Most intriguing from our analysis is the significant enrichments of DMRs within loci involved in a range of GO terms including genes localized to neuronal cellular components with prominent roles in the regulation of development, synaptic plasticity, and neurotransmission (Table 2; Figure 5). Importantly, many of these genes have functional relevance to behavioral and physiological traits we previously demonstrated to be impaired in this rat model (Szutorisz et al, 2014). This included striatal molecular disturbances in adult F1 progeny with parental THC exposure that affected several glutamate receptor subunits at both the mRNA and protein levels, and associated electrophysiological impairments related to dysregulation of synaptic plasticity (Szutorisz et al, 2014). Drawing potential links between DMRs and gene networks suspected to underlie phenotypes in this model, we showed that DMR-associated genes shared many common PPIhub proteins with gene sets specifically known 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.
