Phencyclidine-induced dysregulation of primary cilia in the rodent brain

Significant roles of the primary cilia in the central nervous system have been reported in neural generation and cognitive functions. However, little is known about the possible pathological changes in brain primary cilia in neuropsychiatric disorders. To obtain an insight into the relationship between cilial dysregulation and schizophrenia, we presently investigated the effects of psychotomimetics, phencyclidine, MK-801 (dizocilpine), and methamphetamine, on morphological and molecular indices in the rodent brain. Using an immunohistochemical technique, we found that a subcutaneous injection of phencyclidine, an NMDA type glutamate receptor (NMDAR) antagonist, caused a reduction in the long axis length of a primary cilium in the CA1 region of the hippocampus without affecting that in the dentate gyrus and medial prefrontal cortex of rats and mice. The region-selective modulation of primary cilia was mimicked by another NMDAR antagonist, MK-801, but not by the indirect dopamine agonist methamphetamine. Furthermore, systemic administration of phencyclidine, but not methamphetamine, down-regulated mRNA expression of primary cilium morphology-related genes, including kif3a, 5-HTR6, RPGRIP1L, and TMEM67, and of genes composing the cilial Wnt/β-catenin signaling pathway, β-catenin, syn2 and Bcl-2, in the hippocampus, but not in the cerebral cortex of rats. These findings suggest that NMDAR hypofunction-induced dysregulation of CA1 primary cilia could be involved in the pathophysiology of dopamine transmission-independent symptoms of schizophrenia.