The new paper from Alan Mackay-Sim’s group on molecular profiling with human olfactory neurosphere-derived cell lines (ONS cells) obtained from the olfactory epithelium (OE) of healthy controls and patients with either schizophrenia or Parkinson’s disease is superb. The research group in Australia, including Mackay-Sim and John McGrath, is one of the pioneers that have been studying the olfactory epithelium in schizophrenia research. In this paper, they have, in particular, identified dysregulation of the molecular expression in neurodevelopmental pathways in schizophrenia.

Although postmortem brains have been valuable for exploring disease-specific changes, there are two major limitations. First, even if some changes exist during early neurodevelopment in patients with schizophrenia, such changes may have disappeared, been compensated for, or modified in aged brains. Second, there are many confounding factors that disturb straightforward interpretations of the data from postmortem brains, including effects of long-term use of medications, drug abuse, smoking, malnutrition, and stress. In contrast, use of patient-derived live immature neurons has advantages in that those cells may more directly reflect disease-associated molecular changes in neurons in the developing brain.

Olfactory deficits have been studied extensively in patients with schizophrenia (please see a review by Cascella et al., 2007; Turetsky et al., 2009; Rupp, 2010). Abnormalities in odor identification using the University of Pennsylvania Smell Identification Test (UPSIT) are observed in a majority of patients with schizophrenia, whereas less than 15 percent of the general population shows such deficits (Moberg et al., 1999). In particular, many groups, including ours, report that negative symptoms of schizophrenia specifically correlate with impairment on the UPSIT (Ishizuka et al., 2010; Malaspina et al., 2002; Malaspina et al., 2003; Moberg et al., 2006; Strauss et al., 2009; Good et al., 2006).

Olfactory epithelium (OE) is located at the peripheral end of the olfactory system and is one of the unique nervous tissues where mature neurons generate and differentiate throughout life. In OE, dividing stem and basal precursor cell populations continuously give rise to immature neurons that further differentiate into mature olfactory receptor neurons, send axons to re-innervate the glomeruli of the olfactory bulb, and form new synapses with target neurons there. The Australia group has first established a slice culture of OE and found that the tissue from patients with schizophrenia shows altered adhesion capacity, increased cell proliferation, and reduced apoptosis upon dopamine challenge (Perry et al., 2002; Feron et al., 1998; Feron et al., 1999; McCurdy et al., 2006). In parallel, a group led by Chang-Gyu Hahn and Steven E. Arnold at the University of Pennsylvania has identified abnormal densities and ratios of OE neurons at different stages of development in autopsied brains from patients with schizophrenia by immunohistochemistry, evidence that signs of the deficits associated with neuronal differentiation in schizophrenia may be manifested in OE tissue (Arnold et al., 2001). This U. Penn group has also developed a slice culture from OE (Hahn et al., 2005). Furthermore, both of these groups in Australia and the U.S. have developed dissociated neuron culture from OE, which can be utilized in molecular profiling and functional studies (Murrell et al., 2005; Hahn et al., 2005; Borgmann-Winter et al., 2009). Because the purity of the starting materials is the key for success in molecular profiling, our group published a new method to obtain OE neuronal layers by laser capture microdissection for microarray study (Tajinda et al., 2010).

What will be a next step to further advance schizophrenia research using patient-derived cells? Recently, more attention has been paid to induced pluripotent stem cells (iPS cells) and iPS cell-derived neurons as a potential resource to obtain a variety of types of neurons from the central nervous system. However, at least at present, establishment of iPS cell-derived neurons is much more time consuming, laborious, and much more expensive. There is also some concern about heterogeneity in the generated neurons. From our experiences of generating iPS cells and iPS cell-derived neurons from many patients with schizophrenia and controls, we fully agree with these concerns (Kano, SOBP presentation 2009 and SfN presentation 2009). In these aspects, ONS cells or olfactory neurons are much better than iPS cell-derived neurons. The most productive way to move the field forward would be to consider the advantages and limitations of each tissue resource, such as iPS cells, olfactory cells, and autopsied brains. Finally, it is very important to consider how to link such molecular/cellular studies to clinical issues. The recent work by Bruce I. Turetsky and Paul J. Moberg to explore cAMP-associated OE deficits and clinical issues by using an olfactory threshold sensitivity test is intriguing (Turetsky and Moberg, 2009; Sawa et al., 2009). A combination of cell study at the molecular level, together with molecular brain imaging in the same set of subjects, may also be an alternative future approach.

References:

1. Cascella, N.G., Takaki, M., Lin, S., and Sawa, A. 2007. Neurodevelopmental involvement in schizophrenia: the olfactory epithelium as an alternative model for research. J Neurochem 102:587-594. Abstract

2. Turetsky, B.I., Hahn, C.G., Borgmann-Winter, K., and Moberg, P.J. 2009. Scents and nonsense: olfactory dysfunction in schizophrenia. Schizophr Bull 35:1117-1131. Abstract

3. Rupp, C.I. Olfactory function and schizophrenia: an update. Curr Opin Psychiatry 23:97-102. Abstract

4. Moberg, P.J., Agrin, R., Gur, R.E., Gur, R.C., Turetsky, B.I., and Doty, R.L. 1999. Olfactory dysfunction in schizophrenia: a qualitative and quantitative review. Neuropsychopharmacology 21:325-340. Abstract

5. Ishizuka, K., Tajinda, K., Colantuoni, C., Morita, M., Winicki, J., Le, C., Lin, S., Schretlen, D., Sawa, A., and Cascella, N.G. Negative symptoms of schizophrenia correlate with impairment on the University of Pennsylvania smell identification test. Neurosci Res 66:106-110. Abstract

6. Malaspina, D., Coleman, E., Goetz, R.R., Harkavy-Friedman, J., Corcoran, C., Amador, X., Yale, S., and Gorman, J.M. 2002. Odor identification, eye tracking and deficit syndrome schizophrenia. Biol Psychiatry 51:809-815. Abstract

7. Malaspina, D., and Coleman, E. 2003. Olfaction and social drive in schizophrenia. Arch Gen Psychiatry 60:578-584. Abstract

8. Moberg, P.J., Arnold, S.E., Doty, R.L., Gur, R.E., Balderston, C.C., Roalf, D.R., Gur, R.C., Kohler, C.G., Kanes, S.J., Siegel, S.J., et al. 2006. Olfactory functioning in schizophrenia: relationship to clinical, neuropsychological, and volumetric MRI measures. J Clin Exp Neuropsychol 28:1444-1461. Abstract

9. Strauss, G.P., Allen, D.N., Ross, S.A., Duke, L.A., and Schwartz, J. Olfactory hedonic judgment in patients with deficit syndrome schizophrenia. Schizophr Bull 36:860-868. Abstract

10. Good, K.P., Whitehorn, D., Rui, Q., Milliken, H., and Kopala, L.C. 2006. Olfactory identification deficits in first-episode psychosis may predict patients at risk for persistent negative and disorganized or cognitive symptoms. Am J Psychiatry 163:932-933. Abstract

11. Perry, C., Mackay-Sim, A., Feron, F., and McGrath, J. 2002. Olfactory neural cells: an untapped diagnostic and therapeutic resource. The 2000 Ogura Lecture. Laryngoscope 112:603-607. Abstract

12. Feron, F., Perry, C., McGrath, J.J., and Mackay-Sim, A. 1998. New techniques for biopsy and culture of human olfactory epithelial neurons. Arch Otolaryngol Head Neck Surg 124:861-866. Abstract

13. Feron, F., Perry, C., Hirning, M.H., McGrath, J., and Mackay-Sim, A. 1999. Altered adhesion, proliferation and death in neural cultures from adults with schizophrenia. Schizophr Res 40:211-218. Abstract

14. McCurdy, R.D., Feron, F., Perry, C., Chant, D.C., McLean, D., Matigian, N., Hayward, N.K., McGrath, J.J., and Mackay-Sim, A. 2006. Cell cycle alterations in biopsied olfactory neuroepithelium in schizophrenia and bipolar I disorder using cell culture and gene expression analyses. Schizophr Res 82:163-173. Abstract

15. Arnold, S.E., Han, L.Y., Moberg, P.J., Turetsky, B.I., Gur, R.E., Trojanowski, J.Q., and Hahn, C.G. 2001. Dysregulation of olfactory receptor neuron lineage in schizophrenia. Arch Gen Psychiatry 58:829-835. Abstract

16. Hahn, C.G., Han, L.Y., Rawson, N.E., Mirza, N., Borgmann-Winter, K., Lenox, R.H., and Arnold, S.E. 2005. In vivo and in vitro neurogenesis in human olfactory epithelium. J Comp Neurol 483:154-163. Abstract

17. Murrell, W., Feron, F., Wetzig, A., Cameron, N., Splatt, K., Bellette, B., Bianco, J., Perry, C., Lee, G., and Mackay-Sim, A. 2005. Multipotent stem cells from adult olfactory mucosa. Dev Dyn 233:496-515. Abstract

18. Hahn, C.G., Gomez, G., Restrepo, D., Friedman, E., Josiassen, R., Pribitkin, E.A., Lowry, L.D., Gallop, R.J., and Rawson, N.E. 2005. Aberrant intracellular calcium signaling in olfactory neurons from patients with bipolar disorder. Am J Psychiatry 162:616-618. Abstract

19. Borgmann-Winter, K.E., Rawson, N.E., Wang, H.Y., Wang, H., Macdonald, M.L., Ozdener, M.H., Yee, K.K., Gomez, G., Xu, J., Bryant, B., et al. 2009. Human olfactory epithelial cells generated in vitro express diverse neuronal characteristics. Neuroscience 158:642-653. Abstract

20. Tajinda, K., Ishizuka, K., Colantuoni, C., Morita, M., Winicki, J., Le, C., Lin, S., Schretlen, D., Sawa, A., and Cascella, N.G. Neuronal biomarkers from patients with mental illnesses: a novel method through nasal biopsy combined with laser-captured microdissection. Mol Psychiatry 15:231-232. Abstract

21. Turetsky, B.I., and Moberg, P.J. 2009. An odor-specific threshold deficit implicates abnormal intracellular cyclic AMP signaling in schizophrenia. Am J Psychiatry 166:226-233. Abstract

22. Sawa, A., and Cascella, N.G. 2009. Peripheral olfactory system for clinical and basic psychiatry: a promising entry point to the mystery of brain mechanism and biomarker identification in schizophrenia. Am J Psychiatry 166:137-139. Abstract

View all comments by Shin-ichi Kano
View all comments by Akira Sawa