Developmental pathway genes and neural plasticity underlying emotional learning and stress-related disorders

Abstract

The manipulation of neural plasticity as a means of intervening in the onset and progression of stress-related disorders retains its appeal for many researchers, despite our limited success in translating such interventions from the laboratory to the clinic. Given the challenges of identifying individual genetic variants that confer increased risk for illnesses like depression and post-traumatic stress disorder, some have turned their attention instead to focusing on so-called "master regulators" of plasticity that may provide a means of controlling these potentially impaired processes in psychiatric illnesses. The mammalian homolog of (TLX), Wnt, and the homeoprotein Otx2 have all been proposed to constitute master regulators of different forms of plasticity which have, in turn, each been implicated in learning and stress-related disorders. In the present review, we provide an overview of the changing distribution of these genes and their roles both during development and in the adult brain. We further discuss how their distinct expression profiles provide clues as to their function, and may inform their suitability as candidate drug targets in the treatment of psychiatric disorders.

Methylation in OTX2 and related genes, maltreatment, and depression in children

“…PAX6 is also critical for differentiation of dopaminergic neurons arising from neural stem cells residing in the dorsal paraventricular zone [30]. WNT1 plays a role in the establishment of midbrain-dopaminergic neurons [31] and is a major regulator of neural plasticity in the amygdala and hippocampus following acute stress and fear conditioning [2]. Given the role of WNT1 in neuroplastic processes, it has also been proposed as a "master regulator", which may serve as an important therapeutic target in the treatment of stress-related psychiatric disorders [2].…”

“…WNT1 plays a role in the establishment of midbrain-dopaminergic neurons [31] and is a major regulator of neural plasticity in the amygdala and hippocampus following acute stress and fear conditioning [2]. Given the role of WNT1 in neuroplastic processes, it has also been proposed as a "master regulator", which may serve as an important therapeutic target in the treatment of stress-related psychiatric disorders [2]. None of the negative control genes examined were significant predictors of depression in the GEE models.…”

“…Otx2 is a highly conserved molecule. The two protein isoforms Otx2 encodes are identical in both mice and humans, and functionally indistinguishable in vitro [2]. Otx2 has multiple known roles in embryonic and experience-dependent brain development.…”

“…Although the OTX2 protein is found in the VTA, medial prefrontal cortex (mPFC), and multiple additional cortical regions [10], a similar essential role for Otx2 in defining sensitive windows of development of other neural systems has not yet been established [8]. Given the role of OTX2 in defining sensitive windows of development, OTX2 has been proposed to be a potential "master-regulator" of plasticity, with likely important targets for treating stress-related psychiatric disorders [2].…”

SLC1A3 C3590T but not BDNF G196A is a predisposition factor for stress as well as depression, in an adolescent eastern Indian population

“…BDNF is the most studied gene, which is shown to be associated with many different mental disorders and is known to interact with various developmental pathways [47]. The trafficking and localization of BDNF appears to be controlled by its pro-domain.…”