Serotonin 1A (5-HT1A) autoreceptors located on serotonin neurons inhibit their activity, and thei... more Serotonin 1A (5-HT1A) autoreceptors located on serotonin neurons inhibit their activity, and their upregulation has been implicated in depression, suicide and resistance to antidepressant treatment. Conversely, post-synaptic 5-HT1A heteroreceptors are important for antidepressant response. The transcription factor deformed epidermal autoregulatory factor 1 (Deaf1) acts as a presynaptic repressor and postsynaptic enhancer of 5-HT1A transcription, but the mechanism is unclear. Because Deaf1 interacts with and is phosphorylated by glycogen synthase kinase 3β (GSK3β)—a constitutively active protein kinase that is inhibited by the mood stabilizer lithium at therapeutic concentrations—we investigated the role of GSK3β in Deaf1 regulation of human 5-HT1A transcription. In 5-HT1A promoter-reporter assays, human HEK293 kidney and 5-HT1A-expressing SKN-SH neuroblastoma cells, transfection of Deaf1 reduced 5-HT1A promoter activity by ~45%. To identify potential GSK3β site(s) on Deaf1, point mu...
Serotonin is a key neurotransmitter that is implicated in a wide variety of behavioral and cognit... more Serotonin is a key neurotransmitter that is implicated in a wide variety of behavioral and cognitive phenotypes. Originating in the raphe nuclei, 5-HT neurons project widely to innervate many brain regions implicated in the functions. During the development of the brain, as serotonin axons project and innervate brain regions, there is evidence that 5-HT plays key roles in wiring the developing brain, both by modulating 5-HT innervation and by influencing synaptic organization within corticolimbic structures. These actions are mediated by 14 different 5-HT receptors, with region- and cell-specific patterns of expression. More recently, the role of the 5-HT system in synaptic re-organization during adulthood has been suggested. The 5-HT neurons have the unusual capacity to regrow and reinnervate brain regions following insults such as brain injury, chronic stress, or altered development that result in disconnection of the 5-HT system and often cause depression, anxiety, and cognitive ...
The 5-HT1A autoreceptor mediates feedback inhibition of serotonin (5-HT) neurons, and is implicat... more The 5-HT1A autoreceptor mediates feedback inhibition of serotonin (5-HT) neurons, and is implicated in major depression. The human 5-HT1A gene (HTR1A) rs6295 risk allele prevents Deaf1 binding to HTR1A, resulting in increased 5-HT1A autoreceptor transcription. Since chronic stress alters HTR1A methylation and expression, we addressed whether recruitment of methyl-binding protein MeCP2 may alter Deaf1 regulation at the HTR1A locus. We show that MeCP2 enhances Deaf1 binding to its HTR1A site and co-immunoprecipitates with Deaf1 in cells and brain tissue. Chromatin immunoprecipitation assays showed Deaf1-dependent recruitment of MeCP2 to the mouse HTR1A promoter, and MeCP2 modulated human and mouse HTR1A gene transcription in a Deaf1-dependent fashion, enhancing Deaf1-induced repression at the Deaf1 site. To address the role of MeCP2 in HTR1A regulation in vivo, mice with conditional knockout of MeCP2 in adult 5-HT neurons (MeCP2 cKO) were generated. These mice exhibited increased 5-HT...
Serotonin 1A (5-HT1A) autoreceptors located on serotonin neurons inhibit their activity, and thei... more Serotonin 1A (5-HT1A) autoreceptors located on serotonin neurons inhibit their activity, and their upregulation has been implicated in depression, suicide and resistance to antidepressant treatment. Conversely, post-synaptic 5-HT1A heteroreceptors are important for antidepressant response. The transcription factor deformed epidermal autoregulatory factor 1 (Deaf1) acts as a presynaptic repressor and postsynaptic enhancer of 5-HT1A transcription, but the mechanism is unclear. Because Deaf1 interacts with and is phosphorylated by glycogen synthase kinase 3β (GSK3β)—a constitutively active protein kinase that is inhibited by the mood stabilizer lithium at therapeutic concentrations—we investigated the role of GSK3β in Deaf1 regulation of human 5-HT1A transcription. In 5-HT1A promoter-reporter assays, human HEK293 kidney and 5-HT1A-expressing SKN-SH neuroblastoma cells, transfection of Deaf1 reduced 5-HT1A promoter activity by ~45%. To identify potential GSK3β site(s) on Deaf1, point mu...
Serotonin is a key neurotransmitter that is implicated in a wide variety of behavioral and cognit... more Serotonin is a key neurotransmitter that is implicated in a wide variety of behavioral and cognitive phenotypes. Originating in the raphe nuclei, 5-HT neurons project widely to innervate many brain regions implicated in the functions. During the development of the brain, as serotonin axons project and innervate brain regions, there is evidence that 5-HT plays key roles in wiring the developing brain, both by modulating 5-HT innervation and by influencing synaptic organization within corticolimbic structures. These actions are mediated by 14 different 5-HT receptors, with region- and cell-specific patterns of expression. More recently, the role of the 5-HT system in synaptic re-organization during adulthood has been suggested. The 5-HT neurons have the unusual capacity to regrow and reinnervate brain regions following insults such as brain injury, chronic stress, or altered development that result in disconnection of the 5-HT system and often cause depression, anxiety, and cognitive ...
The 5-HT1A autoreceptor mediates feedback inhibition of serotonin (5-HT) neurons, and is implicat... more The 5-HT1A autoreceptor mediates feedback inhibition of serotonin (5-HT) neurons, and is implicated in major depression. The human 5-HT1A gene (HTR1A) rs6295 risk allele prevents Deaf1 binding to HTR1A, resulting in increased 5-HT1A autoreceptor transcription. Since chronic stress alters HTR1A methylation and expression, we addressed whether recruitment of methyl-binding protein MeCP2 may alter Deaf1 regulation at the HTR1A locus. We show that MeCP2 enhances Deaf1 binding to its HTR1A site and co-immunoprecipitates with Deaf1 in cells and brain tissue. Chromatin immunoprecipitation assays showed Deaf1-dependent recruitment of MeCP2 to the mouse HTR1A promoter, and MeCP2 modulated human and mouse HTR1A gene transcription in a Deaf1-dependent fashion, enhancing Deaf1-induced repression at the Deaf1 site. To address the role of MeCP2 in HTR1A regulation in vivo, mice with conditional knockout of MeCP2 in adult 5-HT neurons (MeCP2 cKO) were generated. These mice exhibited increased 5-HT...
Disregulation of the serotonin (5-HT) system isstrongly implicated in major depression and suicid... more Disregulation of the serotonin (5-HT) system isstrongly implicated in major depression and suicide, and the 5-HT1A receptor is a critical regulator of serotonergic activity. A C(−1019)G 5-HT1A polymorphism was associated with depression and suicide (Lemonde et al.,2003), and blocks the function of transcription factors Deaf-1 and HES5. Since early lifetime, environment-driven promoter methylation can establish lifelong changes in stress reactivity (Meaney and Szyf, 2005), and postnatal alteration in 5-HT1A receptor expression determines lifetime anxiety phenotype in mice (Grosset al., 2002), we hypothesized increased DNA methyla-tion of the 5-HT1A polymorphism may increase risk fordepression or suicide. Subjects: Retrospective psychiatric assessments identi-fied control subjects (n=12), or suicide victims withmajor depression (14), schizophrenia (12), or alcoholism (7), gathered with a modified SADS-L (Spitzer and Endicott, 1978) and diagnoses made according to DSMIIIR. Brain tissue obtained at autopsy (Cleveland,OH) was matched for age, ethnicity and postmorteminterval. Genomic DNA was isolated from cortical braintissue and 5-HT1A polymorphism DNA isolated, amplified and analyzed for methylation using bisulfite modification procedure. Genotyping for 5-HT1A C(−1019)G was done using Taqman method. DNA methylation was examined at two CpG sites:C(−1019) (POLY) and C(−1007) (HES) in the Deaf-1/HES5 elements. Methylation of POLY was low (b10%), detected in schizophrenia, alcoholism and controls. Methylation of HES ranged from 0–15%, with three-fold greater methylation in schizophrenia vs. non-schizophrenia or depressed patient samples. Methylation of both sites was two-fold higher in C/C vs. C/G subjects, and not detected in G/G. In initial studies, Deaf-1 bound to methylated or non-methylated DNA element with similar affinity. In summary, both 5-HT1A polymorphism CpG sites were methylated and this may be associated with schizophrenia. The effect of DNA methylation onDeaf-1/HES5 function and 5-HT1A receptor expression will be addressed.
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