Epigenetic Regulations of GABAergic Neurotransmission: Relevance for Neurological Disorders and Epigenetic Therapy

TLDR

Reelin, a glycoprotein from GABAergic neurons, guides neuronal migration during development and modulates synaptic plasticity postnatally, and its 50 % down‑regulation in post‑mortem psychotic brains has made the reeler heterozygous mouse a valuable psychosis model. The study aims to develop an animal model that combines genetic heterozygosity with epigenetic alterations to elucidate how Reelin down‑regulation contributes to psychosis. The reeler heterozygous mouse exhibits psychosis‑like brain changes—reduced GAD67, diminished dendritic arbors and spine density, impaired LTP—and, like post‑mortem psychotic brains, shows hypermethylation of RELN and GAD67 promoters with up‑regulated DNMT1, a phenotype that can be recapitulated by methionine treatment.

Abstract

Reelin, a large glycoprotein secreted by telencephalic GABAergic neurons, plays an important role in neuronal guidance embryonically and in synaptic plasticity postnatally. The reeler heterozygous mouse (+/rl) appears superficially normal but has been of interest as an animal model for psychosis since the discovery that reelin is 50% down-regulated in postmortem psychotic brain. Brain abnormalities in +/rl are similar to psychotic brain and include a reduction in glutamic acid de carboxylase 67 (GAD67), dendritic arbors and spine density in cortex and hippocampus, and abnormalities in synaptic function including long-term potentiation (LTP). In spite of these abnormalities, behavioral abnormalities in +/rl are subtle and controversial. Recent findings indicate that the reelin (RELN) and GAD67 promoters are hypermethylated in GABAergic neurons of psychotic postmortem brain and that DNA methyltransferase 1 (DNMT1) is up-regulated. Hypermethlyation of RELN and GAD67 promoters can be induced by treating mice with methionine, and these mice display brain and behavioral abnormalities similar to +/rl. Thus, an animal model that combines genetic heterozygocity with epigenesis holds promise for understanding the role of Reelin down-regulation in psychosis.