Identifying Neural Correlates of Nicotine Withdrawal in Mice: The Neuregulin Signaling Pathway

Abstract

Addiction to nicotine and the ability to quit smoking are influenced by genetic factors. Therefore, it is important to understand how genes and drugs of abuse mechanistically impact each other. One well‐characterized protein responsible for regulating both response to drugs and gene expression is the transcription factor cAMP response element‐binding protein (CREB). Work from our lab indicates that hippocampal specific alterations in CREB signaling and synaptic plasticity underlie certain nicotine withdrawal (WD) phenotypes in a region‐specific manner. We found that CREB deletion in the ventral hippocampus (VH), a region known for regulation of mood and emotion, results in amelioration of nicotine WD‐induced anxiety‐like behaviors. High throughput chromatin immunoprecipitation sequencing (ChIP‐seq) studies determined that WD from nicotine differentially modulates CREB binding to the gene Neuregulin‐3 (Nrg3), a neural‐enriched epidermal growth‐like factor that plays a role in the formation and maintenance of mature synapses. Interestingly, genome wide association studies (GWAS) in humans have found that single nucleotide polymorphisms within the NRG3 gene and that of its cognate receptor, ERBB4, are associated with smoking cessation outcomes. In mice, qPCR and Western blotting experiments established that NRG3 and ErbB4 are upregulated at the 24h WD time point in the VH, with expression returning to baseline by 1‐week post WD. Conditional VH deletion of Erbb4 blocked WD‐induced anxiety‐like behaviors. This phenotype was accompanied by decreased levels of inhibitory GABAergic release and altered network clustering of excitatory pyramidal cells within the ventral CA1, an area enriched in Nrg3 and Erbb4 mRNAs and sensitive to nicotine WD. This data suggests that disruption of VH NRG3‐ErbB4 signaling attenuates WD‐induced anxiety‐like phenotypes through altering GABAergic modulation of CA1 pyramidal cell activity. Further examination of downstream signals of ErbB4 activation may lead to the identification of potential targets for treating nicotine withdrawal symptomology.Support or Funding InformationThis study was supported by•NIH/NIDA grant DA032681, the PhRMA Foundation, and the USC ASPIRE Grant program (JRT).•SPARC Grant, University of South Carolina (MLF)