AUTHOR=Spencer Jarrah R., Darbyshire Keturah M., Boucher Aurelie A., Kashem Mohammed A., Long Leonora E., McGregor Iain S., Karl Tim , Arnold Jonathon C.

TITLE=Novel molecular changes induced by Nrg1 hypomorphism and Nrg1-cannabinoid interaction in adolescence: a hippocampal proteomic study in mice

JOURNAL=Frontiers in Cellular Neuroscience

VOLUME=7

YEAR=2013

URL=https://www.frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2013.00015

DOI=10.3389/fncel.2013.00015

ISSN=1662-5102

ABSTRACT=<p>Neuregulin 1 (<italic>NRG1</italic>) is linked to an increased risk of developing schizophrenia and cannabis dependence. Mice that are hypomorphic for <italic>Nrg1</italic> (<italic>Nrg1</italic> HET mice) display schizophrenia-relevant behavioral phenotypes and aberrant expression of serotonin and glutamate receptors. <italic>Nrg1</italic> HET mice also display idiosyncratic responses to the main psychoactive constituent of cannabis, Δ<sup>9</sup>-tetrahydrocannabinol (THC). To gain traction on the molecular pathways disrupted by <italic>Nrg1</italic> hypomorphism and <italic>Nrg1</italic>-cannabinoid interactions we conducted a proteomic study. Adolescent wildtype (WT) and <italic>Nrg1</italic> HET mice were exposed to repeated injections of vehicle or THC and their hippocampi were submitted to 2D gel proteomics. Comparison of WT and <italic>Nrg1</italic> HET mice identified proteins linked to molecular changes in schizophrenia that have not been previously associated with <italic>Nrg1</italic>. These proteins are involved in vesicular release of neurotransmitters such as SNARE proteins; enzymes impacting serotonergic neurotransmission, and proteins affecting growth factor expression. <italic>Nrg1</italic> HET mice treated with THC expressed a distinct protein expression signature compared to WT mice. Replicating prior findings, THC caused proteomic changes in WT mice suggestive of greater oxidative stress and neurodegeneration. We have previously observed that THC selectively increased hippocampal NMDA receptor binding of adolescent <italic>Nrg1</italic> HET mice. Here we observed outcomes consistent with heightened NMDA-mediated glutamatergic neurotransmission. This included differential expression of proteins involved in NMDA receptor trafficking to the synaptic membrane; lipid raft stabilization of synaptic NMDA receptors; and homeostatic responses to dampen excitotoxicity. These findings uncover novel proteins altered in response to <italic>Nrg1</italic> hypomorphism and <italic>Nrg1</italic>-cannabinoid interactions that improves our molecular understanding of <italic>Nrg1</italic> signaling and <italic>Nrg1</italic>-mediated genetic vulnerability to the neurobehavioral effects of cannabinoids.</p>