PhD Candidate UCSD Bellevue, Washington, United States
Abstract: Our lab has shown that the post translational modification of Collapsin Response Mediator Protein 2 (CRMP2), a cytoskeleton modulator that serves as a master regulator of neural network formation and function, is dysregulated in both schizophrenia (SZ) and lithium-responsive bipolar disorder (LiR-BPD). CRMP2 activity, pivotal to dendrite morphometrics and function, is dependent on its phosphorylation state, which, under normal circumstances, is in dynamic equilibrium. Increasingly, researchers are identifying large-scale brain network dysfunction in psychiatric disorders like these with neurocognitive symptoms which may contribute to the complex symptomatology. SZ is a debilitating mental disorder characterized by disruptions in thought processes, perception, emotional responsiveness, and social interactions. BPD is a chronic mental disorder characterized by oscillations between depressive and manic episodes. Both SZ and BPD patients have an elevated risk for premature mortality.
By differentiating LiR-BPD and SZ patient induced pluripotent stem cells (iPSC) into cortical neurons, our lab has identified imbalances between phosphorylated (inactive) and non-phosphorylated (active) CRMP2 and found that this imbalance promotes neuronal hypersynchrony. This leads to neural network hypofunction by promoting overly-synchronous circuits and impairing the transfer of patterned information. We have shown elevated active CRMP2 and reduced total CRMP2 in SZ relative to healthy patients. In contrast, in LiR-BPD, we have seen elevated inactive CRMP2, an imbalance that was normalized by lithium treatment. Elevated active CRMP2 was associated with hypoactive neural networks while elevated inactive CRMP2 was associated with hyperactive neural networks in calcium imaging and microelectrode array. Interestingly, both conditions exhibited hypersynchrony.
As the final pathway of many neurocognitive disorders is neural network dysfunction that results from the linking of hypofunctioning neurons, CRMP2 may be a feasible drug target for improving network function. Elucidating how CRMP2 regulates the molecular machinery underlying network dysfunction may unlock powerful alternatives to treat network hypofunction across neurocognitive disorders.
Funding Source: This research was funded by the Pharmacological Sciences T32 Training Grant.
