Signal Transduction and Genes-to-Behaviors Pathways in Psychiatric Diseases

Abstract

Although psychiatric diseases are among the most common and destructive of all human illnesses, the molecular and cellular mechanisms underlying their complex origins remain to be elucidated. Dysfunction of critical intracellular signaling pathways is very likely to be involved. This conclusion is based on a number of observations, including the short- and long-term cellular effects of psychiatric drugs; the critical role signaling pathways play in neurotransmitter, neuropeptide, and neurohormone communication; and the fact that signaling pathways are principle regulators of the diverse array of behavioral symptoms experienced by patients. The genomics era has brought to psychiatry an abundance of genetic linkage and candidate gene findings. The difficult task--now under way--is to discern the functional relevance of these results. Recent evidence suggests the involvement of the ubiquitous protein phosphatase 2B (calcineurin), a critical regulator of many signal transduction pathways, as a schizophrenia susceptibility gene. It is likely that genetic findings in severe psychiatric disorders will continue to implicate direct and indirect modulation of critical intracellular signaling pathways.

Mechanisms Contributing to the Phase-Dependent Regulation of Neurogenesis by the Novel Antidepressant, Agomelatine, in the Adult Rat Hippocampus

“…Furthermore, inhibition of GSK3b by phosphorylation following lithiuminduced AKT activation has been shown to exert antiapoptotic effects (Jope and Bijur, 2002). These results are consistent with the neurotrophic-neuroprotective effects of mood stabilizers and antidepressants thought, at least partially, to be mediated by inhibition of GSK3b (Manji et al, 2003;Silva et al, 2008). Furthermore, indirect (upstream) regulation of GSK3 constitutes a new target for the control of affective disorders and highlights the role of neuroplasticity in their induction and treatment (Mathew et al, 2008;Jope and Roh, 2006;O'Brien and Klein, 2007;McClung and Nestler, 2008).…”

“…These growth factors generally enhance adult neurogenesis and may exert behavioral antidepressant-like effects (Jin et al, 2002;Anderson et al, 2002;Khawaja et al, 2004;Malberg and Blendy, 2005;Schechter et al, 2005;Schmidt and Duman, 2007). Related to the modulation of trophic factors action, antidepressants and mood stabilizers regulate the activity of signal-transduction pathways, such as the extracellular signal-regulated kinase (ERK), protein kinase B (AKT), and glycogen synthase kinase 3b (GSK3b) cascades, which are strongly implicated in synaptic plasticity, response to stress, and induction of mood disorders (Manji et al, 2003;Duman et al, 2007).…”

Genetic analysis of the calcineurin pathway identifies members of the EGR gene family, specifically EGR3 , as potential susceptibility candidates in schizophrenia

“…Calcineurin and interacting proteins are uniquely positioned to regulate dopaminergic, glutamatergic, and other neuronal signaling pathways, alterations of which are observed in schizophrenia (17,18). Egr2 and Egr3 are regulated by calcineurin through activation of nuclear factor of activated T cells (NFAT)-mediated transcription (19).…”

Discovering Endophenotypes for Major Depression

“…It is now clear that genetic abnormalities in signaling components are often fully compatible with life, and in many instances, despite the often-ubiquitous expression of the signaling protein, these abnormalities are associated with circumscribed clinical manifestations (Manji et al, 2003a). These overt, yet relatively circumscribed, clinical manifestations are believed to ultimately arise from vastly different transcriptomes (all of the transcripts present at a particular time) in different tissues because of tissue-specific expression, haploinsufficiency, genetic imprinting, alternate splicing, varying stoichiometries of the relevant signaling partners in different tissues, and differences in the ability of diverse cell types to compensate for the abnormality (either autocrine or paracrine).…”