Geon The CABT Hypothesis of Schizophrenia



Decades of intensive research has revealed that schizophrenia (SCZ) could be caused by the hypofunction of NMDA receptors (NMDARs). However, the underlying mechanism of NMDAR hypofunction remains unclear. Ketamine, an open channel blocker of NMDARs, has been shown to induce a broad range of SCZ-like symptoms in animal models. This paper will show that, in humans, the progression of schizophrenia could arise from the blockade of NMDAR by the CABT complex, which consists of a CRMP2 monomer, an alpha and a beta tubulin. This hypothesis is supported by a recent finding that, in SCZ patients, the total CRMP2 is abnormally increased without sufficient phosphorylated CRMP2. This will increase the number of CABT complexes, resulting in excessive blockade of NMDARs, i.e., NMDAR hypofunction. Glycogen synthase kinase-3beta (GSK-3β) plays a critical role in CRMP2 phosphorylation. Decreased CRMP2 phosphorylation in SCZ implies abnormally reduced GSK-3β activity. Remarkably, another recent study demonstrated that in SCZ patients a GSK-3β inhibitor, called serum and glucocorticoid kinase 1 (SGK1), was elevated. Therefore, upregulation of SGK1 could be the fundamental cause of SCZ. This points to a new direction for the design of effective drugs against schizophrenia.


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