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This chapter discusses the actions of gonadal hormones on synaptic plasticity and cellular replacement, and the potential mechanisms involved in the hormonal actions. It begins by examining the actions of ovarian hormones—estradiol and progesterone— on neural plasticity, followed by an analysis of the effects of testicular androgens. The neuroplastic effects of the adrenal androgen dehydroepiandrosterone (DHEA) are also considered when analyzing the effects of testicular androgens.

Activity-dependent, long-lasting synaptic enhancement induced by neuronal stimulation, known as long-term potentiation (LTP), is not unique to the hippocampus; rather, it seems to be a fundamental proper of most of the excitatory synapses in the brain. Furthermore, depending on activity patterns, synaptic modification may also result in long-term depression (LTD) of synaptic efficacy. Attempts to elucidate mechanisms underlying synaptic plasticity have been furthered by the observation that these can also be elicited in vitro preparations, including acute brain slices and cultured neurons. LTP and LTD have the ability to increase or decrease synaptic transmission for extended periods and thereby encode change into the central nervous system. These processes are often considered synaptic analogues of learning and memory, and therefore they are of fundamental importance to the understanding of these and related cognitive functions. This chapter focuses on the mechanisms of LTP and LTD, along with developmental plasticity, trophic effects of excitatory amino acids, and role of NMDA receptors in LTP and LTD.

This chapter reviews current understanding of how dopamine (DA) might modulate glutamatergic synaptic plasticity in mesolimbic brain regions. This topic is examined in the context of in vitro brain slice experiments and plasticity induction in the anesthetized animal. The possibility that DA modulation of glutamatergic signaling could occur in the awake animal and contribute to the expression of motivated behavior is discussed.

This chapter begins with a discussion of experimental models of neuronal plasticity. It then discusses temporal phases of synaptic plasticity, Ca²⁺ as the trigger that activates the intracellular processes contributing to neuronal plasticity; rapid, transient plasticity; and slower, sustained plasticity.

Activity-dependent modifications of synaptic efficacy are essential both for the developmental organization of the brain and for the storage of information. It is now well established that the pattern of synaptic activation helps direct whether a synapse is strengthened or weakened. For example, in many regions of the brain, high-frequency stimulation (HFS) of afferents results in a long-term potentiation (LTP) of synaptic efficacy, while low-frequency stimulation (LFS) frequently yields long-term depression (LTD) of synaptic strength. However, the direction and degree of this synaptic plasticity is governed by more than simply the pattern of synaptic activation and the, initial synaptic efficacy; prior synaptic activity can shape subsequent use-dependent synaptic modifications. Thus, the plasticity of synapses varies as a function of their activation history. This modulation of synaptic plasticity has been termed ‘metaplasticity’, and accumulating evidence suggests that this phenomenon is a ubiquitous property of the brain, not only in mammals, but in primitive vertebrates and invertebrates as well.

This chapter summarizes experiments and theory that are relevant to the role of dendrites in plasticity. Since the vast majority of synapses form connections onto the dendritic arbor of a neuron, synaptic plasticity is fundamentally a dendritic phenomenon. Dendrites integrate incoming information to elicit local dendritic spikes that help trigger plasticity mechanisms. However, synapses far from the soma may be relatively more isolated from axonally initiated action potentials, which are important—although not always required—for long-term synaptic plasticity. As the excitability of dendritic arbors is itself plastic, synaptic plasticity must be coordinated with dendritic plasticity for the control of neuronal computations and neural circuit functions.

Most synapses are made onto dendrites, and most excitatory connections are made onto dendritic spines. Synaptic plasticity is thus an intrinsically dendritic phenomenon, but the functional significance of the structural, electrical, and molecular properties of dendrites for synaptic plasticity is still very poorly understood. Do dendrites have a computational or cell biological role in the modification of synaptic strength that is more than circumstantial? This chapter aims to summarize experimental data and theoretical considerations that may be relevant to the role of dendrites in synaptic plasticity. The focus is on associative Hebbian synaptic plasticity, including spike-timing-dependent forms, mediated by NMDA receptor activation.

Wilfrid Rall developed the theoretical foundations for understanding dendritic function almost fifty years ago. Since then his theory has been intensely employed and extended in order to explore the biophysical principles that link together the structure, physiology, and function of dendrites. This chapter highlights some of the main insights that were gained from this theory, specifically emphasizing the relationship between the local activation of a synapse on a dendrite and the overall synaptic activity in the neuron. It discusses the contribution of a single synapse out of numerous active synapses to a neuron's firing pattern and describes a new measure to quantify the efficacy of a single synapse, using tools borrowed from information theory. It reviews the local and global aspects of the electrical activity in dendrites, and explores the effect of local versus global mechanisms of a specific form of synaptic plasticity, homeostatic synaptic plasticity.

Functional synaptic plasticity is a relatively longlasting alteration in the efficiency of synaptic transmission. In biophysical terms, the efficiency of synaptic transmission is determined by two parameters: how much transmitter is released from presynaptic terminals, and what size of postsynaptic response is produced per unit amount of transmitter. Consequently, plastic changes at synapses must be associated with changes in either one or both parameters. The principal questions concern how these changes are induced (acquisition or learning) and maintained (retention or memory). Depending on how long these changes persist, plasticity can be divided into short-term (minutes to hours) and long-term (days to years) alterations. This chapter first focuses on relatively straightforward forms of plastic changes and sees what substrates are involved. For this purpose, the chapter begins with short-term plasticity at the level of peripheral synapses.

Understanding the neurobiology of sensory synapses in the central nervous system provides us with basic knowledge of physiological and pathological pain, and has the potential to reveal possible drug targets for treating chronic pain. Pain-related synapses are found not only in the spinal cord dorsal horn, but also in many cortical areas. More importantly, recent evidence suggests that injury causing chronic pain also triggers long-term plastic changes in sensory synapses, including those in the spinal dorsal horn and frontal cortex. Changes in synaptic plasticity are not just limited in excitatory glutamatergic synapses but are also found in inhibitory synapses. This chapter reviews recent progress in these areas, in particular, integrative physiological investigations of chronic pain. Pain can be divided into two groups: physiological pain and pathological pain. This chapter also discusses peripheral nerves and dorsal root ganglion cells, plastic molecular targets for chronic pain, long-term potentiation in the anterior cingulate cortex, synaptic transmission at the spinal cord dorsal horn, and the role of cortical regions in pain perception.

Many computational models of neural circuits treat neurons as ‘integrate and fire’ devices that linearly sum excitatory and inhibitory inputs and fire an action potential when they pass threshold. While some aspects of neural computation can be successfully captured in this way, these models ignore a rich palette of intrinsic cellular properties that play important roles in generating the output of biological neural circuits. Neurons that fire bursts of action potentials intrinsically, for example, are present in various regions of the central nervous system (CNS), including the spinal cord, the thalamus, and the cortex. The role of such intrinsic bursting in generating rhythmic motor outputs in invertebrates and in spinal locomotor networks is well understood, but ideas about the function of complex intrinsic cellular properties are still largely speculative in many other systems. Nonetheless it is clear that most neurons possess a complex array of ion channels that produce conductances which help shape the response of the neuron to synaptic inputs, influence synaptic plasticity, and bestow very non-linear response properties upon the neurons in which they are expressed. These voltage-dependent conductances can interact in complex ways.

This chapter reviews some of the progress toward a full characterization of one particular form of synaptic plasticity observed in the mammalian brain called long-term potentiation (LTP). LTP is only a laboratory phenomenon. Nevertheless, its mechanisms are now quite well understood, it can be induced in many brain structures that are involved in memory, and there is substantial evidence that the same cellular mechanisms that mediate LTP are required for lasting memory. The chapter reviews the state of our understanding of this important phenomenon as a likely candidate for memory coding in mammalian systems.

The plasticity of the adult nervous system allows it to learn new things and remember them, to adapt to change and to recover from injury. This chapter describes a developmental approach to tackle the technical problem faced in identifying molecular changes underlying plasticity based on the premise that the maturational events of normal brain development offer an experimental model for the study of synaptic plasticity. The many events involved in normal synaptogenesis can be divided into two broad phases: synapse formation and synapse maturation. The postsynaptic density is a protein-rich specialization on the cytoplasmic surface of the postsynaptic membrane at most synapses, irrespective of neurotransmitter type. There is clear evidence from biochemical and morphological studies that, in the forebrain as a whole, synapse formation is still occurring rapidly at hatching and is not complete until about 1–2 weeks post-hatch.

This chapter examines the neuromolecular and plastic brain. Ideas about plasticity and the openness of brains to environment influences, from initial evidence about nerve development, through the recognition that synaptic plasticity was the very basis of learning and memory, to evidence about the influence of environment on gene expression and the persistence throughout life of the capacity to make new neurons—all this made the neuromolecular brain seem exquisitely open to its milieu, with changes at the molecular level occurring throughout the course of a human life and thus shaping the growth, organization, and regeneration of neurons and neuronal circuits at time scales from the millisecond to the decade. This was an opportunity to explore the myriad ways in which the milieu got “under the skin,” implying an openness of these molecular processes of the brain to biography, sociality, and culture, and hence perhaps even to history and politics.

It is well established that a subset of proteins can be translated in dendrites independently of the cell soma. Recent studies have begun to elucidate the dynamic regulation and functional consequences of this local protein synthesis. In addition to more detailed analyses of mRNA localization, translation, and trafficking in dendrites, new research highlights possible roles of local translation in synaptic plasticity, suggesting a critical role for local translation in neuronal activity.

This chapter summarizes the molecular organization of the PSD of neurons in the mammalian central nervous system (CNS), with a specific emphasis on the regulation of ionotropic glutamate receptors (GluRs) in development and plasticity. Various studies have revealed hundreds of molecules associated with the PSD, suggesting daunting complexity in its functional organization. Nonetheless, several approaches have revealed a laminar scaffolding arrangement within the PSD responsible for organizing functionally coupled synaptic proteins. Furthermore, these scaffolding components play a central role in linking the molecular machinery that is responsible for the dynamic regulation of neurotransmission in development and synaptic plasticity, and as such are critically involved in learning and memory.

The morphology and molecular composition of synapses provide the basis of communication between neurons. Synapses are highly ordered, having developed structural and molecular specializations at their pre- and postsynaptic sites. At excitatory synapses, presynaptic sites of communication are faithfully juxtaposed to the postsynaptic density (PSD), an organized micro-compartment housed beneath the postsynaptic membrane. This largely invariant association suggests that the PSD is tightly coupled to synaptic function, allowing the pre-and postsynapse to form a cohesive unit. The PSD comprises several hundred proteins, including receptors, cytoskeletal, scaffolding, and signal transduction components. The organization of the PSD plays a central role in linking the molecular machinery responsible for neurotransmission to synaptic plasticity. This chapter details the structural organization of the PSD, with a particular emphasis on how its molecular constituents influence the structure and function of glutamatergic synapses.

The molecular composition of the excitatory synapses is far from static. Indeed, changes in the localization and density of excitatory amino acid receptors are now recognized as an essential mechanism through which synaptic strength can be modified and regulated. Receptor trafficking refers not only to the movement of proteins from the endoplasmic reticulum to the synaptic membranes, but also to the internalization of these proteins, as well as their lateral movement to and from extrasynaptic locales. In the last few years, there has been an explosion of interest and new information on the trafficking of α-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionate (AMPA) receptors and the relevance of these processes to synaptic plasticity. This chapter discusses the trafficking of AMPA receptors, kainate receptors, NMDA receptors, and metabotropic glutamate receptors.