Genetic approaches for understanding the role of serotonin receptors in mood and behavior

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Serotonin (5-hydroxytryptamine; 5-HT) is an ancient signaling molecule that has a conserved role in modulating mood and behavior. Integral to its pleiotropic actions is the existence of multiple receptors, expressed in distinct but often overlapping patterns within the brain and the periphery. The existence of ∼14 mammalian receptor subtypes, many of which possess similar pharmacological profiles, has made assigning functional roles for these receptors challenging. This challenge has been further compounded by the revelation that a single receptor can have several different functions depending upon where and when it is expressed and activated, that is, in brain versus periphery, or at different developmental time points. This review highlights the contribution of genetic techniques to dissect the specific function of distinct serotonin receptor populations across the life course, with an emphasis on the contribution of different serotonin 1A receptor populations to mood and behavior. Similar approaches hold the promise to elucidate the functional roles of other receptors, as well as the interaction of serotonin with other neuroendocrine modulators of mood and behavior.

Highlights

► Genetic approaches elucidate functional roles for specific serotonin receptors. ► Advances enable both spatially specific and temporally specific receptor manipulation. ► Serotonin 1A receptors have distinct developmental and adult roles.

Introduction

The complexity of the serotonergic system is both exciting and daunting from a scientific perspective. There are 14 known human 5-HT receptors, more than in any other neuromodulatory system; receptor diversity is further amplified by alternative splicing, RNA editing, and heterodimerization [1, 2]. Multiple receptors subtypes can be expressed in the same brain regions, and even within the same cells [2]. Functionally, 5-HT receptors often have similar pharmacological profiles, making it difficult to identify specific antagonists or agonists for each receptor. Likewise, there is a dearth of selective antibodies to effectively label the receptors. Many studies therefore depend upon autoradiographic techniques, which lack cellular resolution and can also, in some cases, lack specificity.

Given this complexity, genetic techniques have proven instrumental in determining the role of different 5-HT receptors in the brain. In particular, refined techniques have moved beyond general questions of receptor function to address how variation in levels of a particular receptor in different brain regions and/or at different developmental time points modulate mood and behavior.

In this review we discuss progress in genetic techniques used to develop mouse models of neuropsychiatric disorders over the last 15 years, beginning with global gene knockout. Using the serotonin 1A receptor (5-HT1A) as an example, we will discuss the benefits and pitfalls of different approaches and provide an overview of how refinement of genetic techniques has contributed to our understanding of the modulatory effects of 5-HT1A on mood and behavior. We also discuss the role of 5-HT1A in the neural circuits involved in anxiety and stress response and briefly highlight future opportunities for use of advanced techniques to investigate complex social behaviors, including mating and aggression.

Section snippets

Serotonin 1A receptors

5-HT1A was the first serotonin receptor to be cloned, and has been intensively studied due to its potential involvement in psychiatric illness  anxiety disorders in particular [3, 4, 5, 6]. 5-HT1A is expressed in the brain, spleen, and neonatal kidney [7, 8, 9]. Within the brain, it is expressed on neuronal somas and dendrites both as an autoreceptor and as a heteroreceptor. Its activation leads to hyperpolarization and reduced firing rates. As such, autoreceptors gate the firing of the dorsal

Germline gene knockout

The use of homologous recombination to eliminate genes from the mouse genome provided an opportunity to selectively study the role of individual serotonergic receptors. Using this technique (Figure 1a), three groups independently discovered that deletion of the serotonin 1A receptor gene in mice yielded increased anxiety levels. In addition, an ‘anti-depressed’ phenotype was observed, characterized by increased active coping in the face of a stressor, such as increased struggling in the forced

Genetic rescue

Perturbations that affect the serotonin system have different effects during development versus adulthood, indicating that sensitive windows may exist for the effects of serotonin on various behavioral phenotypes. Transient pharmacological blockade of the serotonin transporter or of 5-HT1A during post-natal development has long lasting behavioral effects, demonstrating a critical role for serotonin in the maturation of emotional function [16, 17, 18]. As such, genetic techniques that enable not

Determining the necessity of receptor subpopulations

Newer strategies are currently being used to determine the necessity of different receptor subpopulations in the development and expression of anxiety behavior. Similar to the strategy outlined above, Richardson-Jones et al. [20••, 21•] developed a tetracycline-sensitive transgenic system in which selected receptor populations could be suppressed in a temporally selective manner (Figure 1c). This technique was used to assess the role that both 5-HT1A auto-receptors and hetero-receptors play in

Genetic strategies to model natural variation

Null mutations in serotonergic genes in the human population are rare. Manipulations of gene levels within physiologically relevant limits may therefore yield more insight into individual differences and disease risk, and thus provide greater translational impact. Since some natural human genetic variants lead to lower expression levels of genes of interest, the effects of these variants have been indirectly modeled by decreasing, but not eliminating, expression of target genes. In early

Circuitry underlying effects of 5-HT1A on mood and anxiety

Genetic techniques have also begun to shed light on how 5-HT1A affects the circuits underlying mood and anxiety. A more in-depth description of these circuits has been reviewed in detail elsewhere [29]. Substantial work has focused on structural and functional connections between the dorsal raphe nucleus (DRN), medial prefrontal cortex (mPFC) including the anterior cingulate cortex, and the amygdala, although the mesencephalic tectum system and the hippocampus have also been implicated in the

Expanding the scope of genetic studies

Although advanced genetic examination of the serotonin system has focused primarily on its role in mood and anxiety, serotonin is implicated in a wide range of behaviors [62]. Refinement of these techniques [63] will be instrumental for identifying the receptor populations and temporal dynamics of serotonin's effects on complex behaviors, such as aggression and sexual behaviors. For instance, substantial pharmacological evidence suggests that activation of 5-HT1A receptors facilitates male

Conclusions

To date, we have made key advances towards understanding the necessity and sufficiency of various serotonin receptor populations that impact mood and anxiety, and have gained insight into the importance of investigating sensitive periods of gene action. However, these technological and scientific advances remain only a subset of those required to decode the complex evolutionary history underlying 5-HT's myriad roles. We still know little about the role of different receptor populations in

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

The authors would like to acknowledge funding from National Institutes of Health T32 MH015144 (ZRD), R37 MH068542 (RH), K08 MH087718 (SEA), Louis V. Gerstner, Jr Scholars Program (SEA), HDRF (RH), and NYSTEM (C026430). R.H. is a consultant to Lundbeck and Roche.

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