Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

α7 nicotinic acetylcholine receptor, activated glia, and cognitive impairment in schizophrenia: a dual-tracer PET study

Molecular Psychiatry volume 31, pages 739–748 (2026)Cite this article

Subjects

Abstract

The α7 nicotinic acetylcholine receptor (nAChR) plays a crucial role in cognitive function, and its dysfunction has been proposed as a primary pathophysiological factor in schizophrenia. Although the α7 nAChR is expressed in both neuronal and activated glial cells, its association with activated glia and its role in the pathophysiology of schizophrenia remain uncertain. Therefore, we investigated α7 nAChR availability and activated glia evaluated with 18 kDa translocator protein (TSPO) levels in individuals with schizophrenia, and further examined their association and relationships to cognitive impairment. Nineteen individuals with schizophrenia, no smoking history or use of anticholinergic or benzodiazepine medications for at least 6 months, and 20 age- and sex-matched healthy controls underwent [11C](R)-MeQAA and [11C]DPA713 positron emission tomography scans on the same day. Whole-brain analyses revealed significantly higher α7 nAChR availability in the right cerebellum, perihippocampal region, putamen, and occipital cortex in individuals with schizophrenia. In line with previous findings, TSPO levels did not differ between groups. Furthermore, in the schizophrenia group, elevated α7 nAChR availability was significantly positively correlated with TSPO levels and letter fluency performance in various brain regions predominantly in the right hemisphere. Notably, in the right perihippocampal region, there was an overlap in regions showing a significantly higher α7 nAChR availability and regions significantly correlated with activated glia and cognitive dysfunction. Our findings provide novel insights into the role of the α7 nAChR and its association with activated glia in schizophrenia, and the α7 nAChR may serve as a potential therapeutic target for cognitive dysfunction.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Regional distribution of elevated [11C](R)-MeQAA non-displaceable binding potential (BPND), its correlations with [11C]DPA713 BPND and total letter fluency test (LFT) scores, and their overlapping areas in individuals with schizophrenia.

Similar content being viewed by others

Data availability

The datasets analyzed during the current study are not publicly available due to concerns regarding participant privacy and consent, but are available from the corresponding author on reasonable request.

References

  1. Jauhar S, Johnstone M, McKenna PJ. Schizophrenia. Lancet. 2022;399:473–86.

    Article  PubMed  CAS  Google Scholar 

  2. Haddad PM, Correll CU. The acute efficacy of antipsychotics in schizophrenia: a review of recent meta-analyses. Ther Adv Psychopharmacol. 2018;8:303–18.

    Article  PubMed  PubMed Central  Google Scholar 

  3. McCutcheon RA, Keefe RSE, McGuire PK. Cognitive impairment in schizophrenia: aetiology, pathophysiology, and treatment. Mol Psychiatry. 2023;28:1902–18.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Alkondon M, Albuquerque EX. The nicotinic acetylcholine receptor subtypes and their function in the hippocampus and cerebral cortex. Prog Brain Res. 2004;145:109–20.

    Article  PubMed  CAS  Google Scholar 

  5. Graham A, Court JA, Martin-Ruiz CM, Jaros E, Perry R, Volsen SG, et al. Immunohistochemical localisation of nicotinic acetylcholine receptor subunits in human cerebellum. Neuroscience. 2002;113:493–507.

    Article  PubMed  CAS  Google Scholar 

  6. Dineley KT, Pandya AA, Yakel JL. Nicotinic ACh receptors as therapeutic targets in CNS disorders. Trends Pharmacol Sci. 2015;36:96–108.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Leiser SC, Bowlby MR, Comery TA, Dunlop J. A cog in cognition: how the alpha 7 nicotinic acetylcholine receptor is geared towards improving cognitive deficits. Pharmacol Ther. 2009;122:302–11.

    Article  PubMed  CAS  Google Scholar 

  8. Freedman R, Hall M, Adler LE, Leonard S. Evidence in postmortem brain tissue for decreased numbers of hippocampal nicotinic receptors in schizophrenia. Biol Psychiatry. 1995;38:22–33.

    Article  PubMed  CAS  Google Scholar 

  9. Court J, Spurden D, Lloyd S, McKeith I, Ballard C, Cairns N, et al. Neuronal nicotinic receptors in dementia with Lewy bodies and schizophrenia: alpha-bungarotoxin and nicotine binding in the thalamus. J Neurochem. 1999;73:1590–7.

    Article  PubMed  CAS  Google Scholar 

  10. Guan ZZ, Zhang X, Blennow K, Nordberg A. Decreased protein level of nicotinic receptor alpha7 subunit in the frontal cortex from schizophrenic brain. Neuroreport. 1999;10:1779–82.

    Article  PubMed  CAS  Google Scholar 

  11. Marutle A, Zhang X, Court J, Piggott M, Johnson M, Perry R, et al. Laminar distribution of nicotinic receptor subtypes in cortical regions in schizophrenia. J Chem Neuroanat. 2001;22:115–26.

    Article  PubMed  CAS  Google Scholar 

  12. Martin-Ruiz CM, Haroutunian VH, Long P, Young AH, Davis KL, Perry EK, et al. Dementia rating and nicotinic receptor expression in the prefrontal cortex in schizophrenia. Biol Psychiatry. 2003;54:1222–33.

    Article  PubMed  CAS  Google Scholar 

  13. Terry AV Jr, Callahan PM. alpha7 nicotinic acetylcholine receptors as therapeutic targets in schizophrenia: update on animal and clinical studies and strategies for the future. Neuropharmacology. 2020;170:108053.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Antonio-Tolentino K, Hopkins CR. Selective α7 nicotinic receptor agonists and positive allosteric modulators for the treatment of schizophrenia - a review. Expert Opin Investig Drugs. 2020;29:603–10.

    Article  PubMed  CAS  Google Scholar 

  15. Recio-Barbero M, Segarra R, Zabala A, Gonzalez-Fraile E, Gonzalez-Pinto A, Ballesteros J. Cognitive enhancers in schizophrenia: a systematic review and meta-analysis of alpha-7 nicotinic acetylcholine receptor agonists for cognitive deficits and negative symptoms. Front Psychiatry. 2021;12:631589.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Wong DF, Kuwabara H, Horti AG, Roberts JM, Nandi A, Cascella N, et al. Brain PET imaging of alpha7-nAChR with [18F]ASEM: reproducibility, occupancy, receptor density, and changes in schizophrenia. Int J Neuropsychopharmacol. 2018;21:656–67.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Wong NR, Rubin LH, Harrington CK, Jenkins KR, Shinehouse LK, Yoon M, et al. Hippocampal availability of the alpha7 nicotinic acetylcholine receptor in recent-onset psychosis. JAMA Netw Open. 2024;7:e2427163.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Egea J, Buendia I, Parada E, Navarro E, León R, Lopez MG. Anti-inflammatory role of microglial alpha7 nAChRs and its role in neuroprotection. Biochem Pharmacol. 2015;97:463–72.

    Article  PubMed  CAS  Google Scholar 

  19. Shen JX, Yakel JL. Functional α7 nicotinic ACh receptors on astrocytes in rat hippocampal CA1 slices. J Mol Neurosci. 2012;48:14–21.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Wu YJ, Wang L, Ji CF, Gu SF, Yin Q, Zuo J. The role of α7nAChR-mediated cholinergic anti-inflammatory pathway in immune cells. Inflammation. 2021;44:821–34.

    Article  PubMed  CAS  Google Scholar 

  21. Shytle RD, Mori T, Townsend K, Vendrame M, Sun N, Zeng J, et al. Cholinergic modulation of microglial activation by alpha 7 nicotinic receptors. J Neurochem. 2004;89:337–43.

    Article  PubMed  CAS  Google Scholar 

  22. Suzuki T, Hide I, Matsubara A, Hama C, Harada K, Miyano K, et al. Microglial alpha7 nicotinic acetylcholine receptors drive a phospholipase C/IP3 pathway and modulate the cell activation toward a neuroprotective role. J Neurosci Res. 2006;83:1461–70.

    Article  PubMed  CAS  Google Scholar 

  23. Parada E, Egea J, Buendia I, Negredo P, Cunha AC, Cardoso S, et al. The microglial α7-acetylcholine nicotinic receptor is a key element in promoting neuroprotection by inducing heme oxygenase-1 via nuclear factor erythroid-2-related factor 2. Antioxid Redox Signal. 2013;19:1135–48.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Khandaker GM, Cousins L, Deakin J, Lennox BR, Yolken R, Jones PB. Inflammation and immunity in schizophrenia: implications for pathophysiology and treatment. Lancet Psychiatry. 2015;2:258–70.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Cho M, Lee TY, Kwak YB, Yoon YB, Kim M, Kwon JS. Adjunctive use of anti-inflammatory drugs for schizophrenia: a meta-analytic investigation of randomized controlled trials. Aust N Z J Psychiatry. 2019;53:742–59.

    Article  PubMed  Google Scholar 

  26. Meyer JH, Cervenka S, Kim MJ, Kreisl WC, Henter ID, Innis RB. Neuroinflammation in psychiatric disorders: PET imaging and promising new targets. Lancet Psychiatry. 2020;7:1064–74.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Plaven-Sigray P, Matheson GJ, Collste K, Ashok AH, Coughlin JM, Howes OD, et al. Positron emission tomography studies of the glial cell marker translocator protein in patients with psychosis: a meta-analysis using individual participant data. Biol Psychiatry. 2018;84:433–42.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Conen S, Gregory CJ, Hinz R, Smallman R, Corsi-Zuelli F, Deakin B, et al. Neuroinflammation as measured by positron emission tomography in patients with recent onset and established schizophrenia: implications for immune pathogenesis. Mol Psychiatry. 2021;26:5398–406.

    Article  PubMed  CAS  Google Scholar 

  29. Diagnostic and statistical manual of mental disorders: DSM-5. Arlington, VA: American Psychiatric Association; 2013.

  30. Wechsler D. Wechsler adult intelligence scale 3rd edition (WAIS-III). Lisse: Swets & Zeitlinger: Netherland; 1997.

    Google Scholar 

  31. Breese CR, Lee MJ, Adams CE, Sullivan B, Logel J, Gillen KM, et al. Abnormal regulation of high affinity nicotinic receptors in subjects with schizophrenia. Neuropsychopharmacology. 2000;23:351–64.

    Article  PubMed  CAS  Google Scholar 

  32. Brody AL, Hubert R, Enoki R, Garcia LY, Mamoun MS, Okita K, et al. Effect of cigarette smoking on a marker for neuroinflammation: a [(11)C]DAA1106 positron emission Tomography study. Neuropsychopharmacology. 2017;42:1630–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. First MB, Williams JBW, Karg RS, Spitzer RL. SCID-5-CV: structured clinical interview for DSM-5 disorders : clinician version. Washington, DC: American Psychiatric Association Pub.; 2016.

    Google Scholar 

  34. Hollingshead A. Two factor index of social class measurement. New Haven, CT: Yale University; 1957.

    Google Scholar 

  35. Leucht S, Samara M, Heres S, Patel MX, Woods SW, Davis JM. Dose equivalents for second-generation antipsychotics: the minimum effective dose method. Schizophr Bull. 2014;40:314–26.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Inada T, Inagaki A. Psychotropic dose equivalence in Japan. Psychiatry Clin Neurosci. 2015;69:440–7.

    Article  PubMed  Google Scholar 

  37. Inagaki A, Inada T. Dose equivalence of depot antipsychotics IV: aripiprazole once-monthly. Jpn J Clin Psychopharmacol. 2015;18:1475–80.

    Google Scholar 

  38. Inagaki A, Inada T. Dose equivalence of novel antipsychotics: brexpiprazole. Jpn J Clin Psychopharmacol. 2022;25:91–98.

    Google Scholar 

  39. Matsuoka K, Uno M, Kasai K, Koyama K, Kim Y. Estimation of premorbid IQ in individuals with Alzheimer’s disease using Japanese ideographic script (Kanji) compound words: Japanese version of National Adult Reading Test. Psychiatry Clin Neurosci. 2006;60:332–9.

    Article  PubMed  Google Scholar 

  40. Flaaten CB, Melle I, Gardsjord E, Bjella T, Engen MJ, Vaskinn A, et al. Course of intellectual functioning in schizophrenia and bipolar disorder: a 10-year Follow-Up study. Psychol Med. 2023;53:2662–70.

    Article  PubMed  Google Scholar 

  41. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13:261–76.

    Article  PubMed  CAS  Google Scholar 

  42. Maruff P, Thomas E, Cysique L, Brew B, Collie A, Snyder P, et al. Validity of the CogState brief battery: relationship to standardized tests and sensitivity to cognitive impairment in mild traumatic brain injury, schizophrenia, and AIDS dementia complex. Arch Clin Neuropsychol. 2009;24:165–78.

    Article  PubMed  Google Scholar 

  43. Pietrzak RH, Olver J, Norman T, Piskulic D, Maruff P, Snyder PJ. A comparison of the CogState schizophrenia battery and the measurement and treatment research to improve cognition in schizophrenia (MATRICS) battery in assessing cognitive impairment in chronic schizophrenia. J Clin Exp Neuropsychol. 2009;31:848–59.

    Article  PubMed  Google Scholar 

  44. Kern RS, Green MF, Nuechterlein KH, Deng BH. NIMH-MATRICS survey on assessment of neurocognition in schizophrenia. Schizophr Res. 2004;72:11–19.

    Article  PubMed  Google Scholar 

  45. Nuechterlein KH, Green MF, Kern RS, Baade LE, Barch DM, Cohen JD, et al. The MATRICS consensus cognitive battery, part 1: test selection, reliability, and validity. Am J Psychiatry. 2008;165:203–13.

    Article  PubMed  Google Scholar 

  46. Yoshida T, Suga M, Arima K, Muranaka Y, Tanaka T, Eguchi S, et al. Criterion and construct validity of the CogState schizophrenia battery in Japanese patients with schizophrenia. PLoS One. 2011;6:e20469.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Nishinaka H, Nakane J, Nagata T, Imai A, Kuroki N, Sakikawa N, et al. Neuropsychological impairment and its association with violence risk in Japanese forensic psychiatric patients: a Case-Control study. PLoS One. 2016;11:e0148354.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Keefe RS, Goldberg TE, Harvey PD, Gold JM, Poe MP, Coughenour L. The brief assessment of cognition in schizophrenia: reliability, sensitivity, and comparison with a standard neurocognitive battery. Schizophr Res. 2004;68:283–97.

    Article  PubMed  Google Scholar 

  49. Reichenberg A, Harvey PD. Neuropsychological impairments in schizophrenia: integration of performance-based and brain imaging findings. Psychol Bull. 2007;133:833–58.

    Article  PubMed  Google Scholar 

  50. Benoit A, Malla AK, Iyer SN, Joober R, Bherer L, Lepage M. Cognitive deficits characterization using the CogState research battery in first-episode psychosis patients. Schizophr Res Cogn. 2015;2:140–5.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Reitan RM. Validity of the trail making test as an indicator of organic brain damage. Percept Mot Skills. 1958;8:271–6.

    Article  Google Scholar 

  52. Abe M, Suzuki K, Okada K, Miura R, Fujii T, Etsurou M, et al. Normative data on tests for frontal lobe functions: trail making test, verbal fluency, Wisconsin Card Sorting Test (Keio version). No Shinkei. 2004;56:567–74.

    Google Scholar 

  53. Crossley M, D’Arcy C, Rawson NS. Letter and category fluency in community-dwelling Canadian seniors: a comparison of normal participants to those with dementia of the Alzheimer or vascular type. J Clin Exp Neuropsychol. 1997;19:52–62.

    Article  PubMed  CAS  Google Scholar 

  54. Sumiyoshi C, Sumiyoshi T, Matsui M, Nohara S, Yamashita I, Kurachi M, et al. Effect of orthography on the verbal fluency performance in schizophrenia: examination using Japanese patients. Schizophr Res. 2004;69:15–22.

    Article  PubMed  Google Scholar 

  55. Yokokura M, Terada T, Bunai T, Nakaizumi K, Takebayashi K, Iwata Y, et al. Depiction of microglial activation in aging and dementia: Positron emission tomography with [(11)C]DPA713 versus [(11)C](R)PK11195. J Cereb Blood Flow Metab. 2017;37:877–89.

    Article  PubMed  CAS  Google Scholar 

  56. Nakaizumi K, Ouchi Y, Terada T, Yoshikawa E, Kakimoto A, Isobe T, et al. In vivo depiction of alpha7 nicotinic receptor loss for cognitive decline in Alzheimer’s disease. J Alzheimers Dis. 2018;61:1355–65.

    Article  PubMed  CAS  Google Scholar 

  57. Horti AG. Development of [(18)F]ASEM, a specific radiotracer for quantification of the alpha7-nAChR with positron-emission tomography. Biochem Pharmacol. 2015;97:566–75.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Breese CR, Adams C, Logel J, Drebing C, Rollins Y, Barnhart M, et al. Comparison of the regional expression of nicotinic acetylcholine receptor alpha7 mRNA and [125I]-alpha-bungarotoxin binding in human postmortem brain. J Comp Neurol. 1997;387:385–98.

    Article  PubMed  CAS  Google Scholar 

  59. Ogawa M, Tsukada H, Hatano K, Ouchi Y, Saji H, Magata Y. Central in vivo nicotinic acetylcholine receptor imaging agents for positron emission tomography (PET) and single photon emission computed tomography (SPECT). Biol Pharm Bull. 2009;32:337–40.

    Article  PubMed  CAS  Google Scholar 

  60. Lammertsma AA, Hume SP. Simplified reference tissue model for PET receptor studies. Neuroimage. 1996;4:153–8.

    Article  PubMed  CAS  Google Scholar 

  61. Ashburner J, Friston KJ. Unified segmentation. Neuroimage. 2005;26:839–51.

    Article  PubMed  Google Scholar 

  62. Picard F, Bruel D, Servent D, Saba W, Fruchart-Gaillard C, Schollhorn-Peyronneau MA, et al. Alteration of the in vivo nicotinic receptor density in ADNFLE patients: a PET study. Brain. 2006;129:2047–60.

    Article  PubMed  CAS  Google Scholar 

  63. Femminella GD, Ninan S, Atkinson R, Fan Z, Brooks DJ, Edison P. Does microglial activation influence hippocampal volume and neuronal function in Alzheimer’s disease and Parkinson’s disease dementia? J Alzheimers Dis. 2016;51:1275–89.

    Article  PubMed  CAS  Google Scholar 

  64. Mathotaarachchi S, Wang S, Shin M, Pascoal TA, Benedet AL, Kang MS, et al. VoxelStats: a MATLAB package for multi-modal voxel-wise brain image analysis. Front Neuroinform. 2016;10:20.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Terada T, Therriault J, Kang MS, Savard M, Pascoal TA, Lussier F, et al. Mitochondrial complex I abnormalities underlie neurodegeneration and cognitive decline in Alzheimer’s disease. Eur J Neurol. 2022;29:1324–34.

    Article  PubMed  Google Scholar 

  66. Dinesh AA, Islam J, Khan J, Turkheimer F, Vernon AC. Effects of antipsychotic drugs: cross talk between the nervous and innate immune system. CNS Drugs. 2020;34:1229–51.

    Article  PubMed  Google Scholar 

  67. Woodward ND, Purdon SE, Meltzer HY, Zald DH. A meta-analysis of neuropsychological change to clozapine, olanzapine, quetiapine, and risperidone in schizophrenia. Int J Neuropsychopharmacol. 2005;8:457–72.

    Article  PubMed  CAS  Google Scholar 

  68. Clissold M, Crowe SF. Comparing the effect of the subcategories of atypical antipsychotic medications on cognition in schizophrenia using a meta-analytic approach. J Clin Exp Neuropsychol. 2019;41:26–42.

    Article  PubMed  Google Scholar 

  69. Domino EF, Krause RR, Bowers J. Various enzymes involved with putative neurotransmitters. Regional distribution in the brain of deceased mentally normal, chronic schizophrenics or organic brain syndrome patients. Arch Gen Psychiatry. 1973;29:195–201.

    Article  PubMed  CAS  Google Scholar 

  70. Bird ED, Spokes EG, Barnes J, MacKay AV, Iversen LL, Shepherd M. Increased brain dopamine and reduced glutamic acid decarboxylase and choline acetyl transferase activity in schizophrenia and related psychoses. Lancet. 1977;2:1157–8.

    Article  PubMed  CAS  Google Scholar 

  71. McGeer PL, McGeer EG. Possible changes in striatal and limbic cholinergic systems in schizophrenia. Arch Gen Psychiatry. 1977;34:1319–23.

    Article  PubMed  CAS  Google Scholar 

  72. Stefansson H, Rujescu D, Cichon S, Pietilainen OP, Ingason A, Steinberg S, et al. Large recurrent microdeletions associated with schizophrenia. Nature. 2008;455:232–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. International Schizophrenia C. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature. 2008;455:237–41.

    Article  Google Scholar 

  74. Leonard S, Gault J, Hopkins J, Logel J, Vianzon R, Short M, et al. Association of promoter variants in the alpha7 nicotinic acetylcholine receptor subunit gene with an inhibitory deficit found in schizophrenia. Arch Gen Psychiatry. 2002;59:1085–96.

    Article  PubMed  CAS  Google Scholar 

  75. Nakazawa K, Sapkota K. The origin of NMDA receptor hypofunction in schizophrenia. Pharmacol Ther. 2020;205:107426.

    Article  PubMed  CAS  Google Scholar 

  76. Konradsson-Geuken A, Gash CR, Alexander K, Pomerleau F, Huettl P, Gerhardt GA, et al. Second-by-second analysis of alpha 7 nicotine receptor regulation of glutamate release in the prefrontal cortex of awake rats. Synapse. 2009;63:1069–82.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Bortz DM, Mikkelsen JD, Bruno JP. Localized infusions of the partial alpha 7 nicotinic receptor agonist SSR180711 evoke rapid and transient increases in prefrontal glutamate release. Neuroscience. 2013;255:55–67.

    Article  PubMed  CAS  Google Scholar 

  78. Liu ZW, Yang S, Zhang YX, Liu CH. Presynaptic alpha-7 nicotinic acetylcholine receptors modulate excitatory synaptic transmission in hippocampal neurons. Sheng Li Xue Bao. 2003;55:731–5.

    PubMed  CAS  Google Scholar 

  79. Reno LA, Zago W, Markus RP. Release of [(3)H]-L-glutamate by stimulation of nicotinic acetylcholine receptors in rat cerebellar slices. Neuroscience. 2004;124:647–53.

    Article  PubMed  CAS  Google Scholar 

  80. Shen JX, Tu B, Yakel JL. Inhibition of α7‐containing nicotinic ACh receptors by muscarinic M1 ACh receptors in rat hippocampal CA1 interneurones in slices. J Physiol. 2009;587:1033–42.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Dean B, Pavey G, Scarr E. Higher levels of alpha7 nicotinic receptors, but not choline acetyltransferase, in the dorsolateral prefrontal cortex from a sub-group of patients with schizophrenia. Schizophr Res. 2020;222:283–90.

    Article  PubMed  Google Scholar 

  82. Crook JM, Tomaskovic-Crook E, Copolov DL, Dean B. Low muscarinic receptor binding in prefrontal cortex from subjects with schizophrenia: a study of Brodmann’s areas 8, 9, 10, and 46 and the effects of neuroleptic drug treatment. Am J Psychiatry. 2001;158:918–25.

    Article  PubMed  CAS  Google Scholar 

  83. Crook JM, Tomaskovic-Crook E, Copolov DL, Dean B. Decreased muscarinic receptor binding in subjects with schizophrenia: a study of the human hippocampal formation. Biol Psychiatry. 2000;48:381–8.

    Article  PubMed  CAS  Google Scholar 

  84. Dean B, Crook JM, Opeskin K, Hill C, Keks N, Copolov DL. The density of muscarinic M1 receptors is decreased in the caudate-putamen of subjects with schizophrenia. Mol Psychiatry. 1996;1:54–58.

    PubMed  CAS  Google Scholar 

  85. Crook JM, Dean B, Pavey G, Copolov D. The binding of [3H]AF-DX 384 is reduced in the caudate-putamen of subjects with schizophrenia. Life Sci. 1999;64:1761–71.

    Article  PubMed  CAS  Google Scholar 

  86. Zavitsanou K, Katsifis A, Mattner F, Huang XF. Investigation of m1/m4 muscarinic receptors in the anterior cingulate cortex in schizophrenia, bipolar disorder, and major depression disorder. Neuropsychopharmacology. 2004;29:619–25.

    Article  PubMed  Google Scholar 

  87. Terry AV Jr, Gearhart DA, Mahadik SP, Warsi S, Davis LW, Waller JL. Chronic exposure to typical or atypical antipsychotics in rodents: temporal effects on central alpha7 nicotinic acetylcholine receptors. Neuroscience. 2005;136:519–29.

    Article  PubMed  CAS  Google Scholar 

  88. Terry AV Jr, Gearhart DA. Time dependent decreases in central alpha7 nicotinic acetylcholine receptors associated with haloperidol and risperidone treatment in rats. Eur J Pharmacol. 2007;571:29–32.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Crow TJ. Temporal lobe asymmetries as the key to the etiology of schizophrenia. Schizophr Bull. 1990;16:433–43.

    Article  PubMed  CAS  Google Scholar 

  90. Oertel V, Knochel C, Rotarska-Jagiela A, Schonmeyer R, Lindner M, van de Ven V, et al. Reduced laterality as a trait marker of schizophrenia–evidence from structural and functional neuroimaging. J Neurosci. 2010;30:2289–99.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Abdolmaleky HM, Nohesara S, Thiagalingam S. Epigenome defines aberrant brain laterality in major mental illnesses. Brain Sci. 2024;14:261.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Coughlin JM, Wang Y, Ambinder EB, Ward RE, Minn I, Vranesic M, et al. In vivo markers of inflammatory response in recent-onset schizophrenia: a combined study using [(11)C]DPA-713 PET and analysis of CSF and plasma. Transl Psychiatry. 2016;6:e777.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Wimberley C, Lavisse S, Hillmer A, Hinz R, Turkheimer F, Zanotti-Fregonara P. Kinetic modeling and parameter estimation of TSPO PET imaging in the human brain. Eur J Nucl Med Mol Imaging. 2021;49:246–56.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Notter T, Coughlin JM, Sawa A, Meyer U. Reconceptualization of translocator protein as a biomarker of neuroinflammation in psychiatry. Mol Psychiatry. 2018;23:36–47.

    Article  PubMed  CAS  Google Scholar 

  95. Nutma E, Ceyzériat K, Amor S, Tsartsalis S, Millet P, Owen DR, et al. Cellular sources of TSPO expression in healthy and diseased brain. Eur J Nucl Med Mol Imaging. 2021;49:146–63.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Curtis VA, Bullmore ET, Brammer MJ, Wright IC, Williams SC, Morris RG, et al. Attenuated frontal activation during a verbal fluency task in patients with schizophrenia. Am J Psychiatry. 1998;155:1056–63.

    Article  PubMed  CAS  Google Scholar 

  97. Gourovitch ML, Kirkby BS, Goldberg TE, Weinberger DR, Gold JM, Esposito G, et al. A comparison of rCBF patterns during letter and semantic fluency. Neuropsychology. 2000;14:353–60.

    Article  PubMed  CAS  Google Scholar 

  98. Lundin NB, Brown JW, Johns BT, Jones MN, Purcell JR, Hetrick WP, et al. Neural evidence of switch processes during semantic and phonetic foraging in human memory. Proc Natl Acad Sci USA. 2023;120:e2312462120.

    Article  PubMed  PubMed Central  Google Scholar 

  99. Marien P, Ackermann H, Adamaszek M, Barwood CH, Beaton A, Desmond J, et al. Consensus paper: language and the cerebellum: an ongoing enigma. Cerebellum. 2014;13:386–410.

    PubMed  PubMed Central  Google Scholar 

  100. Ogawa M, Nishiyama S, Tsukada H, Hatano K, Fuchigami T, Yamaguchi H, et al. Synthesis and evaluation of new imaging agent for central nicotinic acetylcholine receptor α7 subtype. Nucl Med Biol. 2010;37:347–55.

    Article  PubMed  CAS  Google Scholar 

  101. Selvaraj S, Arnone D, Cappai A, Howes O. Alterations in the serotonin system in schizophrenia: a systematic review and meta-analysis of postmortem and molecular imaging studies. Neurosci Biobehav Rev. 2014;45:233–45.

    Article  PubMed  CAS  Google Scholar 

  102. Owen DR, Yeo AJ, Gunn RN, Song K, Wadsworth G, Lewis A, et al. An 18-kDa translocator protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28. J Cereb Blood Flow Metab. 2012;32:1–5.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We thank all the study participants and staff of Hamamatsu Medical Imaging Center, Hamamatsu Medical Photonics Foundation, Hamamatsu Photonics K.K., and the Department of Psychiatry, Hamamatsu University School of Medicine for their assistance with data collection. We sincerely appreciate the valuable contributions of Hideki Kaiya, Yasuhiko Kato, Daiki Miwa, Shun Takeichi, Marie Mogi, and Shunsuke Suzuki to this study. This research was supported by JSPS KAKENHI Grant Numbers JP19K08070 and JP16K10186, and the Smoking Research Foundation. We thank Sarina Iwabuchi, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

Author information

Author notes

  1. These authors contributed equally: Tomoyasu Wakuda, Masamichi Yokokura.

Authors and Affiliations

  1. Department of Psychiatry, Hamamatsu University School of Medicine, Hamamatsu, Japan

    Tomoyasu Wakuda, Masamichi Yokokura, Chihiro Murayama, Takafumi Goto, Taishi Tamayama, Yosuke Kameno & Hidenori Yamasue

  2. Molecular Imaging Laboratory, Division of Preeminent Bioimaging Research, Institute of Photonics Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan

    Yasuhiro Magata & Chie Suzuki

  3. United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, Suita, Japan

    Toshiki Iwabuchi, Nori Takei & Hidenori Yamasue

  4. Research Center for Child Mental Development, Hamamatsu University School of Medicine, Hamamatsu, Japan

    Toshiki Iwabuchi & Nori Takei

  5. Central Research Laboratory, Hamamatsu Photonics K. K., Hamamatsu, Japan

    Takashi Isobe & Yuya Onishi

  6. Biofunctional Imaging Laboratory, Division of Preeminent Bioimaging Research, Institute of Photonics Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan

    Tatsuhiro Terada & Yasuomi Ouchi

  7. Hamamatsu Medical Imaging Center, Hamamatsu Medical Photonics Foundation, Hamamatsu, Japan

    Yasuomi Ouchi

Authors
  1. Tomoyasu Wakuda
    View author publications

    Search author on:PubMed Google Scholar

  2. Masamichi Yokokura
    View author publications

    Search author on:PubMed Google Scholar

  3. Yasuhiro Magata
    View author publications

    Search author on:PubMed Google Scholar

  4. Chie Suzuki
    View author publications

    Search author on:PubMed Google Scholar

  5. Chihiro Murayama
    View author publications

    Search author on:PubMed Google Scholar

  6. Takafumi Goto
    View author publications

    Search author on:PubMed Google Scholar

  7. Taishi Tamayama
    View author publications

    Search author on:PubMed Google Scholar

  8. Yosuke Kameno
    View author publications

    Search author on:PubMed Google Scholar

  9. Toshiki Iwabuchi
    View author publications

    Search author on:PubMed Google Scholar

  10. Takashi Isobe
    View author publications

    Search author on:PubMed Google Scholar

  11. Yuya Onishi
    View author publications

    Search author on:PubMed Google Scholar

  12. Tatsuhiro Terada
    View author publications

    Search author on:PubMed Google Scholar

  13. Nori Takei
    View author publications

    Search author on:PubMed Google Scholar

  14. Yasuomi Ouchi
    View author publications

    Search author on:PubMed Google Scholar

  15. Hidenori Yamasue
    View author publications

    Search author on:PubMed Google Scholar

Contributions

TW, MY, and YaO designed the study. TW, MY, TTa, YK, and HY recruited participants, conducted clinical interviews, and performed clinical assessments. TW conducted diagnostic interviews and performed neurocognitive assessments. MY, YM, CS, CM, TG, TaI, YuO, and YaO performed PET and MRI imaging. TW, MY, ToI, TTe, NT, YaO, and HY conducted statistical analyses. ToI and TTe analyzed PET and MRI images. TW, YM, NT, YaO, and HY contributed to data interpretation. TW, MY, ToI, and HY drafted the manuscript. All authors contributed to and approved the final version of the manuscript.

Corresponding author

Correspondence to Hidenori Yamasue.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wakuda, T., Yokokura, M., Magata, Y. et al. α7 nicotinic acetylcholine receptor, activated glia, and cognitive impairment in schizophrenia: a dual-tracer PET study. Mol Psychiatry 31, 739–748 (2026). https://doi.org/10.1038/s41380-025-03162-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41380-025-03162-2

Search

Advanced search

Quick links