A mutant allele of glycoprotein M6-B (Gpm6b) facilitates behavioral flexibility but increases delay discounting

Genes Brain Behav. 2022 Apr;21(4):e12800. doi: 10.1111/gbb.12800. Epub 2022 Mar 3.


The neuronal membrane glycoprotein M6B (Gpm6b) gene encodes a membrane glycoprotein that belongs to the proteolipid protein family, and is enriched in neurons, oligodendrocytes, and subset of astrocytes in the central nervous system. GPM6B is thought to play a role in neuronal differentiation, myelination, and inactivation of the serotonin transporter via internalization. Recent human genome-wide association studies (GWAS) have implicated membrane glycoproteins (both GPM6B and GPM6A) in the regulation of traits relevant to psychiatric disorders, including neuroticism, depressed affect, and delay discounting. Mouse studies have implicated Gpm6b in sensorimotor gating and regulation of serotonergic signaling. We used CRISPR to create a mutant Glycoprotein M6B (Gpm6b) allele on a C57BL/6J mouse background. Because Gpm6b is located on the X chromosome, we focused on male Gpm6b mutant mice and their wild-type littermates (WT) in two behavioral tests that measured aspects of impulsive or flexible decision-making. We found that Gpm6b deletion caused deficits in a delay discounting task. In contrast, reward sensitivity was enhanced thereby facilitating behavioral flexibility and improving performance in the probabilistic reversal learning task. Taken together these data further delineate the role of Gpm6b in decision making behaviors that are relevant to multiple psychiatric disorders.

Keywords: GPM6B; behavioral flexibility; delay discounting; depression; genetics; impulsivity; mouse model; psychiatric disorders; serotonin; suicide.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Delay Discounting*
  • Genome-Wide Association Study
  • Humans
  • Impulsive Behavior
  • Male
  • Membrane Glycoproteins* / genetics
  • Mice
  • Mice, Inbred C57BL
  • Nerve Tissue Proteins* / genetics
  • Reward


  • GPM6B protein, human
  • Gpm6b protein, mouse
  • Membrane Glycoproteins
  • Nerve Tissue Proteins