New antidepressant strategy based on acute siRNA silencing of 5-HT1A autoreceptors

Bortolozzi, Anala; Castañé, Anna; Semakova, Jana; Santana, Noemí; Alvarado, G; Cortés, Roser; Ferrés‐Coy, Albert; Fernández, Guillén; Carmona, M.; Tóth, Miklós; Perales, José C.; Montefeltro, Andrés; Artigas, Francesc

doi:10.1038/mp.2012.52

Cited by 14 publications

(14 citation statements)

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“…Specifically, autoreceptor knockdown during post-natal development increases anxiety and decreases levels of social engagement but does not alter stress coping. These findings support and refine previous pharmacological and transgenic work suggesting that the effects of 5-HT1A autoreceptors on anxiety are a developmentally mediated phenotype (Bortolozzi et al, 2012;Lo Iacono and Gross, 2008;Richardson-Jones et al, 2011;Vinkers et al, 2010) and provide insights into how perturbations to the 5-HT1A autoreceptor system during post-natal life can impact more complex social phenotypes, an area that has not been extensively explored in previous literature. Importantly, this work addresses a number of limitations of previous studies.…”

Section: -Ht1a-mediated Anxiety Phenotypes Are Developmental In Originsupporting

confidence: 86%

“…Our results show that decreases in 5-HT1A autoreceptors during development impact anxiety-related behaviors but not depression-related behaviors. In contrast, decreases in 5-HT1A autoreceptors in adulthood have no effect on anxiety-related behavior and result in lower levels of depression-related behaviors (Bortolozzi et al, 2012;Richardson-Jones et al, 2010). Thus, the temporal-and region-specific aspects of receptor variability, as impacted by either genetic or epigenetic factors, may have dissociable effects on psychiatric disease risk at different points of the life course, adding a layer of complexity to our understanding of psychiatric risk alleles.…”

Section: -Ht1a-mediated Anxiety Phenotypes Are Developmental In Originmentioning

confidence: 99%

“…Manipulation of 5-HT1A receptors at different time points has revealed a dissociable role for autoreceptor versus heteroreceptor populations during development and adulthood Richardson-Jones et al, 2011). In particular, whole life, but not adult-specific, suppression of autoreceptors leads to increased anxiety, a finding recently confirmed via RNAi knockdown of autoreceptors in adulthood (Bortolozzi et al, 2012;Richardson-Jones et al, 2010). In contrast, developmental suppression of forebrain heteroreceptors does not affect anxiety levels but appears to be important for modulating stress reactivity and depression-related behaviors (Richardson-Jones et al, 2011).…”

Section: Introductionmentioning

confidence: 98%

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Developmental Effects of Serotonin 1A Autoreceptors on Anxiety and Social Behavior

Donaldson

Piel

Santos

et al. 2013

Neuropsychopharmacol

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The serotonin 1A receptor (5-HT1A) has a major role in modulating the effects of serotonin on mood and behavior. Previous studies have shown that knockout of 5-HT1A selectively in the raphe leads to higher levels of anxiety during adulthood. However, it remains unclear whether this phenotype is due to variation in receptor levels specifically during development or throughout life. To test the hypothesis that developmental sensitivity may underlie the effects of 5-HT1A on anxiety, we used an inducible transgenic system to selectively suppress 5-HT1A levels in serotonergic raphe neurons from post-natal days (P) 14 to P30, with a maximal reduction of 40% at P21 and return to regular levels by P30. This developmental decrease in receptor levels has long-lasting consequences, increasing anxiety and decreasing social investigation in adulthood. In addition, post-natal knockdown of autoreceptors leads to long-term increases in the excitability of serotonergic neurons, which may represent a mechanism underlying the effects of post-natal receptor variation on behavior later in life. Finally, we also examined the interplay between receptor variation and juvenile exposure to stress (applied from P14 to P21). Similar to receptor knockdown, juvenile exposure to stress led to increased anxiety phenotypes but did not exacerbate 5-HT1A knockdown-mediated anxiety levels. This work indicates that the effects of 5-HT1A autoreceptors on anxiety and social behaviors are developmentally mediated and suggests that natural variations in the expression of 5-HT1A may act during development to influence individual anxiety levels and contribute to susceptibility to anxiety disorders.

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Section: -Ht1a-mediated Anxiety Phenotypes Are Developmental In Originsupporting

confidence: 86%

Section: -Ht1a-mediated Anxiety Phenotypes Are Developmental In Originmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

See 1 more Smart Citation

Developmental Effects of Serotonin 1A Autoreceptors on Anxiety and Social Behavior

Donaldson

Piel

Santos

et al. 2013

Neuropsychopharmacol

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“…Specifically, post-natal suppression of 5-HT1A levels selectively in the raphe led to increased anxiety without affecting stress-reactivity (83). Conversely, adult suppression of raphe receptor levels did not affect anxiety, but did increase stress resiliency and antidepressant responsiveness, a finding independently confirmed through the use of siRNAs to decrease adult 5-HT1A levels in the raphe (84, 85). …”

Section: Genetics Of Intermediate Phenotypesmentioning

confidence: 80%

From Psychiatric Disorders to Animal Models: A Bidirectional and Dimensional Approach

Donaldson

Hen

2015

Biological Psychiatry

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Psychiatric genetics research is bidirectional in nature, with human and animal studies becoming more closely integrated as techniques for genetic manipulations allow for more subtle exploration of disease phenotypes. This synergy, however, highlights the importance of considering the way in which we approach the genotype-phenotype relationship. In particular, the nosological divide of psychiatric illness, while clinically relevant, is not directly translatable in animal models. For instance, mice will never fully re-capitulate the broad criteria for many psychiatric disorders; nor will they have guilty ruminations, suicidal thoughts, or rapid speech. Instead, animal models have been and continue to provide a means to explore dimensions of psychiatric disorders in order to identify neural circuits and mechanisms underlying disease-relevant phenotypes. Thus, the genetic investigation of psychiatric illness will yield the greatest insights if efforts continue to identify and utilize biologically valid phenotypes across species. In this review we discuss the progress to date and the future efforts that will enhance translation between human and animal studies, including the identification of intermediate phenotypes that can be studied across species, as well as the importance of refined modeling of human disease-associated genetic variation in mice and other animal models.

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“…A group of scientists in Spain recently addressed this problem using an original strategy. Bortolozzi et al (2012) administered a small-interfering RNA (siRNA) to suppress acutely 5-HT 1A autoreceptor-mediated negative feedback mechanisms in the mouse brain. They developed a conjugated siRNA (C-1A-siRNA) by covalently binding siRNA targeting 5-HT 1A receptor mRNA with the SSRI sertraline in order to concentrate it in serotonin axons, rich in SERT sites.…”

Section: Intracerebral In Vivo Microdialysis In Rodentsmentioning

confidence: 99%

Antidepressant activity: contribution of brain microdialysis in knock-out mice to the understanding of BDNF/5-HT transporter/5-HT autoreceptor interactions

Gardier

2013

Front. Pharmacol.

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Why antidepressants vary in terms of efficacy is currently unclear. Despite the leadership of selective serotonin reuptake inhibitors (SSRIs) in the treatment of depression, the precise neurobiological mechanisms involved in their therapeutic action are poorly understood. A better knowledge of molecular interactions between monoaminergic system, pre- and post-synaptic partners, brain neuronal circuits and regions involved may help to overcome limitations of current treatments and identify new therapeutic targets. Intracerebral in vivo microdialysis (ICM) already provided important information about the brain mechanism of action of antidepressants first in anesthetized rats in the early 1990s, and since then in conscious wild-type or knock-out mice. The principle of ICM is based on the balance between release of neurotransmitters (e.g., monoamines) and reuptake by selective transporters [e.g., serotonin transporter for serotonin 5-hydroxytryptamine (5-HT)]. Complementary to electrophysiology, this technique reflects pre-synaptic monoamines release and intrasynaptic events corresponding to ≈80% of whole brain tissue content. The inhibitory role of serotonergic autoreceptors infers that they limit somatodendritic and nerve terminal 5-HT release. It has been proposed that activation of 5-HT1A and 5-HT1B receptor sub-types limits the antidepressant-like activity of SSRIs. This hypothesis is based partially on results obtained in ICM experiments performed in naïve, non-stressed rodents. The present review will first remind the principle and methodology of ICM performed in mice. The crucial need of developing animal models that display anxiety and depression-like behaviors, neurochemical and brain morphological phenotypes reminiscent of these mood disorders in humans, will be underlined. Recently developed genetic mouse models have been generated to independently manipulate 5-HT1A auto and heteroreceptors and ICM helped to clarify the role of the pre-synaptic component, i.e., by measuring extracellular levels of neurotransmitters in serotonergic nerve terminal regions and raphe nuclei. Finally, we will summarize main advantages of using ICM in mice through recent examples obtained in knock-outs (drug infusion through the ICM probe allows the search of a correlation between changes in extracellular neurotransmitter levels and antidepressant-like activity) or alternatives (infusion of a small-interfering RNA suppressing receptor functions in the mouse brain). We will also focus this review on post-synaptic components such as brain-derived neurotrophic factor in adult hippocampus that plays a crucial role in the neurogenic and anxiolytic/antidepressant-like activity of chronic SSRI treatment. Limitations of ICM will also be considered.

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New antidepressant strategy based on acute siRNA silencing of 5-HT1A autoreceptors

Cited by 14 publications

References 0 publications

Developmental Effects of Serotonin 1A Autoreceptors on Anxiety and Social Behavior

Developmental Effects of Serotonin 1A Autoreceptors on Anxiety and Social Behavior

From Psychiatric Disorders to Animal Models: A Bidirectional and Dimensional Approach

Antidepressant activity: contribution of brain microdialysis in knock-out mice to the understanding of BDNF/5-HT transporter/5-HT autoreceptor interactions

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