338-3p or knockout of Mir338 replicates the TC deficiency of Df(16)1/+ mice.
Figure 5: Probability of glutamate release is reduced at TC projections from Mir338+/− mice.
Figure 6: Deletion of Mir338 in mice eliminates age dependency for sensitivity to antipsychotics and replicates 22q11DS phenotypes.

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References

  1. Dierks, T. et al. Activation of Heschl's gyrus during auditory hallucinations. Neuron 22, 615–621 (1999).

    CAS  PubMed  Google Scholar 

  2. Silbersweig, D.A. et al. A functional neuroanatomy of hallucinations in schizophrenia. Nature 378, 176–179 (1995).

    CAS  PubMed  Google Scholar 

  3. Horga, G., Schatz, K.C., Abi-Dargham, A. & Peterson, B.S. Deficits in predictive coding underlie hallucinations in schizophrenia. J. Neurosci. 34, 8072–8082 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Javitt, D.C. & Sweet, R.A. Auditory dysfunction in schizophrenia: integrating clinical and basic features. Nat. Rev. Neurosci. 16, 535–550 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Chun, S. et al. Specific disruption of thalamic inputs to the auditory cortex in schizophrenia models. Science 344, 1178–1182 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Lindsay, E.A. et al. Congenital heart disease in mice deficient for the DiGeorge syndrome region. Nature 401, 379–383 (1999).

    CAS  PubMed  Google Scholar 

  7. Bassett, A.S. et al. Practical guidelines for managing patients with 22q11.2 deletion syndrome. J. Pediatr. 159, 332–9.e1 (2011).

    PubMed  PubMed Central  Google Scholar 

  8. McDonald-McGinn, D.M. & Sullivan, K.E. Chromosome 22q11.2 deletion syndrome (DiGeorge syndrome or velocardiofacial syndrome). Medicine (Baltimore) 90, 1–18 (2011).

    Google Scholar 

  9. Scambler, P.J. et al. Velocardiofacial syndrome associated with chromosome 22 deletions encompassing the DiGeorge locus. Lancet 339, 1138–1139 (1992).

    CAS  PubMed  Google Scholar 

  10. Karayiorgou, M., Simon, T.J. & Gogos, J.A. 22q11.2 microdeletions: linking DNA structural variation to brain dysfunction and schizophrenia. Nat. Rev. Neurosci. 11, 402–416 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Pulver, A.E. Search for schizophrenia susceptibility genes. Biol. Psychiatry 47, 221–230 (2000).

    CAS  PubMed  Google Scholar 

  12. Chow, E.W., Watson, M., Young, D.A. & Bassett, A.S. Neurocognitive profile in 22q11 deletion syndrome and schizophrenia. Schizophr. Res. 87, 270–278 (2006).

    PubMed  PubMed Central  Google Scholar 

  13. Fung, W.L. et al. Elevated prevalence of generalized anxiety disorder in adults with 22q11.2 deletion syndrome. Am. J. Psychiatry 167, 998 (2010).

    PubMed  PubMed Central  Google Scholar 

  14. Gothelf, D. et al. Clinical characteristics of schizophrenia associated with velocardiofacial syndrome. Schizophr. Res. 35, 105–112 (1999).

    CAS  PubMed  Google Scholar 

  15. Green, T. et al. Psychiatric disorders and intellectual functioning throughout development in velocardiofacial (22q11.2 deletion) syndrome. J. Am. Acad. Child Adolesc. Psychiatry 48, 1060–1068 (2009).

    PubMed  Google Scholar 

  16. Murphy, K.C., Jones, L.A. & Owen, M.J. High rates of schizophrenia in adults with velocardiofacial syndrome. Arch. Gen. Psychiatry 56, 940–945 (1999).

    CAS  PubMed  Google Scholar 

  17. Pulver, A.E. et al. Psychotic illness in patients diagnosed with velocardiofacial syndrome and their relatives. J. Nerv. Ment. Dis. 182, 476–478 (1994).

    CAS  PubMed  Google Scholar 

  18. Shprintzen, R.J., Goldberg, R., Golding-Kushner, K.J. & Marion, R.W. Late-onset psychosis in the velocardiofacial syndrome. Am. J. Med. Genet. 42, 141–142 (1992).

    CAS  PubMed  Google Scholar 

  19. Bassett, A.S., Chow, E.W. & Weksberg, R. Chromosomal abnormalities and schizophrenia. Am. J. Med. Genet. 97, 45–51 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Murphy, K.C. Schizophrenia and velocardiofacial syndrome. Lancet 359, 426–430 (2002).

    PubMed  Google Scholar 

  21. Feinstein, C., Eliez, S., Blasey, C. & Reiss, A.L. Psychiatric disorders and behavioral problems in children with velocardiofacial syndrome: usefulness as phenotypic indicators of schizophrenia risk. Biol. Psychiatry 51, 312–318 (2002).

    PubMed  Google Scholar 

  22. Bassett, A.S. et al. Clinical features of 78 adults with 22q11 deletion syndrome. Am. J. Med. Genet. A. 138, 307–313 (2005).

    PubMed  PubMed Central  Google Scholar 

  23. Vorstman, J.A., Breetvelt, E.J., Thode, K.I., Chow, E.W. & Bassett, A.S. Expression of autism spectrum and schizophrenia in patients with a 22q11.2 deletion. Schizophr. Res. 143, 55–59 (2013).

    PubMed  Google Scholar 

  24. Schneider, M. et al. Psychiatric disorders from childhood to adulthood in 22q11.2 deletion syndrome: results from the International Consortium on Brain and Behavior in 22q11.2 Deletion Syndrome. Am. J. Psychiatry 171, 627–639 (2014).

    PubMed  PubMed Central  Google Scholar 

  25. Bassett, A.S. et al. The schizophrenia phenotype in 22q11 deletion syndrome. Am. J. Psychiatry 160, 1580–1586 (2003).

    PubMed  PubMed Central  Google Scholar 

  26. Mueser, K.T. & McGurk, S.R. Schizophrenia. Lancet 363, 2063–2072 (2004).

    PubMed  Google Scholar 

  27. Lewis, D.A. & Lieberman, J.A. Catching up on schizophrenia: natural history and neurobiology. Neuron 28, 325–334 (2000).

    CAS  PubMed  Google Scholar 

  28. Bauer, S.M. et al. Culture and the prevalence of hallucinations in schizophrenia. Compr. Psychiatry 52, 319–325 (2011).

    PubMed  Google Scholar 

  29. Carlsson, A. The current status of the dopamine hypothesis of schizophrenia. Neuropsychopharmacology 1, 179–186 (1988).

    CAS  PubMed  Google Scholar 

  30. Seeman, P. & Lee, T. Antipsychotic drugs: direct correlation between clinical potency and presynaptic action on dopamine neurons. Science 188, 1217–1219 (1975).

    CAS  PubMed  Google Scholar 

  31. Earls, L.R. et al. Age-dependent microRNA control of synaptic plasticity in 22q11 deletion syndrome and schizophrenia. J. Neurosci. 32, 14132–14144 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Stark, K.L. et al. Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11 deletion mouse model. Nat. Genet. 40, 751–760 (2008).

    CAS  PubMed  Google Scholar 

  33. Ambros, V. The functions of animal microRNAs. Nature 431, 350–355 (2004).

    CAS  PubMed  Google Scholar 

  34. Earls, L.R. & Zakharenko, S.S. A synaptic function approach to investigating complex psychiatric diseases. Neuroscientist 20, 257–271 (2014).

    PubMed  Google Scholar 

  35. Flurkey, K., Currer, J.M. & Harrison, D.E. in The Mouse in Biomedical Research (eds. Fox, J.G. et al.) 637–672 (American College Laboratory Animal Medicine (Elsevier), Burlington, Massachusetts, USA, 2007).

  36. Smith, P.H. & Populin, L.C. Fundamental differences between the thalamocortical recipient layers of the cat auditory and visual cortices. J. Comp. Neurol. 436, 508–519 (2001).

    CAS  PubMed  Google Scholar 

  37. Swerdlow, N.R., Weber, M., Qu, Y., Light, G.A. & Braff, D.L. Realistic expectations of prepulse inhibition in translational models for schizophrenia research. Psychopharmacology (Berl.) 199, 331–388 (2008).

    CAS  PubMed Central  Google Scholar 

  38. Braff, D.L., Geyer, M.A. & Swerdlow, N.R. Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies. Psychopharmacology (Berl.) 156, 234–258 (2001).

    CAS  Google Scholar 

  39. Denzler, R., Agarwal, V., Stefano, J., Bartel, D.P. & Stoffel, M. Assessing the ceRNA hypothesis with quantitative measurements of miRNA and target abundance. Mol. Cell 54, 766–776 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Small, E.M. & Olson, E.N. Pervasive roles of microRNAs in cardiovascular biology. Nature 469, 336–342 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Chun, S., Bayazitov, I.T., Blundon, J.A. & Zakharenko, S.S. Thalamocortical long-term potentiation becomes gated after the early critical period in the auditory cortex. J. Neurosci. 33, 7345–7357 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Emptage, N.J., Reid, C.A., Fine, A. & Bliss, T.V. Optical quantal analysis reveals a presynaptic component of LTP at hippocampal Schaffer-associational synapses. Neuron 38, 797–804 (2003).

    CAS  PubMed  Google Scholar 

  43. Richardson, R.J., Blundon, J.A., Bayazitov, I.T. & Zakharenko, S.S. Connectivity patterns revealed by mapping of active inputs on dendrites of thalamorecipient neurons in the auditory cortex. J. Neurosci. 29, 6406–6417 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Conn, P.J., Tamminga, C., Schoepp, D.D. & Lindsley, C. Schizophrenia: moving beyond monoamine antagonists. Mol. Interv. 8, 99–107 (2008).

    CAS  PubMed  Google Scholar 

  45. Leucht, S. et al. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 373, 31–41 (2009).

    CAS  PubMed  Google Scholar 

  46. Miyamoto, S., Miyake, N., Jarskog, L.F., Fleischhacker, W.W. & Lieberman, J.A. Pharmacological treatment of schizophrenia: a critical review of the pharmacology and clinical effects of current and future therapeutic agents. Mol. Psychiatry 17, 1206–1227 (2012).

    CAS  PubMed  Google Scholar 

  47. Clinton, S.M. & Meador-Woodruff, J.H. Thalamic dysfunction in schizophrenia: neurochemical, neuropathological, and in vivo imaging abnormalities. Schizophr. Res. 69, 237–253 (2004).

    PubMed  Google Scholar 

  48. Cronenwett, W.J. & Csernansky, J. Thalamic pathology in schizophrenia. Curr. Top. Behav. Neurosci. 4, 509–528 (2010).

    PubMed  Google Scholar 

  49. Oke, A.F., Adams, R.N., Winblad, B. & von Knorring, L. Elevated dopamine/norepinephrine ratios in thalami of schizophrenic brains. Biol. Psychiatry 24, 79–82 (1988).

    CAS  PubMed  Google Scholar 

  50. Wong, D.F. et al. Positron emission tomography reveals elevated D2 dopamine receptors in drug-naive schizophrenics. Science 234, 1558–1563 (1986).

    CAS  PubMed  Google Scholar 

  51. Abi-Dargham, A. et al. Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proc. Natl. Acad. Sci. USA 97, 8104–8109 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Behrendt, R.P. Hallucinations: synchronization of thalamocortical gamma oscillations underconstrained by sensory input. Conscious. Cogn. 12, 413–451 (2003).

    CAS  PubMed  Google Scholar 

  53. Llinás, R.R. & Paré, D. Of dreaming and wakefulness. Neuroscience 44, 521–535 (1991).

    PubMed  Google Scholar 

  54. Welsh, R.C., Chen, A.C. & Taylor, S.F. Low-frequency BOLD fluctuations demonstrate altered thalamocortical connectivity in schizophrenia. Schizophr. Bull. 36, 713–722 (2010).

    PubMed  Google Scholar 

  55. Woodward, N.D., Karbasforoushan, H. & Heckers, S. Thalamocortical dysconnectivity in schizophrenia. Am. J. Psychiatry 169, 1092–1099 (2012).

    PubMed  Google Scholar 

  56. Woo, P.Y., Leung, L.N., Cheng, S.T. & Chan, K.Y. Monoaural musical hallucinations caused by a thalamocortical auditory radiation infarct: a case report. J. Med. Case Rep. 8, 400 (2014).

    PubMed  PubMed Central  Google Scholar 

  57. Sobin, C., Kiley-Brabeck, K. & Karayiorgou, M. Associations between prepulse inhibition and executive visual attention in children with the 22q11 deletion syndrome. Mol. Psychiatry 10, 553–562 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Almeida, O.P., Howard, R.J., Levy, R. & David, A.S. Psychotic states arising in late-life (late paraphrenia) psychopathology and nosology. Br. J. Psychiatry 166, 205–214 (1995).

    CAS  PubMed  Google Scholar 

  59. Zhang, J., Engel, J.A., Ericson, M. & Svensson, L. Involvement of the medial geniculate body in prepulse inhibition of acoustic startle. Psychopharmacology (Berl.) 141, 189–196 (1999).

    CAS  Google Scholar 

  60. Thaker, G.K. & Carpenter, W.T. Jr. Advances in schizophrenia. Nat. Med. 7, 667–671 (2001).

    CAS  PubMed  Google Scholar 

  61. Cruikshank, S.J., Rose, H.J. & Metherate, R. Auditory thalamocortical synaptic transmission in vitro. J. Neurophysiol. 87, 361–384 (2002).

    PubMed  Google Scholar 

  62. Blundon, J.A., Bayazitov, I.T. & Zakharenko, S.S. Presynaptic gating of postsynaptically expressed plasticity at mature thalamocortical synapses. J. Neurosci. 31, 16012–16025 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Boyden, E.S., Zhang, F., Bamberg, E., Nagel, G. & Deisseroth, K. Millisecond-timescale, genetically targeted optical control of neural activity. Nat. Neurosci. 8, 1263–1268 (2005).

    CAS  PubMed  Google Scholar 

  64. Dweep, H., Sticht, C., Pandey, P. & Gretz, N. miRWalk—database: prediction of possible miRNA binding sites by 'walking' the genes of three genomes. J. Biomed. Inform. 44, 839–847 (2011).

    CAS  PubMed  Google Scholar 

  65. Christensen, M., Larsen, L.A., Kauppinen, S. & Schratt, G. Recombinant adeno-associated-virus-mediated microRNA delivery into the postnatal mouse brain reveals a role for miR-134 in dendritogenesis. Front. Neural Circuits 3, 16 (2010).

    PubMed  PubMed Central  Google Scholar 

  66. Kluiver, J. et al. Rapid generation of microRNA sponges for microRNA inhibition. PLoS One 7, e29275 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Kluiver, J. et al. Generation of miRNA sponge constructs. Methods 58, 113–117 (2012).

    CAS  PubMed  Google Scholar 

  68. Mellado Lagarde, M.M. et al. Spontaneous regeneration of cochlear supporting cells after neonatal ablation ensures hearing in the adult mouse. Proc. Natl. Acad. Sci. USA 111, 16919–16924 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by the National Institutes of Health grants MH097742 (S.S.Z.), DC012833 (S.S.Z.), and MH095810 (S.S.Z.), the NARSAD Independent Investigator Award (S.S.Z.), and ALSAC (S.S.Z.). The funding sources had no role in the study design, data collection, data analysis, decision to publish, or preparation of the manuscript. We thank the St. Jude Vector Core for producing the AAVs, the St. Jude Hartwell Center for Biotechnology and Bioinformatics for performing the microarrays, the Maryland Brain Collection for providing post-mortem human brain samples, and A. McArthur for editing the manuscript. Knockout mice, viruses and other materials described in this manuscript can be obtained through a material transfer agreement.

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  1. Sungkun Chun, Fei Du & Joby J Westmoreland

    Present address: Present addresses: Department of Physiology, Chonbuk National University Medical School, South Korea (S.C.); Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA (F.D.); Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana, USA (J.J.W.).,

  2. Sungkun Chun, Fei Du and Joby J Westmoreland: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA

    Sungkun Chun, Fei Du, Joby J Westmoreland, Seung Baek Han, Donnie Eddins, Ildar T Bayazitov, Prakash Devaraju, Jing Yu, Marcia M Mellado Lagarde, Kara Anderson & Stanislav S Zakharenko

  2. Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA

    Yong-Dong Wang

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Contributions

S.S.Z., J.J.W., F.D., and S.C. designed the research; S.C. performed the whole-cell recordings; F.D., J.J.W., and S.B.H. designed and constructed the microRNA molecular tools and verified these tools in vitro and in vivo; Y.-D.W. performed the microRNA array analysis; I.T.B. and P.D. performed the two-photon imaging and whole-cell recordings; J.Y. and K.A. assisted with qRT–PCR and western blotting analyses; D.E. and M.M.M.L. performed the mouse behavior experiments; and S.S.Z. wrote the paper with help from the other authors.

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Correspondence to Stanislav S Zakharenko.

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Chun, S., Du, F., Westmoreland, J. et al. Thalamic miR-338-3p mediates auditory thalamocortical disruption and its late onset in models of 22q11.2 microdeletion. Nat Med 23, 39–48 (2017). https://doi.org/10.1038/nm.4240

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