Focus on HTR2C: A possible suggestion for genetic studies of complex disorders

Abstract

HTR2C is one of the most relevant and investigated serotonin receptors. Its role in important brain structures such as the midbrain, the lateral septal complex, the hypothalamus, the olfactory bulb, the pons, the choroid plexus, the nucleus pallidus, the striatum and the amygdala, the nucleus accumbens and the anterior cingulated gyrus candidate it as a promising target for genetic association studies. The biological relevance of these brain structures is reviewed by way of the focus on HTR2C activity, with a special attention paid to psychiatric disorders. Evidence from the genetic association studies that dealt with HTR2C is reviewed and discussed alongside the findings derived from the neuronatmic investigations. The reasons for the discrepancies between these two sets of reports are discussed. As a result, HTR2C is shown to play a pivotal role in many different psychiatric behaviors or psychiatric related disrupted molecular balances, nevertheless, genetic association studies brought inconsistent results so far. The most replicated association involve the feeding behavior and antipsychotic induced side effects, both weight gain and motor related: Cys23Ser (rs6318) and -759C/T (rs3813929) report the most consistent results. The lack of association found in other independent studies dampens the clinical impact of these reports. Here, we report a possible explanation for discrepant findings that is poorly or not at all usually considered, that is that HTR2C may exert different or even opposite activities in the brain depending on the structure analyzed and that mRNA editing activity may compensate possible genetically controlled functional effects. The incomplete coverage of the HTR2C variants is proposed as the best cost-benefit ratio bias to fix. The evidence of brain area specific HTR2C mRNA editing opens a debate about how the brain can differently modulate stress events, and process antidepressant treatments, in different brain areas. The mRNA editing activity on HTR2C may play a major role for the negative association results.

Genomic–anatomic evidence for distinct functional domains in hippocampal field CA1

“…The former is selectively involved in cognitive aspects of the learning and memory associated with navigation, exploration, and locomotion, whereas in contrast the latter is part of the temporal lobe associated most directly with motivational and emotional aspects of the classic Klüver-Bucy Syndrome. In fact, at least two CA1v marker genes, Grp and Htr2c, have been implicated in psychiatric disorders (38,39).…”

CREB mediates brain serotonin regulation of bone mass through its expression in ventromedial hypothalamic neurons

“…The fact that Htr2c belongs to a subfamily of serotonergic receptors using calcium as a second messenger (Fink and Gothert 2007;Drago and Serretti 2009), along with the importance of CREB in neurobiology (Dash et al 1990;Bourtchuladze et al 1994;Yin et al 1994Yin et al , 1995Bartsch et al 1995;Petrij et al 1995;Nestler et al 2002;Peters et al 2003;Josselyn and Nguyen 2005), led us to explore the possibility that serotonin could use a CaM signaling pathway in VMH neurons to phosphorylate and activate CREB. This would ultimately result in a decrease of the activity of the sympathetic nervous system, and an increase in bone mass accrual.…”

“…Htr2c is a G protein-coupled receptor using Ca 2+ as a second messenger in a signal transduction pathway that requires the intervention of the calcium-binding protein CaM (Fink and Gothert 2007;Drago and Serretti 2009). To mediate its diverse functions, CaM can activate numerous enzymes, including several CaM kinases called CaMKI, CaMKII, or CaMKIV (Haribabu et al 1995;Schulman et al 1995;Tokumitsu and Soderling 1996).…”

Serotonin receptor 2C gene polymorphism associated with post-stroke depression in Chinese patients

“…Serotonin receptor 2C (HTR2C) is one of the most relevant and investigated serotonin receptors in both human and animal studies (Drago and Serretti, 2009). It has been shown to play a pivotal role in many different psychiatric behaviors, including major depression, bipolar disorder, suicide, and schizophrenia (Lerer et al, 2001;Iwamoto et al, 2009).…”