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

Abstract

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.

Kidins220/ARMS is dynamically expressed during Xenopus laevis development

“…4 M-O), supports this hypothesis. Furthermore it is in agreement with the observation of an abnormal myelination of the CNS including all cortical layers, striatum, hippocampus and the underlying white matter in Kidins220/ARMS +/− mice (Duffy et al, 2011). Immunofluorescent staining of cryosections of stage 42 embryos double-labeled for Kidins220 and acetylated tubulin reveal a Kidins220-positive signal in dorsal and ventral regions of the spinal cord (Fig.…”

Suppression of Adult Neurogenesis Increases the Acute Effects of Kainic Acid

“…Procedures for immunofluorescence are described in detail elsewhere (Duffy et al, 2011). In brief, free-floating sections were washed in 0.1 M phosphate buffer (PB), blocked in 5% goat serum for 1 hr and incubated in primary antibody (Iba-1, 1:500, #019-19741, Wako USA Inc., Richmond, VA) overnight at room temperature.…”

Sex differences in the neurobiology of epilepsy: A preclinical perspective

“…The neurons that had weak expression of NeuN also showed pkynosis using cresyl violet as a stain, which historically is considered to be a sign of cellular damage. These findings were made in rats or mice and were exacerbated by age and loss of neurotrophic support (Duffy et al, 2011). Prior studies have documented that diverse insults and injury, ranging from age to soman toxicity, can lead to phosphorylation of NeuN and as a result, reduction of immunodetection using an antibody raised against NeuN (for detailed discussion, see (Duffy et al, 2011).…”

“…These findings were made in rats or mice and were exacerbated by age and loss of neurotrophic support (Duffy et al, 2011). Prior studies have documented that diverse insults and injury, ranging from age to soman toxicity, can lead to phosphorylation of NeuN and as a result, reduction of immunodetection using an antibody raised against NeuN (for detailed discussion, see (Duffy et al, 2011). Presumably there is a loss of NeuN immunoreactivity because the antibody to NeuN does not recognize the conformational change in the protein that has been phosphorylated.…”