to regulate synaptic plasticity and glutamatergic synaptic transmission (Figure 5). The most significant of these PPIhub enrichments involved Dlg4, encoding Psd-95, a membrane associated guanylate kinase scaffolding protein located in neural postsynaptic densities, involved in the regulation of dopamine–glutamate interactions. It associates with the NMDA subtype of GluR's and is required for synaptic plasticity associated with NMDA receptor signaling. Interestingly, it has recently been shown that epigenetic dysregulation of Dlg4 contributed to abnormal glutamatergic transmission and rewarding behavior induced by morphine conditioning (Wang et al, 2014), consistent with our observations of increased heroin self-administration in adult F1s in the model investigated here (Szutorisz et al, 2014). Although we did not identify a DMR within Dlg4 meeting our stringent criteria, we found that Dlg4 mRNA levels were statistically higher in F1 offspring of THC-exposed parents. In addition, four other DMR-associated genes in this interaction network were also differentially expressed, highlighting the importance of this pathway in our model.
