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Published in final edited form as: J Cell Biochem. 2014 Dec;115(12):2065–2072. doi: 10.1002/jcb.24883

The Developmental Basis of Epigenetic Regulation of HTR2A and Psychiatric Outcomes

Alison G Paquette 1, Carmen J Marsit 1,2,*
PMCID: PMC4199868  NIHMSID: NIHMS613031  PMID: 25043477

Abstract

The serotonin receptor 5-HT2A (encoded by HTR2A) is an important regulator of fetal brain development and adult cognitive function. Environmental signals that induce epigenetic changes of serotonin response genes, including HTR2A, have been implicated in adverse mental health outcomes. The objective of this perspective article is to address the medical implications of HTR2A epigenetic regulation, which has been associated with both infant neurobehavioral outcomes and adult mental health. Ongoing research has identified a region of the HTR2A promoter that has been associated with a number of medical outcomes in adults and infants, including bipolar disorder, schizophrenia, chronic fatigue syndrome, borderline personality disorder, suicidality, and neurobehavioral outcomes. Epigenetic regulation of HTR2A has been studied in several different types of tissues, including the placenta. The placenta is an important source of serotonin during fetal neurodevelopment, and placental epigenetic variation of HTR2A has been associated with infant neurobehavioral outcomes, which may represent the basis of adult mental health disorders. Further analysis is needed to identify intrinsic and extrinsic factors modulate HTR2A methylation, and the mechanism by which this epigenetic variation influences fetal growth and leads to altered brain development, manifesting in psychiatric disorders.

Keywords: Developmental Origins of Adult Disease, HTR2A, Serotonin, Psychiatric Outcomes, Neurobehavior, Epigenetics, Placenta

The developmental origins of adult disease model (DoHAD) highlights the importance of the intrauterine developmental period in defining lifelong health including cognitive and mental health outcomes. Serotonin response genes, including the post synaptic serotonin receptor HTR2A, can be epigenetically regulated through DNA methylation, and have been shown to influence infant brain development. Thus, it has been posited that HTR2A epigenetic regulation within key tissues during fetal development has the potential to influence life-long mental health. This prospective article will address the medical implications of HTR2A epigenetic regulation, which has been associated with infant neurobehavioral outcomes and adult mental health. The goal of this prospective article is to (1) provide an overview of mechanistic data regarding the importance of HTR2A and other serotonin response genes and infant growth and brain development, (2) highlight current research regarding HTR2A and medical outcomes, focusing on epigenetic regulation of HTR2A on human psychiatric and neurobehavioral outcomes, and (3) discuss the implications of this research and important questions generated.

I. The Significance of Placental Serotonin During Neurodevelopment

The serotonin response pathway is one of the most well studied pathways in psychology. In adults, serotonin is largely produced by intestinal enterochromaffin cells, and modulates human behavioral and neuropsychological processes (1). There are many components of this serotonin response pathway, ranging from the enzymes that synthesize serotonin from its precursor tryptophan, to the genes that metabolize serotonin within the presynapse, the serotonin transporters, and pre and post synaptic serotonin receptors. These genes have the potential to be transcriptionally regulated, altering serotonin response (2), which has important consequences for physiological and behavioral processes. We performed a literature search of the 21 most important regulatory genes of the serotonin response pathway as highlighted in (2), and found a total of 3229 articles published within from 10 years (2004–2014). This search only included human studies and excluded review articles. As shown in Figure 1, the majority of the studies focused on the serotonin transporter SLC6A4 (N=1474). Although there are 12 pre and post synaptic receptors highlighted in this search, the serotonin receptor HTR2A was much more extensively studied than any other receptor, with a total of 246 publications. Mechanistic data suggests that HTR2A expression in important developmental tissues such as the placenta may play an important role in infant neurodevelopment. Thus, we concentrate this review on the elucidating the relationship between HTR2A and mental health outcomes.

Figure 1.

Figure 1

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Pubmed publications of human studies of genes involved in the regulation of the Serotonin response pathway (2004–2014, excluding reviews)

The developing serotonin response pathway plays a distinct role in fetal brain development. Serotonin influences the identity of callosal projection neurons and shapes fetal brain circuits (2, 3). Serotonin signaling is also intimately involved in the formation of the fetal HPA axis, the hormonal signaling pathway comprised of the hypothalamus, pituitary, and adrenal glands, which is responsible for responding to stress. Animal models have revealed the consequences of dysregulation of serotonin response pathways. The absence of serotonin during the development of the central nervous system caused severe brain abnormalities in mice (4, 5), and reductions in perinatal serotonin concentration were associated with reduced anxiety-like behavior in adult rats (6). Thus, changes to serotonin levels during pregnancy have the potential to influence the formation of brain circuits, leading to neurological and cognitive deficits that persist into adulthood, consistent with the developmental origins of adult disease model.

During the period of fetal development, the placenta is an important regulatory organ that links the mother and fetus and regulates the fetal environment. Factors that may influence placental gene expression and subsequently placental physiology, such as epigenetic regulation, may modulate downstream outcomes such as infant growth and long term health. The placental methylome is dynamic throughout gestation, and demonstrates DNA methylation patterning of partially methylated domains similar to the neuronal system (7). This epigenome is modulated by genetic and environmental factors (8), and has been associated with a number of human pregnancy outcomes, ranging from infant birth weight and physiological outcomes, as reviewed in (8), to infant neurobehavior, as reviewed in (9). Variation within the placental epigenome may influence placental physiology and the environment of the developing infant. This may subsequently alter neurodevelopmental trajectories and have lifelong impacts on cognitive and mental health outcomes.

The placenta possesses many components of the serotonergic pathway, and there is a degree of serotonin signaling that occurs during pregnancy, with consequences for placental physiology and infant neurodevelopment. Infants develop serotonergic response pathways before they produce their own serotonin (10). During the prenatal period, the fetal brain is exposed to serotonin from the maternal environment (11). This serotonin can cross the placental barrier, and is also actively synthesized from its precursor tryptophan within the placenta (10). In addition to producing serotonin, the placenta also expresses a number of components of the serotonin response pathway, including the primary serotonin receptor 5-HT2A. In the adult brain, 5-HT2A acts as a post synaptic inhibitory receptor, but within the placenta it appears to play a mitogenic role by activating the JAK2/STAT pathway (12). This activation of the placental 5-HT2A receptor has been predicted influence placental implantation. The placental environment plays a crucial role in neurodevelopment, with placental abnormalities linked to a number of developmental disorders (13). Decreased levels of serotonin derived from placental tissue have been hypothesized to result in a hypo-serotonergic environment in the fetal forebrain, leading to mis-wiring of regions and an overgrowth of serotonergic fibers, manifesting in the autism phenotype, which is characterized by alterations in the pre frontal cortex and increased response to serotonin (14). This elegant hypothesis has not been tested, and it is possible that the placental 5-HT2A receptor may also play a role in this signaling. Overall, it is clear that serotoninergic tone within the placenta has important implications for infant neurodevelopment.

II. Associations between HTR2A and Medical Outcomes

The serotonin receptor HTR2A plays an important role in mood regulation in adults, and serotonin signaling is also crucial during development. HTR2A genetic polymorphisms are associated with a number of psychiatric disorders, as reviewed in (15). We analyzed the 264 articles published in the last 10 years that focused on human studies of the gene encoding serotonin receptor 5-HT2A (excluding review articles), and identified 183 studies that identified associations between this gene and medical outcomes, as shown in Figure 2. The majority of these studies involved schizophrenia and depression, with a particular focus on pharmacologic response to antipsychotics and antidepressants. There were only 20 studies that found associations with neurodevelopmental disorders, and most of these studies focused on common neurodevelopmental conditions including attention deficit disorder (ADHD) and autism. The developmental origins of adult disease theory suggests that a variety of psychological disorders may be traced back to events that occurred in utero. For example, schizophrenia has specifically been associated with in utero conditions ranging from birth month, to exposure to maternal stress, to maternal dietary insufficiency, as reviewed in (16). These disorders are not well understood, and although not classified as neurodevelopmental disorders, may also be rooted to in utero distress, with detectable biological differences manifesting during infancy. There is a need for better understanding of how disorders associated with dysregulation of HTR2A alter brain function throughout life, as well as the development of better biomarkers of psychiatric diseases.

Figure 2.

Figure 2

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Pubmed publications of human studies of HTR2A (2004–2014, excluding reviews) (A) stratified by DSMIV criteria, (B) with medical outcome of interest. ADHD= Attention Deficit Hyperactivity Disorder; ALZ= Alzheimers; APD=Antisocial Personality Disorder; ASD=Autism Spectrum Disorder; BD= Bipolar Disorder; BPD=Borderline Personality Disorder; CFS= Chronic Fatigue Syndrome; OCD=Obsessive Compulsive Disorder; SAD= Seasonal Affective Disorder; SCZ= Schizophrenia; TMD= Temporomandibular Disorder

III. Epigenetic regulation of HTR2A

Epigenetic regulation during the in utero period has been suggested to be the mechanism by which fetal programming occurs. Epigenetic variation including DNA methylation, histone acetylation, and microRNA expression have important regulatory roles within the placenta, and have been associated with a number of developmental outcomes, as reviewed in (9). The most well characterized epigenetic modifications in epidemiological studies is DNA methylation, which can alter the transcription or transcriptional potential of genes, and is usually associated with transcriptional repression. During fetal development, DNA methylation is erased then reset in a tissue specific manner, which is crucial for cell and tissue differentiation (17). This reprogramming occurs during crucial windows of development during which the maternal environmental can influence the placental and fetal epigenome, and have lifelong impacts on fetal health. More research is needed to understand the mechanism by which these epigenetic changes occur as well as identify how epigenetic variation of specific genes influences fetal development, specifically neurodevelopment.

Epigenetic variation of the serotonin receptor HTR2A has been associated with psychological and medical outcomes in a limited number of studies. Of the 246 studies from 2004–2014 involving HTR2A (Figure 2), only 5 of these studies analyzed the relationship between HTR2A epigenetic variation and medical outcomes (Table 1). Epigenetic variation to the HTR2A promoter region in adults was associated with schizophrenia(18, 19), psychosis related suicide(20), borderline personality disorder(21), and chronic fatigue syndrome(22). DNA methylation has been shown to be altered within specific CpG islands by environmental exposures in a tissue and age specific manner(23), highlighting the need for sampling of DNA methylation in functional tissues. These studies examined DNA methylation in blood (20–22) or saliva (18, 19), which imposes a significant limitation to their interpretation as these are not the tissues generally considered to be producing or responding to this receptor and are not the most functionally relevant. However, similar patterns of DNA methylation were identified between saliva and the pre frontal cortex in a limited study analyzing associations between schizophrenia and suicide (18),which suggests that saliva may be used as an appropriate surrogate tissue.

Table 1.

Human studies involving Epigenetic Regulation of HTR2A and Medical Outcomes

Outcome of
Interest		 Region of HTR2A
studied		 Significant Finding Ref.
SCZ and BD Entire HTR2A promoter region (qMSP) hypermethylation at−1438 (rs6311), hypomethylation at rs6313 of SCZ and BD vs. controls (PFC) (18)
SCZ and BD Entire HTR2A promoter region (qMSP) Increased methylation of −1439 (rs6311), −1420 and −1224 (saliva), decreased methylation of rs6313 (saliva) in SCZ, BD, and SCZ FDR vs. controls (19)
Suicidality in patients with major psychosis Rs6313 (T102C) (MSRD) Increased methylation at T102C (rs6313) associated with SHZ suicide attempters compared to SHZ non attempters (peripheral leukocytes) (20)
BPD 143 bp CpG island of HTR2A promoter region (47470800-47470140) (qMSP) Increased HTR2A methylation in BPD patients vs controls at 2 out of 8 CpGs examined (Whole Blood) (21)
CFS 17 CpGs located −1500 bp upstream of TSS (qMSP) Increased HTR2A expression in CFS cases, modulated by CpGs −1438 (rs6311), −1420, and −1224 (PBMCs) (22)
Infant neurobehavioral outcomes CpGs located 1439 (rs6311), 1420 and 1224 upstream of TSS (Pyrosequencing) Mean methylation (placenta) positively associated with Infant attention score and negative associated with quality of movement (26)
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BD=Bipolar Disorder; BPD=Borderline Personality; CFS=Chronic Fatigue; FDR= First Degree Relatives Disorder; MSRD= Methylation Sensitive Restriction Digest, PBMC=peripheral blood mononuclear cell Syndrome; PFC=Pre Frontal Cortex, qMSP=Quantitative methylation specific PCR; SCZ=Schizophrenia; TSS=Transcriptional Start Site

These studies quantified methylation within the HTR2A promoter region up to 1500 base pairs upstream (figure 3), and predominantly focused their analysis on three CpGs located 1439, 1420 and 1224 base pairs upstream of the transcriptional start site. The CpG position at −1439 is dependent on the genotype at rs6311, which is in linkage disequilibrium with rs6313, located 102 base pairs downstream of the transcriptional start site(22), which was also analyzed (18– 20). Based on a meta-analysis of several adult populations, rs6311 is associated with increased risk of schizophrenia and bipolar disorder in Caucasian populations (24). Falkenberg et al explored transcription factors bound to the promoter region, and the association between specific CpG sites and expression(22). They found that the methylation of a CpG located 1224 base pairs upstream of the TSS altered the binding of transcription activator SP1. They developed a model in which the allele specific CpG located 1439 base pairs upstream, as well as CpGs located 1420 and 1224 base pairs upstream modulated expression of HTR2A in PBMCs(22). These combined studies have revealed a specific epigenetic regulation of HTR2A expression by these 3 CpGs within the HTR2A promoter region and their association with medical outcomes. The mechanism by which these CpG sites control gene expression remains unclear, as well as the factors that contribute to this epigenetic variation within populations.

Figure 3.

Figure 3

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Map of HTR2A promoter region, with CpGs of interest indicated by open circles.

Fetal programming of HTR2A through epigenetic regulation may have long term impacts on infant neurobehavioral health. Specifically, HTR2A has been associated with placental mitogenesis(25), so DNA methylation of HTR2A on the placenta may alter fetal serotonin signaling and placental implantation and physiology, which can be linked to significant reproductive outcomes including fetal growth restriction and preeclampsia.

Epigenetic variation of the mean of the CpG sites located 1420 base pairs and 1224 base pairs upstream of the transcriptional start site have been associated with infant neurobehavioral outcomes using the Neonatal Intensive Care Unit (NICU) Network Neurobehavioral Scale (NNNS)(26). This validated series of assessments has established predictive value for medical and behavioral problems at age 4 ½ (27). The CpG sites from this analysis have been associated with chronic fatigue syndrome as well as schizophrenia in adults (Figure 3), further validating the influence of this region on medical outcomes. Mean methylation at these CpG sites was associated with increased infant attention score, which characterizes the infants ability to follow auditory and visual stimuli, and attention is generally associated with enhanced development(27). However, a high infant attention score may represent a maladaptive response to the environment, manifesting later in life as increased anxiety and difficulty focusing on a task (28). Thus, the association observed in this population of low risk, health infants may represent an adaptive response to the maternal environment, in concurrence with the predictive response model, but it is unclear if there is a tipping point in which this response may become inappropriate. This study also identified a negative relationship between HTR2A mean promoter methylation and infant quality of movement scores, which characterizes infant’s smoothness of motor control, and may predict non-optimal motor development later in life (27). These results suggest that HTR2A methylation may influence cognitive and motor control regions of the brain differently, manifesting as differences in association with these NNNS scores.

This study demonstrated a degree of variation of HTR2A DNA methylation present at birth using the placenta as a relevant biomarker of the fetal environment, and suggests that HTR2A epigenetic regulation may influence expression within the placenta, with long term impacts on infant neurobehavior. The source of this variation, and the mechanism by which it influences neurological outcomes remain unclear, but since 5-HT2A receptor stimulation can induce placental mitogenesis (12), increased placental methylation may influence 5-HT2A expression within the placenta, modulating placental growth and physiology (See figure 4). The placenta plays a crucial role during development, and placental physiology is associated with a number of infant health outcomes, including neurodevelopmental outcomes (29). As previously discussed, serotonin is crucial to the fetal brain and central nervous system during development, and guides the formation of fetal brain circuits. The main source of serotonin during early fetal development is through the placenta(10). We hypothesize that HTR2A regulation with the placenta may play a larger, unknown role in placental serotonergic tone, and influence the timing and amount of serotonin reaching the fetal brain during these crucial developmental periods, thus influencing infant neurodevelopment (Figure 4). These hypotheses require further examination in animal models in order to understand the mechanistic basis, as well as the long term implications for psychiatric disease.

Figure 4.

Figure 4

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Flow chart of the hypothetical mechanism by which placental HTR2A promoter methylation may influence neurobehavioral outcomes. More research is needed to identify intrinsic and extrinsic factors that influence methylation, the mechanism by which they alter htr2a promoter methylation, and the mechanism by which this altered methylation influences placental growth and function and fetal serotonin signaling.

IV. Limitations of Current Approaches

Epigenetic regulation of HTR2A contributes to psychiatric outcomes, which may manifest during fetal development. More research is needed to (1) examine the mechanisms by which epigenetic changes within the placenta occur, (2) understand how these epigenetic changes influence neurodevelopment, and (3) identify factors that induce this epigenetic regulation within the placenta. Our current understanding of these mechanisms is hampered by a number of experimental and technical challenges, which will require interdisciplinary collaboration to overcome.

The placenta is an important regulator of the fetal environment and plays a significant role in shaping infant health outcomes (30). There is an extensive body of work reviewing placental epigenetics in human studies (31), but we have limited understanding of the molecular mechanism that underlie these interactions. The placenta is a major source of fetal serotonin early in development (10), when the fetal brain is maturing. It remains unclear how changes in serotonin signaling change the physiology of the placenta in a manner that alters neurodevelopment, if the 5-HT2A receptors within the placenta alter the active conversion of serotonin, and the degree of influence of placental serotonin signaling on fetal brain development.

Our ability to study the underlying mechanisms governing placental serotonin signaling is limited due to the unique nature of the human placenta. There are significant interspecies differences in placental physiology, which creates challenges to studying the placenta using animal models (32). Due to ethical issues and risks associated with intrauterine tissue sampling, human studies of the placenta are largely limited to samples collected at the end of successful pregnancy. Limited studies have profiled placental methylation in tissues from early gestation (33), and identified that this relationship changes over the course of gestation. In addition, studies examining methylation of placental tissue are confounded by cellular heterogeneity, as DNA methylation profiling is highly tissue specific. One potential solution to this problem is to adjust for cellular heterogeneity in genome-scale studies of placenta and other relevant tissues, using novel methodology which can account for this confounding (34). In vitro studies analyzing underlying molecular mechanisms must consider species and cell type differences in placental methylation and physiology.

Studies of HTR2A methylation have identified an epigenetic regulatory region within the promoter that is associated with cognitive and neurological outcomes, ranging from early behavioral outcomes to diseases that manifest later in life such as schizophrenia and chronic fatigue syndrome. Based on the developmental origins of adult disease theory, we suspect that epigenetic variation adults associated with psychiatric outcomes may reflect epigenetic variation that occurred during early development. Genetic variation in conjunction with DNA methylation is associated with these medical outcomes, revealing a complex interplay between environmental factors and genetics that may contribute to predisposition to disease types. There are a number of intrinsic and extrinsic factors that have been shown to induce DNA methylation of other genes, and we suspect that these factors may also induce changes in DNA methylation of HTR2A (Figure 4).

HTR2A methylation was associated with neurobehavioral outcomes in infants from low risk, non-pathological pregnancies, which are generalizable to the population as a whole. This study identified a high degree in variability of methylation of the HTR2A promoter region, but from this study it is unclear what is causing this epigenetic variation. Intrinsic factors including maternal genetics (35), maternal stress and mood (36), and maternal anthropomorphic characteristics (37) have been associated with infant neurobehavioral outcomes and later life health in adults. Maternal mood has been shown to induce changes in methylation of other serotonin response genes, such as SLC6A4 (35). Thus, we encourage further study in more “at risk” populations or with more complete assessments of psycho-social factors during pregnancy to identify how these intrinsic factors may influence HTR2A promoter methylation to modulate infant neurobehavioral outcomes.

Extrinsic factors have also been shown to influence long term mental health, possibly modulated through promoter methylation. Infant neurobehavior has been associated with pharmaceutical and recreational drugs (38), chemical exposures (39), maternal socioeconomic status (40), and maternal diet (41). One potential candidate modulator of these outcomes is maternal selective serotonin reuptake inhibitors (SSRIs), which are prescribed to pregnant women for a number of mood related disorders. SSRIs have been shown to cross the placental barrier to influence infant developmental outcomes (42). SSRIs are associated with changes in promoter DNA methylation within maternal peripheral leukocytes as well as fetal umbilical leukocytes (35), suggesting that SSRIs may induce epigenetic changes in developing infants. SSRI use has also been associated with a number of infant neurological outcomes (42), including cognitive outcomes in older infants (43). More research is needed to identify other extrinsic factors that influence methylation of HTR2A and the mechanism by which this occurs.

V. Conclusions and Future Directions

The 5-HT2A receptor has been implicated in a number of psychological and cognitive outcomes, including neurobehavioral outcomes that occur early in life. Neurobehavioral disorders are extremely prevalent in the U.S population, and place a large burden on society (44). In particular, autism spectrum disorders are increasing in prevalence, but the biological mechanisms underpinning these disorders remain unclear. Current treatment for neurobehavioral disorders is hampered by a lack of well understood molecular mechanisms, as well as an absence of valid biomarkers of disease (45). Epigenetic regulation has arisen as a potential way to explain psychiatric disorders, including affective disorder (46). HTR2A epigenetic regulation has been suggested as a candidate biomarker for schizophrenia (19), and it may be an ideal biomarker for other neurobehavioral disorders.

Previous studies have studied HTR2A epigenetic regulation in saliva or brain samples, and are limited by the difficulty of identifying an easily accessible and relevant tissue. Placental gene expression has been used as a diagnostic tool for diseases such as down syndrome (47), and there is a growing interest in using the placental methylation as a biomarker of the fetal environment (8). In addition, the placenta is a known source of fetal serotonin during development, suggesting it is a functionally relevant tissue of study. Thus, HTR2A placental methylation could serve as a useful biomarker of future adverse neurological outcomes. More research is necessary to identify clinical relevant measures of HTR2A methylation by examining more at risk populations, as well as to identify more long term outcomes associated with HTR2A promoter methylation.

Well defined biomarkers of early life neurobehavioral outcomes are needed because it is crucial to identify infants at risk for cognitive and behavioral deficits early in development, where pharmacological and cognitive interventions have been proven to be more effective. It is also important to be able to quantitatively validate the efficacy of these interventions. The brain epigenome exhibits a degree of plasticity throughout life that can be modulated by environmental cues and parental effects, as reviewed in (48). This suggests that cognitive therapies may be associated with measurable epigenetic changes within tissues. In addition, pharmacologic agents that induce epigenetic changes have been proposed for the treatment of certain cognitive disorders (49). For example, valproic acid, which inhibits histone deacetylation and acts as an epigenetic modulator, is used to treat a number of psychiatric disorders, including bipolar disorder and schizophrenia (50). The limitation to current epigenetic therapies is that they induce epigenetic changes in a nonspecific manner, which can limit efficacy and cause increased side effects. Before these epigenetic biomarkers can be used for therapeutic applications, it is necessary to identify valid genomic locations. A series studies in unrelated populations have revealed a region of the HTR2A promoter that is associated with psychiatric outcomes in adults and infants, and may represent one such key region of epigenetic regulation.

Acknowledgments

This work has been sponsored by:

Grant Sponsor: NIH-NIMH, Grant Number: R01MH094609; Grant Sponsor: NIH-NIEHS, Grant Number: R01ES022223;Grant Sponsor: NIH-NIEHS, Grant Number: P01 ES022832; Grant Sponsor: EPA, Grant Number: RD83544201 and Grant Sponsor:NIH-NCI, Grant Number: P30CA23108

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