Convergent Evidence from Mouse and Human Studies Suggests the Involvement of Zinc Finger Protein 326 Gene in Antidepressant Treatment Response

Abstract

ObjectivesThe forced swim test (FST) is a commonly used model to predict antidepressant efficacy. Uncovering the genetic basis of the model may unravel the mechanism of antidepressant treatment.MethodsFVB/NJ (FVB) and C57BL/6J (B6) were first identified as the response and non-response strains to fluoxetine (a serotonin-specific reuptake inhibitor antidepressant) treatment in the mouse FST. Simple-interval (SIM) and composite-interval (CIM) mappings were applied to map the quantitative trait loci (QTLs) of the anti-immobility effect of fluoxetine in FST (FSTFLX) in 865 male B6×FVB-F2 mice. The brain mRNA expressions of the gene with the maximum QTL-linkage signal for FSTFLX after the FST were compared between B6 and FVB mice and also compared between fluoxetine and saline treatment. The association of the variants in the human homologue of the mouse FSTFLX-QTL gene with major depressive disorder (MDD) and antidepressant response were investigated in 1080 human subjects (MDD/control = 582/498).ResultsOne linkage signal for FSTFLX-QTL was detected at an intronic SNP (rs6215396) of the mouse Zfp326 gene (maximal CIM-LOD = 9.36). The Zfp326 mRNA expression in the FVB thalamus was significantly down-regulated by fluoxetine in the FST, and the higher FVB-to-B6 Zfp326 mRNA expressions in the frontal cortex, striatum and hypothalamus diminished after fluoxetine treatment. Two coding-synonymous SNPs (rs2816881 and rs10922744) in the human homologue of Zfp326, ZNF326, were significantly associated with the 8-week antidepressant treatment response in the MDD patients (Bonferroni-corrected p = 0.004–0.028).ConclusionsThe findings suggest the involvement of the Zfp326 and ZNF326 genes in antidepressant treatment response.

Long Noncoding RNA-Associated Transcriptomic Changes in Resiliency or Susceptibility to Depression and Response to Antidepressant Treatment

“…LH vs TC group comparison resulted in 3 target genes followed by the identification of one potential target gene from the NLH vs TC group. Furthermore, identification of Zbtb20 and Zfp385b genes from the zinc finger binding protein family indicated the authenticity of this cis target prediction analysis because of their previously discussed role in stress and depression pathology ( Liou et al, 2012 ; Davies et al, 2014 ). Predicting the trans-regulatory role of differentially regulated lncRNA, 16 protein coding genes were found as targets of 20 dysregulated lncRNAs from NLH vs TC group comparison.…”

Zinc as a Gatekeeper of Immune Function

“…Zinc-dependent epigenetic changes in the MT-2 gene in utero caused significantly higher MT-2 expression in the liver later in life as observed in mice [ 249 ]. Similarly, not only the function, but also the expression of zinc-finger proteins, including ZNF804A and ZNF326, was affected by the zinc status via epigenetic mechanisms [ 250 , 251 ]. As found during investigations in autistic patients, zinc deficiency during pregnancy caused epigenetic abnormalities in genes encoding MTF1, ZnT5, COMMD1 (COMM domain-containing protein 1), ERK1, TrkB (tyrosine-related kinase B), and ProSAP/Shank (proline-rich synapse-associated protein/SH3 and multiple ankyrin repeat domains) [ 252 , 253 , 254 , 255 ].…”

Zinc finger proteins in psychiatric disorders and response to psychotropic medications

“…Antidepressants Liou et al (2012) carried out an integrated study using mice and a human sample of MDD patients to explore the genetics of response to fluoxetine. Response to antidepressants in mice was evaluated using the forced swimming test.…”

“…QTLs where then identified based on different response and two significant SNPs, located in the zinc finger protein 326 (ZNF326) gene (rs2816881 and rs10922744), were genotyped in a sample of 262 Han Chinese MDD patients. Response to 8-week treatment with fluoxetine or citalopram was defined as a decrease >50% at the 21-item Hamilton Depression Rating Scale (Liou et al, 2012). The A allele of rs2816881 and the G allele of rs10922744 were associated with positive response, suggesting that also this zinc finger gene could be involved in response to antidepressants.…”