title: Increased stability of microtubules in cultured olfactory neuroepithelial cells from individuals with schizophrenia.
abstract: Microtubules (MTs) are essential components of the cytoskeleton that play critical roles in neurodevelopment and adaptive central nervous system functioning. MTs are essential to growth cone advance and ultrastructural events integral to synaptic plasticity; these functions figure significantly into current pathophysiologic conceptualizations of schizophrenia. To date, no study has directly investigated MT dynamics in humans with schizophrenia. We therefore compared the stability of MTs in olfactory neuroepithelial (OE) cells between schizophrenia cases and matched nonpsychiatric comparison subjects. For this purpose, we applied nocodazole (Nz) to cultured OE cells obtained from tissue biopsies from seven living schizophrenia patients and seven matched comparison subjects; all schizophrenia cases were on antipsychotic medications. Nz allows MT depolymerization to be followed but prevents repolymerization, so that in living cells treated for varying time intervals, the MTs that are stable for a given treatment interval remain. Our readout of MT stability was the time at which fewer than 10 MTs per cell could be distinguished by anti-β-tubulin immunofluorescence. The percentage of cells with ≥10 intact MTs at specified intervals following Nz treatment was estimated by systematic uniform random sampling with Visiopharm software. These analyses showed that the mean percentages of OE cells with intact MTs were significantly greater for schizophrenia cases than for the matched comparison subjects at 10, 15, and 30min following Nz treatment indicating increased MT stability in OE cells from schizophrenia patients (p=0.0007 at 10min; p=0.0008 at 15min; p=0.036 at 30min). In conclusion, we have demonstrated increased MT stability in nearly all cultures of OE cells from individuals with schizophrenia, who received several antipsychotic treatments, versus comparison subjects matched for age and sex. While we cannot rule out a possible confounding effect of antipsychotic medications, these findings may reflect analogous neurobiological events in at least a subset of immature neurons or other cell types during gestation, or newly generated cells destined for the olfactory bulb or hippocampus, suggesting a mechanism that underlies findings of postmortem and neuroimaging investigations of schizophrenia. Future studies aimed at replicating these findings, including samples of medication-naïve subjects with schizophrenia, and reconciling the results with other studies, will be necessary. Although the observed abnormalities may suggest one of a number of putative pathophysiologic anomalies in schizophrenia, this work may ultimately have implications for an improved understanding of pathogenic processes related to this disorder.
authors: Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY 10032, USA; Department of Epidemiology, Columbia University Mailman School of Public Health, 722 W 168th Street, New York, NY 10032, USA. Electronic address: asb11@columbia.edu.
authors: Alan S
authors: AS
authors: Brown
authors: Cellular and Molecular Neuropathology Program, Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania, 125 South 31st Street, Philadelphia, PA 19104, USA.
authors: Karin
authors: K
authors: Borgmann-Winter
authors: Cellular and Molecular Neuropathology Program, Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania, 125 South 31st Street, Philadelphia, PA 19104, USA.
authors: Chang-Gyu
authors: CG
authors: Hahn
authors: Department of Neurobiology and Behavior, State University of New York at Stony Brook, Stony Brook, NY 11794, USA.
authors: Lorna
authors: L
authors: Role
authors: Department of Pharmacology, State University of New York at Stony Brook, Basic Science Tower 8-140, Stony Brook, NY 11794, USA.
authors: David
authors: D
authors: Talmage
authors: Departments of Psychiatry, Neurology, and Radiology, University of Pennsylvania Medical Center, 10th Floor, Gates Building, Philadelphia, PA 19104, USA.
authors: Raquel
authors: R
authors: Gur
authors: Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY 10032, USA.
authors: Jacky
authors: J
authors: Chow
authors: Department of Epidemiology, Columbia University Mailman School of Public Health, 722 W 168th Street, New York, NY 10032, USA.
authors: Patric
authors: P
authors: Prado
authors: Cellular and Molecular Neuropathology Program, Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania, 125 South 31st Street, Philadelphia, PA 19104, USA.
authors: Thelma
authors: T
authors: McCloskey
authors: Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY 10032, USA.
authors: Yuanyuan
authors: Y
authors: Bao
authors: Department of Biological Sciences, Columbia University, 1212 Amsterdam Avenue, New York, NY 10027, USA.
authors: J Chloe
authors: JC
authors: Bulinski
authors: Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University, 1051 Riverside Drive, New York, NY 10032, USA; Macedonian Academy of Sciences and Arts, Skopje 1000, Macedonia.
authors: Andrew J
authors: AJ
authors: Dwork
keywords: Microtubules; Olfactory; Schizophrenia