The initial identification of CREM based on our animal studies was supported by an independent bioinformatic evaluation of overlapping genes which revealed that the most significant network shared between impulsivity and heroin abuse related to CREM. Intriguingly, the results of this approach were validated by the presence of ADGRL3, previously known as Latrophilin-3 (LPHN3), which has recently been strongly implicated in ADHD31, 36. ADGRL3 is thought to transynaptically regulate excitatory synapses37 and the SHRs’ reduced AcbC Adgrl3 expression is consistent with the finding that decreased Lphn3 activity elicits ADHD-like behavior38. Dysregulated actin cytoskeleton, a process tightly coupled to dendritic spine morphology, was also identified in our network analysis. Since the role of CREM in striatal cytoarchitecture was not previously recognized in studies of addiction, our finding that Crem directly regulates dendritic spine morphology in medium spiny neurons opens new avenues of research.
