Limits...
Aging and chronic administration of serotonin-selective reuptake inhibitor citalopram upregulate Sirt4 gene expression in the preoptic area of male mice.

Wong DW, Soga T, Parhar IS - Front Genet (2015)

Bottom Line: Moreover, the number of SIRT4 immuno-reactive neurons increased with aging in the medial septum area (12 weeks = 1.00 ± 0.15 vs. 36 weeks = 1.68 ± 0.14 vs. 52 weeks = 1.54 ± 0.11, p < 0.05).In contrast, the number of sirt4-immunopositive cells did not show a statistically significant change with CIT treatment, suggesting that the increase in sirt4 mRNA levels may occur in cells in which sirt4 is already being expressed.Taken together, these studies suggest that CIT treatment and the process of aging utilize the serotonergic system to up-regulate SIRT4 in the POA as a common pathway to deregulate social cognitive and reproductive functions.

View Article: PubMed Central - PubMed

Affiliation: Brain Research Institute, School of Medicine and Health Sciences, Monash University Malaysia Selangor, Malaysia.

ABSTRACT
Sexual dysfunction and cognitive deficits are markers of the aging process. Mammalian sirtuins (SIRT), encoded by sirt 1-7 genes, are known as aging molecules which are sensitive to serotonin (5-hydroxytryptamine, 5-HT). Whether the 5-HT system regulates SIRT in the preoptic area (POA), which could affect reproduction and cognition has not been examined. Therefore, this study was designed to examine the effects of citalopram (CIT, 10 mg/kg for 4 weeks), a potent selective-serotonin reuptake inhibitor and aging on SIRT expression in the POA of male mice using real-time PCR and immunocytochemistry. Age-related increases of sirt1, sirt4, sirt5, and sirt7 mRNA levels were observed in the POA of 52 weeks old mice. Furthermore, 4 weeks of chronic CIT treatment started at 8 weeks of age also increased sirt2 and sirt4 mRNA expression in the POA. Moreover, the number of SIRT4 immuno-reactive neurons increased with aging in the medial septum area (12 weeks = 1.00 ± 0.15 vs. 36 weeks = 1.68 ± 0.14 vs. 52 weeks = 1.54 ± 0.11, p < 0.05). In contrast, the number of sirt4-immunopositive cells did not show a statistically significant change with CIT treatment, suggesting that the increase in sirt4 mRNA levels may occur in cells in which sirt4 is already being expressed. Taken together, these studies suggest that CIT treatment and the process of aging utilize the serotonergic system to up-regulate SIRT4 in the POA as a common pathway to deregulate social cognitive and reproductive functions.

No MeSH data available.


Related in: MedlinePlus

A hypothetical diagram of sirt4 gene regulation by serotonin (5-HT) in the preoptic area (POA) of intact adult, chronic citalopram (CIT) treated adult and aged animals. (A) In the intact adult, sirt4 gene expression levels do not change; (B) in the chronic CIT treated adult, the inhibition of 5-HT re-uptake results in decreased presynaptic 5-HT content (pathway ①) or desensitization of postsynaptic receptors that could subsequently be less activated in the presence of normal, or even increased, synaptic 5-HT concentrations (pathway ②), either of which can result in decreased 5-HT neurotransmission and increased sirt4 gene expression; (C) in aged animals, the serotonergic system may be impaired by decreased 5-HT synthesis (pathway ③) or a decrease in postsynaptic 5-HT receptors (dotted receptor) (pathway ④) to explain sirt4 upregulation, or an unknown age related effect could increase sirt4 gene expression. These 5-HT signaling pathways could facilitate sirt4 gene expression in the POA leading to reproductive and cognitive failure.  5-HT receptors  Desensitized 5-HT receptors  Decrease 5-HT receptors  5-HT transporter  re-uptake  Inhibition of re-uptake  increase  No change in gene expression, ① decrease 5-HT neurotransmission, ② desensitized receptor, ③ decrease 5-HT neurotransmission, ④unknown age-related factors could activate sirt4 gene expression.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4584971&req=5

Figure 6: A hypothetical diagram of sirt4 gene regulation by serotonin (5-HT) in the preoptic area (POA) of intact adult, chronic citalopram (CIT) treated adult and aged animals. (A) In the intact adult, sirt4 gene expression levels do not change; (B) in the chronic CIT treated adult, the inhibition of 5-HT re-uptake results in decreased presynaptic 5-HT content (pathway ①) or desensitization of postsynaptic receptors that could subsequently be less activated in the presence of normal, or even increased, synaptic 5-HT concentrations (pathway ②), either of which can result in decreased 5-HT neurotransmission and increased sirt4 gene expression; (C) in aged animals, the serotonergic system may be impaired by decreased 5-HT synthesis (pathway ③) or a decrease in postsynaptic 5-HT receptors (dotted receptor) (pathway ④) to explain sirt4 upregulation, or an unknown age related effect could increase sirt4 gene expression. These 5-HT signaling pathways could facilitate sirt4 gene expression in the POA leading to reproductive and cognitive failure. 5-HT receptors Desensitized 5-HT receptors Decrease 5-HT receptors 5-HT transporter re-uptake Inhibition of re-uptake increase No change in gene expression, ① decrease 5-HT neurotransmission, ② desensitized receptor, ③ decrease 5-HT neurotransmission, ④unknown age-related factors could activate sirt4 gene expression.

Mentions: We speculate that the up-regulation of sirt4 gene expression in the POA might occur through one or several potential mechanisms, such as: (1) the blockade of 5-HT uptake by chronic CIT treatment could decrease presynaptic 5-HT content or desensitize postsynaptic 5-HT receptors; (2) the aging process might be associated with a decrease in 5-HT synthesis or a decline in postsynaptic 5-HT receptors (Figure 6). According to our model, any of these events could explain a change in sirt4 expression associated with a decrease in serotonergic tone.


Aging and chronic administration of serotonin-selective reuptake inhibitor citalopram upregulate Sirt4 gene expression in the preoptic area of male mice.

Wong DW, Soga T, Parhar IS - Front Genet (2015)

A hypothetical diagram of sirt4 gene regulation by serotonin (5-HT) in the preoptic area (POA) of intact adult, chronic citalopram (CIT) treated adult and aged animals. (A) In the intact adult, sirt4 gene expression levels do not change; (B) in the chronic CIT treated adult, the inhibition of 5-HT re-uptake results in decreased presynaptic 5-HT content (pathway ①) or desensitization of postsynaptic receptors that could subsequently be less activated in the presence of normal, or even increased, synaptic 5-HT concentrations (pathway ②), either of which can result in decreased 5-HT neurotransmission and increased sirt4 gene expression; (C) in aged animals, the serotonergic system may be impaired by decreased 5-HT synthesis (pathway ③) or a decrease in postsynaptic 5-HT receptors (dotted receptor) (pathway ④) to explain sirt4 upregulation, or an unknown age related effect could increase sirt4 gene expression. These 5-HT signaling pathways could facilitate sirt4 gene expression in the POA leading to reproductive and cognitive failure.  5-HT receptors  Desensitized 5-HT receptors  Decrease 5-HT receptors  5-HT transporter  re-uptake  Inhibition of re-uptake  increase  No change in gene expression, ① decrease 5-HT neurotransmission, ② desensitized receptor, ③ decrease 5-HT neurotransmission, ④unknown age-related factors could activate sirt4 gene expression.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4584971&req=5

Figure 6: A hypothetical diagram of sirt4 gene regulation by serotonin (5-HT) in the preoptic area (POA) of intact adult, chronic citalopram (CIT) treated adult and aged animals. (A) In the intact adult, sirt4 gene expression levels do not change; (B) in the chronic CIT treated adult, the inhibition of 5-HT re-uptake results in decreased presynaptic 5-HT content (pathway ①) or desensitization of postsynaptic receptors that could subsequently be less activated in the presence of normal, or even increased, synaptic 5-HT concentrations (pathway ②), either of which can result in decreased 5-HT neurotransmission and increased sirt4 gene expression; (C) in aged animals, the serotonergic system may be impaired by decreased 5-HT synthesis (pathway ③) or a decrease in postsynaptic 5-HT receptors (dotted receptor) (pathway ④) to explain sirt4 upregulation, or an unknown age related effect could increase sirt4 gene expression. These 5-HT signaling pathways could facilitate sirt4 gene expression in the POA leading to reproductive and cognitive failure. 5-HT receptors Desensitized 5-HT receptors Decrease 5-HT receptors 5-HT transporter re-uptake Inhibition of re-uptake increase No change in gene expression, ① decrease 5-HT neurotransmission, ② desensitized receptor, ③ decrease 5-HT neurotransmission, ④unknown age-related factors could activate sirt4 gene expression.
Mentions: We speculate that the up-regulation of sirt4 gene expression in the POA might occur through one or several potential mechanisms, such as: (1) the blockade of 5-HT uptake by chronic CIT treatment could decrease presynaptic 5-HT content or desensitize postsynaptic 5-HT receptors; (2) the aging process might be associated with a decrease in 5-HT synthesis or a decline in postsynaptic 5-HT receptors (Figure 6). According to our model, any of these events could explain a change in sirt4 expression associated with a decrease in serotonergic tone.

Bottom Line: Moreover, the number of SIRT4 immuno-reactive neurons increased with aging in the medial septum area (12 weeks = 1.00 ± 0.15 vs. 36 weeks = 1.68 ± 0.14 vs. 52 weeks = 1.54 ± 0.11, p < 0.05).In contrast, the number of sirt4-immunopositive cells did not show a statistically significant change with CIT treatment, suggesting that the increase in sirt4 mRNA levels may occur in cells in which sirt4 is already being expressed.Taken together, these studies suggest that CIT treatment and the process of aging utilize the serotonergic system to up-regulate SIRT4 in the POA as a common pathway to deregulate social cognitive and reproductive functions.

View Article: PubMed Central - PubMed

Affiliation: Brain Research Institute, School of Medicine and Health Sciences, Monash University Malaysia Selangor, Malaysia.

ABSTRACT
Sexual dysfunction and cognitive deficits are markers of the aging process. Mammalian sirtuins (SIRT), encoded by sirt 1-7 genes, are known as aging molecules which are sensitive to serotonin (5-hydroxytryptamine, 5-HT). Whether the 5-HT system regulates SIRT in the preoptic area (POA), which could affect reproduction and cognition has not been examined. Therefore, this study was designed to examine the effects of citalopram (CIT, 10 mg/kg for 4 weeks), a potent selective-serotonin reuptake inhibitor and aging on SIRT expression in the POA of male mice using real-time PCR and immunocytochemistry. Age-related increases of sirt1, sirt4, sirt5, and sirt7 mRNA levels were observed in the POA of 52 weeks old mice. Furthermore, 4 weeks of chronic CIT treatment started at 8 weeks of age also increased sirt2 and sirt4 mRNA expression in the POA. Moreover, the number of SIRT4 immuno-reactive neurons increased with aging in the medial septum area (12 weeks = 1.00 ± 0.15 vs. 36 weeks = 1.68 ± 0.14 vs. 52 weeks = 1.54 ± 0.11, p < 0.05). In contrast, the number of sirt4-immunopositive cells did not show a statistically significant change with CIT treatment, suggesting that the increase in sirt4 mRNA levels may occur in cells in which sirt4 is already being expressed. Taken together, these studies suggest that CIT treatment and the process of aging utilize the serotonergic system to up-regulate SIRT4 in the POA as a common pathway to deregulate social cognitive and reproductive functions.

No MeSH data available.


Related in: MedlinePlus