Defining the regulatory role of CalDAG-GEFI in the striatal pathophysiology underlying Parkinson’s disease and levodopa-induced dyskinesia

. Recent work by the Graybiel and Surmeier laboratories has solidified the connection between CDGI, synaptic function and PD. The key observations from the Graybiel and Surmeier laboratories in this regard are: • CDGI deletion alters the dendritic excitability of iSPNs and dSPNs. Deletion of CDGI also may disrupt the induction of long-term potentiation at glutamatergic synapses. • In PD models, CDGI is down-regulated following the administration of levodopa, suggesting that it is a potential mediator of the cellular and network adaptations causing dyskinesia (Crittenden et al., 2009). CDGI regulation of extracellular regulated kinases (ERKs) appears to be a key step in this process. • Deletion of CDGI blunts the development of striatal adaptations associated with LID in PD models, as well as the dyskinetic behavior itself. In particular, deletion of CDGI prevents the levodopa-mediated re-establishment of spines on iSPNs, thus preventing the re-establishment of potentially aberrant corticostriatal synapses on iSPNs accompanying the emergence of dyskinesia. Deletion also slows the development of dyskinetic behavior with levodopa administration in PD models. Taken together, these lines of evidence place CDGI as an important regulator of striatal connectivity and cellular plasticity in PD and LID. A better understanding of its role in controlling striatal synaptic integration and plasticity could lead to novel and potent symptomatic therapies for PD patients, which have not fundamentally changed in more than 50 years.