The Role of 5-HT Systems on Memory and Dysfunctional Memory

Emergent Targets for Memory Formation and Memory Alterations

Alfredo Meneses

• Publisher: Academic Press
• Year: 2014
• Print ISBN: 9780128008362
• eBook ISBN: 9780128010839
• Topic: Biological Sciences
• Subtopic: Cognitive Psychology & Cognition
• Index: Biological Sciences

Drugs acting through 5-HT (5-hydroxytryptamine, or serotonin) systems modulate memory and its alterations, but the mechanisms by which they do so are poorly understood. Agonists and antagonists for 5-HT receptors, as well as serotonin uptake inhibitors, present promnesic (memory-promoting) and/or anti-amnesic effects under different conditions, and 5-HT receptors are also associated with neural changes. The Role of 5-HT Systems on Memory and Dysfunctional Memory: Emergent Targets for Memory Formation and Memory Alterations reviews and summarizes the most recent research related to 5-HT drugs and the mechanisms by which they effect alterations in memory. This latest evidence is reviewed in the context of memory deficits related to brain disorders, such as post-traumatic stress disorder, schizophrenia, post-stroke cognitive dysfunctions, Parkinson's disease, and infection-induced memory impairments. Written by an expert in the field of memory, The Role of 5-HT Systems on Memory and Dysfunctional Memory provides an introduction to the latest research on 5-HT receptors and their contributions to the physiological and pharmacological basis of memory.- Examines and summarizes the recent advances in drugs that act through the 5-HT systems- Reviews findings in the context of brain disorders that involve memory deficits- Covers emergent targets for memory formation and memory alterations

Chapter 1

Introduction

The identification of 5-HT receptor families and its transporter in mammalian species and drugs selective for these sites have allowed dissecting their participation in learning and memory. Importantly, some 5-HT drugs may present promnesic and/or antiamnesic effects. 5-HT consists that it has diverse pharmacological and genetic tools, neurotoxins, receptor agonist and antagonists and a well studied signaling and synaptic modulation in mammal species. Growing evidence indicates that 5-HT receptors and SERT are involved in normal, pathophysiological and therapeutic aspects of learning and memory. However, 5-HT has been linked to emotional and motivational aspects of human behavior, including anxiety, depression, impulsivity, etc; hence, whether the role of serotonin is related to memory and/or behavioral/emotional aspects, it remains an important question and evidence revised is supporting the former. Whether 5-HT markers directly or indirectly participate and/or contribute to the physiological and pharmacological basis of memory and its pathogenesis is a timely question and they seem to be important neurobiological markers. 5-HT has been also implicated in diseases with memory disorders. Future works should clarify these memory dysfunctions, including delimitations.

Keywords

5-HT markers; 5-HT systems; learning; memory; dysfunctional memory

Drugs acting through 5-hydroxytryptamine (serotonin or 5-HT) systems modulate memory and its alterations, although the mechanisms involved are poorly understood. The neurotransmitter 5-HT was discovered more than 50 years ago, and currently it still continues to generate interest as one of the most successful targets for therapeutic applications (e.g., depression, schizophrenia, anxiety, learning, and memory disorders) (Nordquist and Oreland, 2010; Ruiz and Oranias, 2010). Memory had been classified according to content, time, and its neuroanatomical and biological basis (Meneses, 2013, 2014; Meneses et al., 2011a, b). Diverse brain areas (hippocampus, prefrontal cortex (PFC), etc.) and neurotransmission systems mediate memory systems, including the cholinergic, glutamatergic, dopaminergic, and serotonergic (Burghardt and Bauer, 2013; Cassel, 2010; Eppinger and Hämmerer, 2012; Meneses, 2014; Rodríguez et al., 2012; Singh et al., 2013), and this notion has gained wider acceptance and interest. It is well known that serotonin plays a central role in neural plasticity using different 5-HT receptors (Bockaert et al., 2010; Millan, 2011; Mnie-Filali et al., 2007; Renoir et al., 2012; Olivier et al., 2013; Shimizu et al., 2013; Sodhi and Sanders-Bush, 2004). Phrasing serotonin and neural plasticity in PubMed showed that one paper was published in 1981, while 72 (2012) and 25 (June 2013) or 30 and 39 (July and September 2013) papers have been published. Hence, the major aim of this book is to examine and summarize recent advances for academia and students. It should be noted, however, that the data commented herein had been mainly observed in adult mammal animals; notwithstanding, some important recent advances in invertebrate species are commented below. Very importantly, as 5-HT receptors may determine occurrence, magnitude, and specificity of plasticity sign on invertebrates and mammals (Kirkwood, 2000), then 5-HT systems could exert multiple functions on memory formation and its alterations (Meneses et al., 2009).

Considering a growing scientific and public interest in mnemonic functions and dysfunctions on humans, it will be of great value that future works attempt to integrate invertebrate and vertebrate studies involving serotonin mnemonic actions. For instance, it is heuristic to look for parallels among species, which might open new avenues to the understanding of neuronal functions and dysfunctions (Meneses et al., 2009; Meneses, 2013).

5-HT systems are involved in memory in different species. For instance, according to Guan et al. (2002) although much is known about short-term integration, little is known about how neurons sum opposing signals for long-term synaptic plasticity and memory storage. In the invertebrate Aplysia, Guam et al. (2012) found that when a sensory neuron simultaneously receives inputs from the facilitatory transmitter 5-HT at one set of synapses and the inhibitory transmitter FMRFamide at another, long-term facilitation is blocked and synapse-specific long-term depression dominates. Guam et al. (2012) reported that chromatin immunoprecipitation assays show that 5-HT induces the downstream gene C/EBP by activating CREB1, which recruits CBP for histone acetylation, whereas FMRFa leads to CREB1 displacement by CREB2 and recruitment of HDAC5 to deacetylate histones. When the two transmitters are applied together, facilitation is blocked because CREB2 and HDAC5 displace CREB1-CBP, thereby deacetylating histones (Guan et al., 2002). Moreover, Rahn et al. (2013) characterize epigenetic mechanisms as critical for the gene expression profile necessary to induce and maintain long-lasting neuronal plasticity and behavior; broadly defined epigenetic mechanisms are a set of processes and modifications influencing gene function without alteration of the primary DNA sequence. Canonical epigenetic mechanisms include histone posttranslational modifications (PTMs) and DNA methylation, although recent research has also identified a number of other processes involved in epigenetic regulation, including noncoding RNAs, prions, chromosome position effects, and Polycomb repressors (Rahn et al., 2013). Notably, Jarome and Lubin (2013) highlight that histone lysine methylation is a well-established transcriptional mechanism for the regulation of gene expression changes in eukaryotic cells and is now believed to function in neurons of the central nervous system (CNS) to mediate the process of memory formation and behavior. In mature neurons, methylation of histone proteins can serve to both activate and repress gene transcription. This is in stark contrast to other epigenetic modifications, including histone acetylation and DNA methylation, which have largely been associated with one transcriptional state in the brain. Jarome and Lubin (2013) discuss the evidence for histone methylation mechanisms in the coordination of complex cognitive processes such as long-term memory (LTM) formation and storage; in addition, the current literature highlights the role of histone methylation in intellectual disability, addiction, schizophrenia, autism, depression, and neurodegeneration (Jarome and Lubin, 2013). Likewise, these authors discuss histone methylation within the context of other epigenetic modifications and the potential advantages of exploring this newly identified mechanism of cognition, emphasizing the possibility that this molecular process may provide an alternative locus for intervention in long-term psychopathologies that cannot be clearly linked to genes or environment alone. Importantly, epigenetic mechanisms, serotonin, and memory seem to have an important link in vertebrate species (Kuhn et al., 2013; Rahn et al., 2013).

Importantly, Monje et al. (2013) reported that Flotillin-1 is an evolutionary-conserved memory-related protein upregulated in implicit and explicit learning paradigms; thus, translational approach from invertebrates to rodents led to the identification of Flotillin-1 as evolutionary-conserved memory-related protein (Monje et al., 2013). Hawkins (2013) hypothesized that in Aplysia, spontaneous release is enhanced by the activation of presynaptic serotonin receptors, but presynaptic D1 dopamine receptors or nicotinic acetylcholine receptors could play a similar role in mammals; similar plasticity occurs in mammals, where it may contribute to reward, memory, and their dysfunctions in several psychiatric disorders.

Certainly, in the last few years a growing number of papers had appeared to directly or indirectly implicate 5-HT systems in learning and memory in species ranging from humans to invertebrates (e.g., see Rajasethupathy et al., 2012; for the original paraphrasing, see Meneses and Perez-Garcia, 2007), and this trend continues (see below). An important insight is provided by PubMed showing that in 1960 two papers were published while 354 publications appeared in 2012, with a peak (370 papers) in 2008, 334 until December 2013, and 3 for publication in 2014. Notwithstanding a limited number of selective 5-HT receptor agonists and antagonists, growing evidence indicates that 5-HT serves as a link between synaptic plasticity at receptor and postreceptor levels (i.e., signal transduction pathways) during learning and memory formation in mammals (Meneses et al., 2009). The above evidence is not only indicating numbers but also quality.

Chapter 2

5-HT Systems and Neurobiological Markers Related to Memory Systems

The identification of 5-HT receptor families and its transporter in mammalian species and drugs selective for these sites have allowed dissecting their participation in learning and memory. Importantly, some 5-HT drugs may present promnesic and/or antiamnesic effects. 5-HT consists that it has diverse pharmacological and genetic tools, neurotoxins, receptor agonist and antagonists and a well studied signaling and synaptic modulation in mammal species. Growing evidence indicates that 5-HT receptors and SERT are involved in normal, pathophysiological and therapeutic aspects of learning and memory. However, 5-HT has been linked to emotional and motivational aspects of human behavior, including anxiety, depression, impulsivity, etc; hence, whether the role of serotonin is related to memory and/or behavioral/emotional aspects, it remains an important question and evidence revised is supporting the former. Whether 5-HT markers directly or indirectly participate and/or contribute to the physiological and pharmacological basis of memory and its pathogenesis is a timely question and they seem to be important neurobiological markers. 5-HT has been also implicated in diseases with memory disorders. Future works should clarify these memory dysfunctions, including delimitations.

Keywords

5-HT markers; 5-HT systems; learning; memory; dysfunctional memory

The identification of 5-HT₁ to 5-HT₇ receptor families and its transporter in mammalian species and drugs selective for these sites (Fink and Göthert, 2007; Hoyer et al., 1994) have allowed to dissect their participation in learning and memory (Dougherty and Oristaglio, 2013; King et al., 2008; Puig and Gulledge, 2011; Rodríguez et al., 2012; Terry et al., 2008). Importantly, some 5-HT drugs may present promnesic and/or antiamnesic effects (Table 2.1). Herein, it should be highlighted perhaps an important advantage of 5-HT is that it has diverse pharmacological and genetic tools, neurotoxins, receptor agonist and antagonists (see below), and a well-studied signaling an...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Dedication
• Acknowledgments
• Chapter 1. Introduction
• Chapter 2. 5-HT Systems and Neurobiological Markers Related to Memory Systems
• Chapter 3. 5-HT Pathways, Receptors and Transporter: Memory Functions and Dysfunctions
• Chapter 4. 5-HT1A Receptor
• Chapter 5. 5-HT1B Receptor
• Chapter 6. 5-HT1E/1F Receptor
• Chapter 7. 5-HT2A/2B/2C Receptor
• Chapter 8. 5-HT3 Receptor
• Chapter 9. 5-HT4 Receptor
• Chapter 10. 5-HT5 Receptor
• Chapter 11. 5-HT6 Receptor
• Chapter 12. 5-HT7 Receptor
• Conclusions
• References