Serotonin (5-hydroxytryptamine) receptor 2a (5-HT2AR) signaling is important for modulation of
corticostriatal pathways and prefrontal activity during cognition. Furthermore, newer antipsychotic
drugs target 5-HT2AR. A single-nucleotide polymorphism in the 5-HT2AR gene (HTR2A
rs6314, C>T; OMIM 182135) has been weakly associated with differential 5-HT2AR signaling and with
physiologic as well as behavioral effects.
To use a hierarchical approach to determine the functional effects of this single-nucleotide
polymorphism on 5-HT2AR messenger RNA and protein expression, on prefrontal phenotypes linked with
genetic risk for schizophrenia, and on treatment with olanzapine.
In silico predictions, in vitro, and case-control investigations.
Academic and clinical facilities.
The postmortem study included 112 brains from healthy individuals; the in vivo investigation
included a total sample of 371 healthy individuals and patients with schizophrenia.
Patients received olanzapine monotherapy for 8 weeks.
Main Outcomes and Measures
In silico predictions, messenger RNA, and protein expression in postmortem human prefrontal
cortex and HeLa cells, functional magnetic resonance imaging prefrontal activity and behavior during
working memory and attention in healthy individuals, and response to an 8-week trial of olanzapine
treatment in patients with schizophrenia.
Bioinformatic analysis predicted that rs6314 alters patterns of splicing, with possible effects
on HTR2A expression. Moreover, the T allele was associated with reduced prefrontal
messenger RNA expression in postmortem prefrontal cortex, with reduced protein expression in vitro,
inefficient prefrontal blood oxygen level–dependent functional magnetic resonance imaging
response during working memory and attentional control processing, and impaired working memory and
attention behavior, as well as with attenuated improvement in negative symptoms after olanzapine
Conclusions and Relevance
Our results suggest that HTR2A rs6314 affects 5-HT2AR expression and
functionally contributes to genetic modulation of known endophenotypes of schizophrenia-like
higher-level cognitive behaviors and related prefrontal activity, as well as response to treatment