คาสิโนไทย The CABT Hypothesis of Schizophrenia

 

Abstract

Decades of intensive investigations have revealed that the hypofunction of NMDA receptors (NMDARs) could be the convergence point for progression and symptoms of schizophrenia. On the other hand, compelling evidence suggests that schizophrenia could originate from elevated GluN2B/GluN2A ratio in the postsynaptic membrane. The CABT Hypothesis may provide the missing link between GluN2B/GluN2A elevation and NMDAR hypofunction. This hypothesis posits that NMDARs could be blocked by the CABT complex, which consists of a CRMP2 monomer, an alpha and a beta tubulin. Both CRMP2 and tubulin have been shown to interact with the GluN2B subunit of NMDARs, but not GluN2A. Therefore, the CABT complex can block only GluN2B-containing NMDARs, without affecting GluN2A-NMDARs. This explains why GluN2B/GluN2A elevation may cause NMDAR hypofunction.

Glycogen synthase kinase 3 (GSK-3) is the convergent target of most antipsychotics. It has a plethora of substrates. Which one is critical for the regulation of NMDAR functions is unclear. In the dendritic spine, CABT may bind either filamenous actin (F-actin) or GluN2B. Binding of CABT to F-actin would not block NMDAR currents. However, if F-actin is depolymerized, CABT would be forced to bind and block GluN2B-NMDARs. The activity-regulated cytoskeletal-associated (Arc) protein is known to prevent F-actin depolymerization. Strikingly, a recent study demonstrates that GSK-3 promotes Arc degradation. The CABT Hypothesis suggests that Arc could be the long-sought target of GSK-3.

 

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Notes

(2018-11-20). The mechanisms underlying the findings of Managò et al., 2016:

  1. Genetic disruption of Arc → Arc deficiency → promoting CABT-GluN2B binding → NMDAR hypofunction → hyperactive and hypoactive dopamine signaling in the striatum and prefrontal cortex, respectively (Figure 1).
  2. The Arc-dependent abnormalities in 1 can be rescued by application of a D1R agonist to the prefrontal cortex or a D2R antagonist in the striatum because in either case the PKA activity increases, which may prevent the CABT-GluN2B binding.

(2018-11-12). More evidence for the involvement of Arc in schizophrenia: