The 5-HT1A receptor: Signaling to behavior

Major depression and anxiety are highly prevalent and involve chronic dysregulation of serotonin, but they remain poorly understood. Here, we review novel transcriptional (genetic, epigenetic) and posttranscriptional (microRNA, alternative splicing) mechanisms implicated in mental illness, focusing on a key serotonin-related regulator, the serotonin 1A (5-HT 1A) receptor. Functional single-nucleotide polymorphisms and stress-induced DNA methylation of the 5-HT 1A promoter converge to differentially alter pre-and postsynaptic 5-HT 1A receptor expression associated with major depression and reduced therapeutic response to serotonergic antidepressants. Major depression is also associated with altered levels of splice factors and microRNA, posttranscriptional mechanisms that regulate RNA stability. The human 5-HT 1A 3′-untranslated region is alternatively spliced, removing microRNA sites and increasing 5-HT 1A expression, which is reduced in major depression and may be genotype-dependent. Thus, the 5-HT 1A receptor gene illustrates the convergence of genetic, epigenetic and posttranscriptional mechanisms in gene expression, neurodevelopment and neuroplasticity, and major depression. Understanding gene regulatory mechanisms could enhance the detection, categorization and personalized treatment of major depression.

show abstract

“…130 The 5-HT 1A signalling mechanisms to neuroplasticity-induced behavioural changes remain incompletely understood, as reviewed recently. 131…”

Section: Htr1a Genotype Neurodevelopment and Neuroplasticitymentioning

confidence: 99%

Genetic, epigenetic and posttranscriptional mechanisms for treatment of major depression: the 5-HT1A receptor gene as a paradigm

Albert

François

Vahid-Ansari

2019

jpn

Self Cite

View full text Add to dashboard Cite

show abstract

“…Research has shown that BDNF-mediated PLCG1 signaling is required for the formation and function of inhibitory synapses, whereby the disruption of PLCG1 signaling in the hippocampus leads to such dysfunctions. Interestingly, a clinical study showed that 5-HT1A signaling through tyrosine kinase receptors activates PLC/protein kinase C (PKC) signaling, mediating the synaptogenesis and behavioral actions of anti-depressants (60). Furthermore, previous studies have demonstrated that PLAUR plays a role in inflammation, tissue regeneration and axonal regeneration within the central nervous system (CNS) (45).…”

Section: Mdd Major Depressive Disorder; Cns Central Nervous Systemmentioning

confidence: 99%

Identification of Key Genes and the Pathophysiology Associated With Major Depressive Disorder Patients Based on Integrated Bioinformatics Analysis

Zhang

et al. 2020

Front. Psychiatry

View full text Add to dashboard Cite

Background: At present, laboratory blood tests to support major depressive disorder (MDD) diagnosis are not available. This study aimed to screen potential mRNAs for peripheral blood biomarkers and novel pathophysiology of MDD. Methods: The present study utilized public data from two mRNA microarray datasets to analyze the hub genes changes related to MDD. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of differentially expressed genes (DEGs) were performed. Finally, some potential mRNA quality biomarkers for hub gene expression in blood were identified. Results: A total of 25 significantly co-upregulated DEGs and 98 co-downregulated DEGs were obtained from two datasets. The pathway enrichment analyses showed that co-upregulated genes were significantly enriched in the regulation of cell-matrix adhesion and mitochondrial membrane permeability which were involved in the apoptotic process. Co-downregulated genes were mainly involved in the neutrophil activation which in turn was involved in the immune response, degranulation and cell-mediated immunity, positive regulation of immune response, the Toll-like receptor signaling pathway, and the NOD-like receptor signaling pathway. From the PPI network, 14 hub genes were obtained. Among them, the subnetworks of PLCG1, BCL2A1, TLR8, FADD, and TLR4 screened out from our study have been shown to play a role in immune and inflammation responses. Discussion: The potential molecular mechanisms that have been identified simultaneously include innate immunity, neuroinflammation, and neurotrophic factors for synapse function and development.

show abstract

“…The 5-HT1A receptor signals via inhibitory G proteins (Gi/Go) to reduce neuronal excitability and inhibit firing rate. The 5-HT1A auto- and hetero-receptors have the same intronless coding sequence and share canonical Gi/Go signaling pathways including: inhibition of adenylyl cyclase to reduce PKA activity; opening of G-protein inward rectifying potassium (GIRK) channels to hyperpolarize membrane potential; and inhibition of voltage-gated calcium channels (Ca 2+ ) to reduce calcium influx and calcium-calmodulin kinase activity (Raymond et al, 1999; Albert and Vahid-Ansari, 2018). Nevertheless, they appear to signal differently to G proteins and to tyrosine kinase effectors such as ERK1/2 and Akt-GSK3 (Polter and Li, 2010; Albert and Vahid-Ansari, 2018).…”

Section: -Ht1a Receptorsmentioning

confidence: 99%

“…The 5-HT1A auto- and hetero-receptors have the same intronless coding sequence and share canonical Gi/Go signaling pathways including: inhibition of adenylyl cyclase to reduce PKA activity; opening of G-protein inward rectifying potassium (GIRK) channels to hyperpolarize membrane potential; and inhibition of voltage-gated calcium channels (Ca 2+ ) to reduce calcium influx and calcium-calmodulin kinase activity (Raymond et al, 1999; Albert and Vahid-Ansari, 2018). Nevertheless, they appear to signal differently to G proteins and to tyrosine kinase effectors such as ERK1/2 and Akt-GSK3 (Polter and Li, 2010; Albert and Vahid-Ansari, 2018). For example, 5-HT1A autoreceptors couple to inhibition of ERK1/2 activation in raphe RN46A cells (Kushwaha and Albert, 2005), while the hippocampal 5-HT1A heteroreceptor activates ERK1/2 via a PKC-mediated pathway (Adayev et al, 1999; Mogha et al, 2012).…”

Section: -Ht1a Receptorsmentioning

confidence: 99%

“…Importantly, global 5-HT1A knockout (Santarelli et al, 2003) or specific deletion of the gene in hippocampal dentate gyrus granule cells (Samuels et al, 2015) prevents fluoxetine-induced hippocampal neurogenesis and anti depressant and anti-anxiety actions, implicating hippocampal 5-HT1A receptors in fluoxetine action (Figure 2). Taken together, 5-HT1A autoreceptors and heteroreceptors signal to diverse, sometimes opposing pathways to mediate the acute and sustained effects of the serotonin system on anxiety and depression (Albert and Vahid-Ansari, 2018). Identifying biased 5-HT1A ligands that target autoreceptor vs. heteroreceptor signaling may provide useful tools to separately target these receptors that have opposite effects on depression and SSRI response (Figure 2) (Assie et al, 2010; Becker et al, 2016).…”

Section: -Ht1a Receptorsmentioning

confidence: 99%

See 1 more Smart Citation

Overcoming Resistance to Selective Serotonin Reuptake Inhibitors: Targeting Serotonin, Serotonin-1A Receptors and Adult Neuroplasticity

et al. 2019

Self Cite

View full text Add to dashboard Cite

Major depressive disorder (MDD) is the most prevalent mental illness contributing to global disease burden. Selective serotonin (5-HT) reuptake inhibitors (SSRIs) are the first-line treatment for MDD, but are only fully effective in 30% of patients and require weeks before improvement may be seen. About 30% of SSRI-resistant patients may respond to augmentation or switching to another antidepressant, often selected by trial and error. Hence a better understanding of the causes of SSRI resistance is needed to provide models for optimizing treatment. Since SSRIs enhance 5-HT, in this review we discuss new findings on the circuitry, development and function of the 5-HT system in modulating behavior, and on how 5-HT neuronal activity is regulated. We focus on the 5-HT1A autoreceptor, which controls 5-HT activity, and the 5-HT1A heteroreceptor that mediates 5-HT actions. A series of mice models now implicate increased levels of 5-HT1A autoreceptors in SSRI resistance, and the requirement of hippocampal 5-HT1A heteroreceptor for neurogenic and behavioral response to SSRIs. We also present clinical data that show promise for identifying biomarkers of 5-HT activity, 5-HT1A regulation and regional changes in brain activity in MDD patients that may provide biomarkers for tailored interventions to overcome or bypass resistance to SSRI treatment. We identify a series of potential strategies including inhibiting 5-HT auto-inhibition, stimulating 5-HT1A heteroreceptors, other monoamine systems, or cortical stimulation to overcome SSRI resistance.

show abstract

The 5-HT1A receptor: Signaling to behavior

Cited by 141 publications

References 166 publications

Genetic, epigenetic and posttranscriptional mechanisms for treatment of major depression: the 5-HT1A receptor gene as a paradigm

Genetic, epigenetic and posttranscriptional mechanisms for treatment of major depression: the 5-HT1A receptor gene as a paradigm

Identification of Key Genes and the Pathophysiology Associated With Major Depressive Disorder Patients Based on Integrated Bioinformatics Analysis

Overcoming Resistance to Selective Serotonin Reuptake Inhibitors: Targeting Serotonin, Serotonin-1A Receptors and Adult Neuroplasticity

Contact Info

Product

Resources

About