Positive allosteric interaction between agonist 5‐HT2A receptor autoantibodies and LY 379268, a selective metabotropic glutamate 2/3 receptor agonist

Abstract

Metabotropic glutamate 2 (mGlu2) receptor signaling interacts with 5‐HT2A receptor signaling in causing psychosis induced by the hallucinogen DOI,1‐(2, 5‐dimethoxy‐4‐iodophenyl)‐2‐aminopropane. Complex interactions between mGlu2R‐mediated, Gi/o coupled signaling and 5‐HT2AR‐mediated, Gq/11 coupled signaling is thought to contribute (in part) to dysregulated serotonergic and glutamatergic signaling underlying positive and negative symptoms in schizophrenia. Circulating 5HT2AR autoantibodies were previously reported to function as long‐acting agonists in diabetic angiopathy subsets having major depression and Parkinson's disease; they were also evident in a subset of diabetes having schizophrenia. The aim of the present study was to test for an interaction between mGlu2/3 R agonism (LY379268) and diabetic autoantibodies in patients susceptible to psychosis. We tested plasma IgG (obtained by protein‐A chromatography) alone and together with LY379268 (a selective mGlu2/3 R agonist) for acute neurite shortening in mouseN2A neuroblastoma cells, defined as the percent change in neurite length after ten minutes. Three of three schizophrenia plasma IgGs tested caused dose‐dependent neurite retraction and exhibited positive allosteric interaction(s) with (5–10 μM) LY379268. Highly potent diabetic schizophrenia IgG autoantibodies (400 nM) caused 90% neurite retraction; co‐administration of LY379268 (10 μM) lowered the IC50 for IgG‐induced neurite retraction from ~36 to ~ 18 nM. The hallucinogen DOI (20 μM) caused 40% peak neurite retraction; co‐administration of LY379268 (10 μM) lowered the IC50 for DOI‐ induced neurite retraction from 5 to 2.5 μM. Schizophrenia plasma IgG‐induced acute neurite retraction was completely blocked by co‐administration of (500 nM) M100907, a selective 5‐HT2AR antagonist. LY379268 (10 μM) alone had no effect on neurite retraction or N2A survival (after 24 hours). Taken together, these data suggest a subset of diabetic (n=2) and non‐diabetic (n=1) schizophrenia plasma IgG autoantibodies target the 5‐HT2A receptor on N2A cells causing potent neurite shortening. Positive allosteric interaction by LY379268 (10 μM) on 5‐HT2AR‐activating autoantibody‐mediated neurite shortening was observed for both paranoid schizophrenia and Parkinson's disease autoantibodies, the latter from a patient experiencing hallucinations. Our finding that mGlu2/3 agonism sensitized cells to neurite inhibition mediated by 5HT2AR‐activating autoantibodies is consistent with reports that mGlu2/3 agonists increased the affinity of 5‐HT2AR ligands at cortical 5HT2A/mGlu2 receptor heterocomplexes. More study is needed to determine whether divalent IgG autoantibody structure may facilitate heteroreceptor complex formation and contribute to unusually long‐lasting, potent effects.Support or Funding InformationVeterans Biomedical Research Institute, East Orange, New JerseyThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.