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Stem cell-derived interneuron transplants as a treatment for schizophrenia: preclinical validation in a rodent model

Abstract

An increasing literature suggests that schizophrenia is associated with a reduction in hippocampal interneuron function. Thus, we posit that stem cell-derived interneuron transplants may be an effective therapeutic strategy to reduce hippocampal hyperactivity and attenuate behavioral deficits in schizophrenia. Here we used a dual-reporter embryonic stem cell line to generate enriched populations of parvalbumin (PV)- or somatostatin (SST)-positive interneurons, which were transplanted into the ventral hippocampus of the methylazoxymethanol rodent model of schizophrenia. These interneuron transplants integrate within the existing circuitry, reduce hippocampal hyperactivity and normalize aberrant dopamine neuron activity. Further, interneuron transplants alleviate behaviors that model negative and cognitive symptoms, including deficits in social interaction and cognitive inflexibility. Interestingly, PV- and SST-enriched transplants produced differential effects on behavior, with PV-enriched populations effectively normalizing all the behaviors examined. These data suggest that the stem cell-derived interneuron transplants may represent a novel therapeutic strategy for schizophrenia.

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References

  1. Seeman P, Chau-Wong M, Tedesco J, Wong K . Brain receptors for antipsychotic drugs and dopamine: direct binding assays. Proc Natl Acad Sci USA 1975; 72: 4376–4380.

    Article  CAS  Google Scholar 

  2. Leucht S, Cipriani A, Spineli L, Mavridis D, Örey D, Richter F et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 2013; 382: 951–962.

    Article  CAS  Google Scholar 

  3. Strassnig MT, Raykov T, O'Gorman C, Bowie CR, Sabbag S, Durand D et al. Determinants of different aspects of everyday outcome in schizophrenia: the roles of negative symptoms, cognition, and functional capacity. Schizophr Res. 2015; 165: 76–82.

    Article  Google Scholar 

  4. Citrome L . Unmet needs in the treatment of schizophrenia: new targets to help different symptom domains. J Clin Pychiatry 2014; 75 (Suppl 1): 21–26.

    Article  CAS  Google Scholar 

  5. Lodge DJ, Grace AA . Hippocampal dysregulation of dopamine system function and the pathophysiology of schizophrenia. Trends Pharmacol Sci 2011; 32: 507–513.

    Article  CAS  Google Scholar 

  6. Legault M, Wise RA . Injections of N-methyl-D-aspartate into the ventral hippocampus increase extracellular dopamine in the ventral tegmental area and nucleus accumbens. Synapse 1999; 31: 241–249.

    Article  CAS  Google Scholar 

  7. Rosene DL, Hoesen GWV . Hippocampal efferents reach widespread areas of cerebral cortex and amygdala in the rhesus monkey. Science 1977; 198: 315–317.

    Article  CAS  Google Scholar 

  8. Birrell JM, Brown VJ . Medial frontal cortex mediates perceptual attentional set shifting in the rat. J Neurosci 2000; 20: 4320–4324.

    Article  CAS  Google Scholar 

  9. 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: 171–178.

    Article  CAS  Google Scholar 

  10. Malaspina D, Storer S, Furman V, Esser P, Printz D, Berman A et al. SPECT study of visual fixation in schizophrenia and comparison subjects. Biol Psychiatry 1999; 46: 89–93.

    Article  CAS  Google Scholar 

  11. Schobel SA, Lewandowski NM, Corcoran CM, Moore H, Brown T, Malaspina D et al. DIfferential targeting of the ca1 subfield of the hippocampal formation by schizophrenia and related psychotic disorders. Arch Gen Psychiatry 2009; 66: 938–946.

    Article  Google Scholar 

  12. Heckers S, Konradi C . GABAergic mechanisms of hippocampal hyperactivity in schizophrenia. Schizophr Res 2014; 167: 4–11.

    Article  Google Scholar 

  13. Lewis DA, Hashimoto T, Volk DW . Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci 2005; 6: 312–324.

    Article  CAS  Google Scholar 

  14. Zhang ZJ, Reynolds GP . A selective decrease in the relative density of parvalbumin-immunoreactive neurons in the hippocampus in schizophrenia. Schizophr Res 2002; 55: 1–10.

    Article  Google Scholar 

  15. Konradi C, Yang CK, Zimmerman EI, Lohmann KM, Gresch P, Pantazopoulos H et al. Hippocampal interneurons are abnormal in schizophrenia. Schizophr Res 2011; 131: 165–173.

    Article  Google Scholar 

  16. Boley AM, Perez SM, Lodge DJ . A fundamental role for hippocampal parvalbumin in the dopamine hyperfunction associated with schizophrenia. Schizophr Res 2014; 157: 238–243.

    Article  Google Scholar 

  17. Perez SM, Lodge DJ . Hippocampal interneuron transplants reverse aberrant dopamine system function and behavior in a rodent model of schizophrenia. Mol Psychiatry 2013; 18: 1193–1198.

    Article  CAS  Google Scholar 

  18. Wonders CP, Anderson SA . The origin and specification of cortical interneurons. Nat Rev Neurosci 2006; 7: 687–696.

    Article  CAS  Google Scholar 

  19. Wichterle H, Turnbull DH, Nery S, Fishell G, Alvarez-Buylla A . In utero fate mapping reveals distinct migratory pathways and fates of neurons born in the mammalian basal forebrain. Development 2001; 128: 3759–3771.

    CAS  PubMed  Google Scholar 

  20. Gilani AI, Chohan MO, Inan M, Schobel SA, Chaudhury NH, Paskewitz S et al. Interneuron precursor transplants in adult hippocampus reverse psychosis-relevant features in a mouse model of hippocampal disinhibition. Proc Natl Acad Sci 2014; 111: 7450–7455.

    Article  CAS  Google Scholar 

  21. 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: 1267–1278.

    Article  CAS  Google Scholar 

  22. Lodge DJ, Grace AA . Gestational methylazoxymethanol acetate administration: a developmental disruption model of schizophrenia. Behav Brain Res 2009; 204: 306–312.

    Article  CAS  Google Scholar 

  23. Ranck JBJ . Studies on single neurons in dorsal hippocampal formation and septum in unrestrained rats. I. Behavioral correlates and firing repertoires. Exp Neurol 1973; 41: 461–531.

    Article  Google Scholar 

  24. Grace AA, Bunney BS . Intracellular and extracellular electrophysiology of nigral dopaminergic neurons—1. Identification and characterization. Neuroscience 1983; 10: 301–315.

    Article  CAS  Google Scholar 

  25. 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: 1139–1147.

    Article  CAS  Google Scholar 

  26. Lapiz MD, Morilak DA . Noradrenergic modulation of cognitive function in rat medial prefrontal cortex as measured by attentional set shifting capability. Neuroscience 2006; 137: 1039–1049.

    Article  CAS  Google Scholar 

  27. Lodge DJ, Grace AA . Aberrant Hippocampal Activity Underlies the Dopamine Dysregulation in an Animal Model of Schizophrenia. J Neurosci 2007; 27: 11424–11430.

    Article  CAS  Google Scholar 

  28. Lodge DJ, Grace AA . The hippocampus modulates dopamine neuron responsivity by regulating the intensity of phasic neuron activation. Neuropsychopharmacology 2006; 31: 1356–1361.

    Article  CAS  Google Scholar 

  29. Floresco SB, Todd CL, Grace AA . Glutamatergic afferents from the hippocampus to the nucleus accumbens regulate activity of ventral tegmental area dopamine neurons. J Neurosci 2001; 21: 4915–4922.

    Article  CAS  Google Scholar 

  30. Pantelis C, Barber FZ, Barnes TRE, Nelson HE, Owen AM, Robbins TW . Comparison of set-shifting ability in patients with chronic schizophrenia and frontal lobe damage. Schizophr Res 1999; 37: 251–270.

    Article  CAS  Google Scholar 

  31. Gastambide F, Cotel M-C, Gilmour G, O'Neill MJ, Robbins TW, Tricklebank MD . Selective Remediation of Reversal Learning Deficits in the Neurodevelopmental MAM Model of Schizophrenia by a Novel mGlu5 Positive Allosteric Modulator. Neuropsychopharmacology 2012; 37: 1057–1066.

    Article  CAS  Google Scholar 

  32. Wonders CP, Welagen J, Taylor L, Mbata IC, Xiang JZ, Anderson SA . A spatial bias for the origins of interneuron subgroups within the medial ganglionic eminence. Dev Biol 2008; 314: 127–136.

    Article  CAS  Google Scholar 

  33. Inan M, Welagen J, Anderson SA . Spatial and temporal bias in the mitotic origins of somatostatin- and parvalbumin-expressing interneuron subgroups and the chandelier subtype in the medial ganglionic eminence. Cereb Cortex 2012; 22: 820–827.

    Article  Google Scholar 

  34. Xu Q, Wonders CP, Anderson SA . Sonic hedgehog maintains the identity of cortical interneuron progenitors in the ventral telencephalon. Development 2005; 132: 4987–4998.

    Article  CAS  Google Scholar 

  35. Xu Q, Guo L, Moore H, Waclaw RR, Campbell K, Anderson SA . Sonic hedgehog signaling confers ventral telencephalic progenitors with distinct cortical interneuron fates. Neuron 2010; 65: 328–340.

    Article  CAS  Google Scholar 

  36. DeBoer EM, Anderson SA . Fate determination of cerebral cortical GABAergic interneurons and their derivation from stem cells. Brain Res (in press).

  37. Tyson JA, Anderson SA . The protracted maturation of human ESC-derived interneurons. Cell Cycle 2013; 12: 3129–3130.

    Article  CAS  Google Scholar 

  38. Markram H, Toledo-Rodriguez M, Wang Y, Gupta A, Silberberg G, Wu C . Interneurons of the neocortical inhibitory system. Nat Rev Neurosci 2004; 5: 793–807.

    Article  CAS  Google Scholar 

  39. Kawaguchi Y . Physiological subgroups of nonpyramidal cells with specific morphological characteristics in layer II/III of rat frontal cortex. J Neurosci 1995; 15: 2638–2655.

    Article  CAS  Google Scholar 

  40. Kawaguchi Y, Kubota Y . Physiological and morphological identification of somatostatin- or vasoactive intestinal polypeptide-containing cells among GABAergic cell subtypes in rat frontal cortex. TJ Neurosci 1996; 16: 2701–2715.

    Article  CAS  Google Scholar 

  41. Davis KL, Kahn RS, Ko G, Davidson M . Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry 1991; 148: 1474–1486.

    Article  CAS  Google Scholar 

  42. Kehagia AA, Murray GK, Robbins TW . Learning and cognitive flexibility: frontostriatal function and monoaminergic modulation. Curr Opin Neurobiol 2010; 20: 199–204.

    Article  CAS  Google Scholar 

  43. Dias R, Robbins TW, Roberts AC . Dissociation in prefrontal cortex of affective and attentional shifts. Nature 1996; 380: 69–72.

    Article  CAS  Google Scholar 

  44. Cools R, Frank MJ, Gibbs SE, Miyakawa A, Jagust W, D'Esposito M . Striatal dopamine predicts outcome-specific reversal learning and its sensitivity to dopaminergic drug administration. J Neurosci 2009; 29: 1538–1543.

    Article  CAS  Google Scholar 

  45. Jocham G, Klein TA, Neumann J, von Cramon DY, Reuter M, Ullsperger M . Dopamine DRD2 polymorphism alters reversal learning and associated neural activity. J Neurosci 2009; 29: 3695–3704.

    Article  CAS  Google Scholar 

  46. Clarke HF, Walker SC, Dalley JW, Robbins TW, Roberts AC . Cognitive inflexibility after prefrontal serotonin depletion is behaviorally and neurochemically specific. Cereb Cortex 2007; 17: 18–27.

    Article  CAS  Google Scholar 

  47. Clarke HF, Hill GJ, Robbins TW, Roberts AC . Dopamine, but not serotonin, regulates reversal learning in the marmoset caudate nucleus. J Neurosci 2011; 31: 4290–4297.

    Article  CAS  Google Scholar 

  48. Boulougouris V, Castañé A, Robbins T . Dopamine D2/D3 receptor agonist quinpirole impairs spatial reversal learning in rats: investigation of D3 receptor involvement in persistent behavior. Psychopharmacology 2009; 202: 611–620.

    Article  CAS  Google Scholar 

  49. Lee B, Groman S, London ED, Jentsch JD . Dopamine D2/D3 receptors play a specific role in the reversal of a learned visual discrimination in monkeys. Neuropsychopharmacology 2007; 32: 2125–2134.

    Article  CAS  Google Scholar 

  50. Bunney WE, Bunney BG . Evidence for a compromised dorsolateral prefrontal cortical parallel circuit in schizophrenia. Brain Res Rev 2000; 31: 138–146.

    Article  CAS  Google Scholar 

  51. Tyson PJ, Laws KR, Roberts KH, Mortimer AM . Stability of set-shifting and planning abilities in patients with schizophrenia. Psychiatry Res 2004; 129: 229–239.

    Article  Google Scholar 

  52. Leeson VC, Robbins TW, Matheson E, Hutton SB, Ron MA, Barnes TRE et al. Discrimination learning, reversal, and set-shifting in first-episode schizophrenia: Stability over six years and specific associations with medication type and disorganization syndrome. Biol Psychiatry 2009; 66: 586–593.

    Article  Google Scholar 

  53. Jay TM, Witter MP . Distribution of hippocampal CA1 and subicular efferents in the prefrontal cortex of the rat studied by means of anterograde transport of Phaseolus vulgaris-leucoagglutinin. J Comp Neurol 1991; 313: 574–586.

    Article  CAS  Google Scholar 

  54. Korenbrot CC, Huhtaniemi IT, Weiner RI . Preputial separation as an external sign of pubertal development in the male rat. Biol Reprod 1977; 17: 298–303.

    Article  CAS  Google Scholar 

  55. Chen L, Perez SM, Lodge DJ . An augmented dopamine system function is present prior to puberty in the methylazoxymethanol acetate rodent model of schizophrenia. Dev Neurobiol 2014; 74: 907–917.

    Article  CAS  Google Scholar 

  56. Perkins DO, Gu H, Boteva K, Lieberman JA . Relationship between duration of untreated psychosis and outcome in first-episode schizophrenia: a critical review and meta-analysis. Am J Psychiatry 2005; 162: 1785–1804.

    Article  Google Scholar 

  57. Mendez I, Vinuela A, Astradsson A, Mukhida K, Hallett P, Robertson H et al. Dopamine neurons implanted into people with Parkinson's disease survive without pathology for 14 years. Nat Med 2008; 14: 507–509.

    Article  CAS  Google Scholar 

  58. Steinbeck Julius A, Studer L . Moving stem cells to the clinic: potential and limitations for brain repair. Neuron 2015; 86: 187–206.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by the Owens Foundation and by R01 MH090067 (DL) and R01 MH066912 (SA), and R01 DA032701 (MB) 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). We would like to acknowledge Jordan Thomas for his technical assistance.

Author contributions

JJD and DJL participated in research design. JJD and SYB conducted experiments. JAT and SAA contributed new reagents. JJD, SYB, MJB and DJL performed the data analysis. All authors wrote or contributed to the writing of the manuscript.

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Correspondence to J J Donegan.

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Donegan, J., Tyson, J., Branch, S. et al. Stem cell-derived interneuron transplants as a treatment for schizophrenia: preclinical validation in a rodent model. Mol Psychiatry 22, 1492–1501 (2017). https://doi.org/10.1038/mp.2016.121

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