Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.26.269209v1?rss=1 Authors: Niere, F., Cacheaux, L. P., Klorig, D. C., Taylor, W. C., Smith, T., Godwin, D. W., Raab-Graham, K. F. Abstract: Tuberous sclerosis complex (TS) is a dominant, multisystem disorder with devastating neurological symptoms. Approximately 85% of TS patients suffer from epilepsy over their lifespan and roughly 25-50% of those patients develop Autism Spectrum Disorder (1, 2). Current seizure therapies are effective in some, but not all, and often have significant risk factors associated with their use (1, 3). Thus, there is a critical need for new medication development or drug repositioning. Herein, we leveraged proteomic signatures of epilepsy and ASD, often comorbid in TS, to utilize an in silco approach to identify new drug therapies for TS-related seizures. We have discovered that activation of L-type voltage dependent calcium channels (L-VDCC) by Bay-K8644 (BayK) in a preclinical mouse model of TS curtails seizure frequency. Remarkably, at the molecular level, excess expression of ionotropic, AMPA-subtype glutamate (GluA) receptors is rescued by the administration of BayK. As added proof of BayK working through L-VDCC to regulate GluA levels, we found that increasing expression of alpha2delta2 (2{delta}2), an auxiliary calcium channel subunit that boosts L-VDCC surface expression, similarly lowers the surface expression of dendritic GluA in TS. These BayK-induced molecular and functional alterations may underlie the longer lifespan of TS mice treated with BayK. Copy rights belong to original authors. Visit the link for more info