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.