Reduced cue-induced reinstatement of cocaine-seeking behavior in Plcb1 +/− mice

Abstract

Cocaine addiction causes serious health problems, and no effective treatment is available yet. We previously identified a genetic risk variant for cocaine addiction in the PLCB1 gene and found this gene upregulated in postmortem brains of cocaine abusers and in human dopaminergic neuron-like cells after an acute cocaine exposure. Here, we functionally tested the contribution of the PLCB1 gene to cocaine addictive properties using Plcb1+/− mice. First, we performed a general phenotypic characterization and found that Plcb1+/− mice showed normal behavior, although they had increased anxiety and impaired short-term memory. Subsequently, mice were trained for operant conditioning, self-administered cocaine for 10 days, and were tested for cocaine motivation. After extinction, we found a reduction in the cue-induced reinstatement of cocaine-seeking behavior in Plcb1+/− mice. After reinstatement, we identified transcriptomic alterations in the medial prefrontal cortex of Plcb1+/− mice, mostly related to pathways relevant to addiction like the dopaminergic synapse and long-term potentiation. To conclude, we found that heterozygous deletion of the Plcb1 gene decreases cue-induced reinstatement of cocaine-seeking, pointing at PLCB1 as a possible therapeutic target for preventing relapse and treating cocaine addiction.

Branch point evolution controls species-specific alternative splicing and regulates long term potentiation

“…For example, substrates only found for the Δ16,17 isoform are enriched in the GO term “myelin sheath” (GO:0043209) (Figure 5G), suggesting a potential isoform-specific functionality. Interestingly, a substrate specifically phosphorylated by the primate-specific isoforms is the catalytically-relevant Y-box of phospholipase C β1 (Plcb1) (Supplementary data 2), an enzyme involved in inositol triphosphate (IP 3 ) signaling that has been connected to learning and memory (Cabana-Domínguez et al, 2021). These results suggest that apart from differences in catalytic activity, CaMKIIβ isoforms differ in their substrate preferences, with primate-specific isoforms preferentially targeting specific proteins related to neuronal functions.…”

Branch point strength controls species-specificCAMK2Balternative splicing and regulates LTP

“…For example, substrates only found for the Δ16,17 isoform are enriched in the GO term "myelin sheath" (GO:0043209) (Fig 5G ), suggesting a potential isoform-specific functionality. Interestingly, a substrate specifically phosphorylated by the primate-specific isoforms is the catalytically relevant Y-box of phospholipase C-β1 (Plcb1) (Supplemental Data 2), an enzyme involved in inositol triphosphate (IP 3 ) signaling that has been connected to learning and memory (Cabana-Domínguez et al, 2021). Although individual targets have not yet been validated, these data suggest that CaMKIIβ isoforms differ in their substrate preferences, with primate-specific isoforms targeting several proteins related to key neuron functions.…”