A selective role for ARMS/Kidins220 scaffold protein in spatial memory and trophic support of entorhinal and frontal cortical neurons

Progressive cortical pathology is common to several neurodegenerative and psychiatric disorders. The entorhinal cortex (EC) and frontal cortex (FC) are particularly vulnerable, and neurotrophins have been implicated because they appear to be protective. A downstream signal transducer of neurotrophins, the ankyrin repeat-rich membrane spanning scaffold protein/Kidins 220 (ARMS) is expressed in the cortex, where it could play an important role in trophic support. To test this hypothesis, we evaluated mice with a heterozygous deletion of ARMS (ARMS+/− mice). Remarkably, the EC and FC were the regions that demonstrated the greatest defects. Many EC and FC neurons became pyknotic in ARMS+/− mice, so that large areas of the EC and FC were affected by 12 months of age. Areas with pyknosis in the EC and FC of ARMS+/− mice were also characterized by a loss of immunoreactivity to a neuronal antigen, NeuN, which has been reported after insult or injury to cortical neurons. Electron microscopy showed that there were defects in mitochondria, myelination, and multilamellar bodies in the EC and FC of ARMS+/− mice. Although primarily restricted to the EC and FC, pathology appeared to be sufficient to cause functional impairments, because ARMS+/− mice performed worse than wild-type on the Morris water maze. Comparisons of males and females showed that female mice were the affected sex in all comparisons. Taken together, the results suggest that the expression of a prominent neurotrophin receptor substrate normally protects the EC and FC, and that ARMS may be particularly important in females.

Research highlights
► Reducing a substrate for neurotrophins, ARMS, leads to pathology in the 12-month-old mouse cortex.
► Pathology is primarily located in the entorhinal cortex and frontal cortex.
► Pathology features pyknosis, weak NeuN expression, damaged mitochondria and myelin.
► Mice with reduced ARMS levels show deficits in spatial learning and memory.
► Pathology and behavioral deficits are specific to females.