Geon The CABT Hypothesis of Schizophrenia



Decades of intensive investigations have revealed that the hypofunction of NMDA receptors (NMDARs) could be the convergent point of schizophrenia (SCZ). The NMDAR Hypofunction Model stems from the findings that the NMDAR blockers, ketamine and phencyclidine, can induce a broad range of SCZ-like symptoms. This paper shows that the SCZ-inducing effects of ketamine are not caused by the blockade of NMDARs per se, but by the ultimate upregulation of brain-derived neurotrophic factor (BDNF) and synaptic GluN2B-containing NMDARs in layer 3 pyramidal neurons of dorsolateral prefrontal cortex. GluN2B-NMDARs, but not GluN2A-NMDARs, are subject to the occlusion of the CABT complex, which consists of a CRMP2 monomer and a tubulin heterodimer. The CABT occlusion of GluN2B-NMDARs can be prevented by protein kinase A (PKA). This mechanism is supported by the emergence of phosphodiesterase (PDE) as a therapeutic target for SCZ. PDE catalyzes the breakdown of cAMP. Its inhibitors may elevate cAMP level, thus enhancing PKA activity.


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