Advances in Neurobiology

Dendritic spine features in human neurons follow the up-to-date knowledge presented in the previous chapters of this book. Human dendrites are notable for their heterogeneity in branching patterns and spatial distribution. These data relate to circuits and specialized functions. Spines enhance neuronal connectivity, modulate and integrate synaptic inputs, and provide additional plastic functions to microcircuits and large-scale networks. Spines present a continuum of shapes and sizes, whose number and distribution along the dendritic length are diverse in neurons and different areas...

Dendritic spines, key sites for neural plasticity, are influenced by gonadal steroids. In this chapter, we review the effects of gonadal steroids on dendritic spine density in areas important to cognitive function, the hippocampus, and prefrontal cortex. Most of these animal model studies investigated the effects of estrogen in females, but we also include more recent data on androgen effects in both males and females. The underlying genomic and non-genomic mechanisms related to gonadal steroid-induced spinogenesis are also reviewed...

The central nervous system is composed of neural ensembles, and their activity patterns are neural correlates of cognitive functions. Those ensembles are networks of neurons connected to each other by synapses. Most neurons integrate synaptic signal through a remarkable subcellular structure called spine. Dendritic spines are protrusions whose diverse shapes make them appear as a specific neuronal compartment, and they have been the focus of studies for more than a century. Soon after their first description by Ramón y Cajal, it has been hypothesized that spine morphological changes could modify neuronal connectivity and sustain cognitive abilities...

Glia comprise a heterogeneous group of cells involved in the structure and function of the central and peripheral nervous system. Glial cells are found from invertebrates to humans with morphological specializations related to the neural circuits in which they are embedded. Glial cells modulate neuronal functions, brain wiring and myelination, and information processing. For example, astrocytes send processes to the synaptic cleft, actively participate in the metabolism of neurotransmitters, and release gliotransmitters, whose multiple effects depend on the targeting cells...

Dendritic spines are highly dynamic structures that play important roles in neuronal plasticity. The morphologies and the numbers of dendritic spines are highly variable, and this diversity is correlated with the different morphological and physiological features of this neuronal compartment. Dendritic spines can change their morphology and number rapidly, allowing them to adapt to plastic changes. Neurotrophic factors play important roles in the brain during development. However, these factors are also necessary for a variety of processes in the postnatal brain...

Synaptic overproduction and elimination is a regular developmental event in the mammalian brain. In the cerebral cortex, synaptic overproduction is almost exclusively correlated with glutamatergic synapses located on dendritic spines. Therefore, analysis of changes in spine density on different parts of the dendritic tree in identified classes of principal neurons could provide insight into developmental reorganization of specific microcircuits.The activity-dependent stabilization and selective elimination of the initially overproduced synapses is a major mechanism for generating diversity of neural connections beyond their genetic determination...

For many years, synaptic transmission was considered as information transfer between presynaptic neuron and postsynaptic cell. At the synaptic level, it was thought that dendritic arbors were only receiving and integrating all information flow sent along to the soma, while axons were primarily responsible for point-to-point information transfer. However, it is important to highlight that dendritic spines play a crucial role as postsynaptic components in central nervous system (CNS) synapses, not only integrating and filtering signals to the soma but also facilitating diverse connections with axons from many different sources...

A tiny detail visible on certain neurons at the limit of resolution in light microscopy went in 130 years of neuroscience research through a dazzling career from suspicious staining artifact to what we recognize today as a complex postsynaptic molecular machine: the dendritic spine.This chapter deals with techniques to make spines visible. The original technique, Golgi silver staining, is still being used today. Electron microscopy and automated field ion beam scanning electron microscopy are ultrahigh resolution techniques, albeit specialized...

Dendritic spines are cellular specializations that greatly increase the connectivity of neurons and modulate the "weight" of most postsynaptic excitatory potentials. Spines are found in very diverse animal species providing neural networks with a high integrative and computational possibility and plasticity, enabling the perception of sensorial stimuli and the elaboration of a myriad of behavioral displays, including emotional processing, memory, and learning. Humans have trillions of spines in the cerebral cortex, and these spines in a continuum of shapes and sizes can integrate the features that differ our brain from other species...

In recent years, the number of studies implicating lipids in the regulation of synaptic vesicle exocytosis has risen considerably. It has become increasingly clear that lipids such as phosphoinositides, lysophospholipids, cholesterol, arachidonic acid and myristic acid play critical regulatory roles in the processes leading up to exocytosis. Lipids may affect membrane fusion reactions by altering the physical properties of the membrane, recruiting key regulatory proteins, concentrating proteins into exocytic "hotspots" or by modulating protein functions allosterically...

The synapse is a highly specialized asymmetric structure that transmits and stores information in the brain. The size of pre- and postsynaptic structures and function is well coordinated at the individual synapse level. For example, large postsynaptic dendritic spines have a larger postsynaptic density with higher α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) number on their surface, while juxtaposing presynaptic terminals have a larger active zone and higher release probability...

K+ channels play potent roles in the process of neurotransmitter release by influencing the action potential waveform and modulating neuronal excitability and release probability. These diverse effects of K+ channel activation are ensured by the wide variety of K+ channel genes and their differential expression in different cell types. Accordingly, a variety of K+ channels have been implicated in regulating neurotransmitter release, including the Ca2+ - and voltage-gated K+ channel Slo1 (also known as BK channel), voltage-gated K+ channels of the Kv3 (Shaw-type), Kv1 (Shaker-type), and Kv7 (KCNQ) families, G-protein-gated inwardly rectifying K+ (GIRK) channels, and SLO-2 (a Ca2+ -...

Ryanodine receptors (RyRs) are Ca2+ release channels located in the endoplasmic reticulum membrane. Presynaptic RyRs play important roles in neurotransmitter release and synaptic plasticity. Recent studies suggest that the proper function of presynaptic RyRs relies on several regulatory proteins, including aryl hydrocarbon receptor-interacting protein, calstabins, and presenilins. Dysfunctions of these regulatory proteins can greatly impact neurotransmitter release and synaptic plasticity by altering the function or expression of RyRs...

Neurotransmitter release is a spatially and temporally tightly regulated process, which requires assembly and disassembly of SNARE complexes to enable the exocytosis of transmitter-loaded synaptic vesicles (SVs) at presynaptic active zones (AZs). While the requirement for the core SNARE machinery is shared by most membrane fusion processes, SNARE-mediated fusion at AZs is uniquely regulated to allow very rapid Ca2+ -triggered SV exocytosis following action potential (AP) arrival. To enable a sub-millisecond time course of AP-triggered SV fusion, synapse-specific accessory SNARE-binding proteins are required in addition to the core fusion machinery...

Soluble NSF attachment protein receptor (SNARE) proteins play a central role in synaptic vesicle (SV) exocytosis. These proteins include the vesicle-associated SNARE protein (v-SNARE) synaptobrevin and the target membrane-associated SNARE proteins (t-SNAREs) syntaxin and SNAP-25. Together, these proteins drive membrane fusion between synaptic vesicles (SV) and the presynaptic plasma membrane to generate SV exocytosis. In the presynaptic active zone, various proteins may either enhance or inhibit SV exocytosis by acting on the SNAREs...

Neurotransmitters are released from synaptic and secretory vesicles following calcium-triggered fusion with the plasma membrane. These exocytotic events are driven by assembly of a ternary SNARE complex between the vesicle SNARE synaptobrevin and the plasma membrane-associated SNAREs syntaxin and SNAP-25. Proteins that affect SNARE complex assembly are therefore important regulators of synaptic strength. In this chapter, we review our current understanding of the roles played by two SNARE interacting proteins: UNC-13/Munc13 and UNC-18/Munc18...

Voltage-gated calcium channels (VGCCs), especially Cav 2.1 and Cav 2.2, are the major mediators of Ca2+ influx at the presynaptic membrane in response to neuron excitation, thereby exerting a predominant control on synaptic transmission. To guarantee the timely and precise release of neurotransmitters at synapses, the activity of presynaptic VGCCs is tightly regulated by a variety of factors, including auxiliary subunits, membrane potential, G protein-coupled receptors (GPCRs), calmodulin (CaM), Ca2+ -binding proteins (CaBP), protein kinases, various interacting proteins, alternative splicing events, and genetic variations...

Calcium ions (Ca2+ ) play a critical role in triggering neurotransmitter release. The rate of release is directly related to the concentration of Ca2+ at the presynaptic site, with a supralinear relationship. There are two main sources of Ca2+ that trigger synaptic vesicle fusion: influx through voltage-gated Ca2+ channels in the plasma membrane and release from the endoplasmic reticulum via ryanodine receptors. This chapter will cover the sources of Ca2+ at the presynaptic nerve terminal, the relationship between neurotransmitter release rate and Ca2+ concentration, and the mechanisms that achieve the necessary Ca2+ concentrations for triggering synaptic exocytosis at the presynaptic site...

Calcium (Ca2+ ) plays a critical role in triggering all three primary modes of neurotransmitter release (synchronous, asynchronous, and spontaneous). Synaptotagmin1, a protein with two C2 domains, is the first isoform of the synaptotagmin family that was identified and demonstrated as the primary Ca2+ sensor for synchronous neurotransmitter release. Other isoforms of the synaptotagmin family as well as other C2 proteins such as the double C2 domain protein family were found to act as Ca2+ sensors for different modes of neurotransmitter release...

Neurotransmitters are stored in small membrane-bound vesicles at synapses; a subset of synaptic vesicles is docked at release sites. Fusion of docked vesicles with the plasma membrane releases neurotransmitters. Membrane fusion at synapses, as well as all trafficking steps of the secretory pathway, is mediated by SNARE proteins. The SNAREs are the minimal fusion machinery. They zipper from N-termini to membrane-anchored C-termini to form a 4-helix bundle that forces the apposed membranes to fuse. At synapses, the SNAREs comprise a single helix from syntaxin and synaptobrevin; SNAP-25 contributes the other two helices to complete the bundle...