Neuronal Growth and Trophic Factors

Neural development requires the participation of growth factors that regulate neuronal determination, proliferation, migration, and differentiation. Molecular genetic approaches using Drosophila, as well as other creatures whose genetics is well understood, have provided insights into the mechanisms of action of some of these developmental factors. Other factors are soluble and are secreted by nearby cells or other neurons. These include neurotrophins such as NGF and BDNF, cytokines such as CNTF, as well as GDNF and steroid hormones. Current research aims to identify key growth factors required for producing different types of neurons, and different patterns of transcription factor activated by different combinations of these factors. This knowledge may eventually allow medical therapies to convert a stem cell into a sympathetic neuron, a motor neuron, or any one of the thousands of other types of neurons that make up a mature nervous system.

The Birth and Death of a Neuron

The development of the nervous system requires the participation of a variety of factors that influence neuronal determination, proliferation, migration, and differentiation. The earliest steps in the formation of a neuron involve the actions of factors such as the bone morphogenetic proteins and neural inducers. Acting on cells that still have the potential to develop into many different types of cells, these factors control the synthesis of transcription factors and determine whether the complement of genes that becomes activated corresponds to those required for building a neuron. The birth of new neurons occurs at a high rate early in development, but in some brain regions persists in adults. The normal formation of the nervous system also requires the programmed death of many neurons. Decisions as to whether a specific neuron survives or perishes during development are made by factors that control the permeability of the outer mitochondrial membrane.

How Neurons Communicate: Gap Junctions and Neurosecretion

Two ways that neurons communicate with one another are by direct electrical coupling and by the secretion of neurotransmitters. Electrical coupling arises from the existence of proteins, known as connexins, that form pores linking the cytoplasm of adjacent cells. Ions and small molecules can carry signals from one cell to another through these pores. Neurosecretion is a more complex process whereby different categories of molecules are sorted into cytoplasmic vesicles. Chemical processes within these vesicles ensure that they contain biologically active transmitters or hormones. SNARE complex proteins cooperate with other proteins to allow synaptic vesicles containing neurotransmitter to release their components into the external medium following calcium entry into nerve terminals. Such exocytosis of synaptic vesicles can be monitored with imaging techniques using fluorescent dyes or proteins, or by capacitance measurements. A second set of molecules retrieves the membrane of synaptic vesicles back from the plasma membrane through endocytosis.

Form and Function in Cells of the Brain

This chapter examines unique mechanisms that the neuron has evolved to establish and maintain the form required for its specialized signaling functions. Unlike some other organs, the brain contains a variety of cell types including several classes of glial cells, which play a critical role in the formation of the myelin sheath around axons and may be involved in immune responses, synaptic transmission, and long-distance calcium signaling in the brain. Neurons share many features in common with other cells (including glia), but they are distinguished by their highly asymmetrical shapes. The neuronal cytoskeleton is essential for establishing this cell shape during development and for maintaining it in adulthood. The process of axonal transport moves vesicles and other organelles to regions remote from the neuronal cell body. Proteins such as kinesin and dynein, called molecular motors, make use of the energy released by hydrolysis of ATP to drive axonal transport.

Learning and Memory

Psychologists have described different kinds of learning and memory, and there is an ongoing search for the physical basis of these distinctions and for the cellular and molecular mechanisms responsible. Because of the complexity of most nervous systems, the search has focused to a large extent on animals with relatively simple nervous systems and on reduced preparations. Common themes have emerged, such as the requirement for signaling pathways linked to calcium and cyclic AMP, and the fact that pathways used in normal development continue to be used for plasticity in adults. At the same time, it is clear that there is an enormous diversity of cellular mechanisms that contribute to short-term and long-term phases of memory formation. These include long-term potentiation (LTP), long-term depression (LTD), spike-timing dependent plasticity, synaptic tagging, and synaptic scaling. Each type of synaptic connection has its own personality such that, in response to a particular pattern of stimulation, one synapse may increase its postsynaptic receptors while another may expand its presynaptic terminals.

Membrane Ion Channels and Ion Currents

Electrical activity in neurons (and other kinds of cells) results from the movement of ions across the plasma membrane through specialized membrane proteins known as ion channels. Exquisitely sensitive patch clamp techniques are available to measure the current passing through single ion channels, as well as the macroscopic membrane current carried by a population of ion channels. These techniques have enabled the detailed characterization of various essential properties of ion channels, including their selectivity for particular ions, their pharmacology, and the way their activity is regulated by membrane voltage and other factors. There are many different kinds of ion channels in the neuronal plasma membrane, and their activities sum to generate action potentials and complex patterns of action potential firing.

Intrinsic Neuronal Properties, Neural Networks, and Behavior

Complex interactions among large numbers of neurons are required to generate most behaviors. Studies in biological model systems—such as the stomatogastric ganglion of lobsters and crabs, and neurons controlling reproduction in Aplysia—have provided insights into how the intrinsic electrical properties of neurons shape network activity and animal behavior. Some neurons can participate simultaneously in more than a single network, and the properties of a network may be modulated by the actions of neurotransmitters and hormones. Changes in the intrinsic excitability of a single command neuron or command systems of neurons can trigger a complicated and long-lasting behavior. Cellular mechanisms that regulate the accuracy of timing of action potentials, both within a network and in different parts of a dendritic tree, are also important for the interpretation of sensory information and for the ability of a neuron to modify the strength of the connections it makes with other neurons.

Formation, Maintenance, and Plasticity of Chemical Synapses

When developing axons reach their appropriate postsynaptic target, they stop elongating. A series of characteristic morphological and biochemical changes, culminating in synapse formation, then occur. Among the cues used by an excitatory neuron in choosing its correct postsynaptic partner are chemical labels such as Ephrins and Eph receptors. Not all synapses that form during development persist in adult animals. Certain synapses are selectively stabilized; others are lost. In many cases such rearrangements follow a Hebbian rule, whereby excitatory synapses are stabilized when they trigger postsynaptic action potentials. Such reorganization of connections is therefore regulated by patterns of electrical activity and involves the coordinated activity of metalloproteases, NMDA receptors, and the secretion of factors such BDNF. Other agents involved include agrin, rapsyn, the immediate early genes fos and Arg, and the fragile X mental retardation protein (FMRP). Much information on factors that regulate the clustering of postsynaptic receptors and the way that postsynaptic sites come to be linked to presynaptic terminals has come from studies of molecules at the neuromuscular junction.

Adhesion Molecules and Axon Pathfinding

Developing neurons extend neurites, which become the axons and dendrites of the adult neuron. These neurites follow specific paths and branch in characteristic ways. The leading tip of the neurite, the growth cone, appears to sample the extracellular environment and contribute to decisions about the direction of extension. Various molecules are essential for appropriate pathfinding by growing neurites. For example, neurites grow selectively toward or away from guidance molecules such as semaphorins, netrins, slits, and ephrins. In addition, adhesion molecules such as fibronectin and laminin mediate specific adhesion of the neurite to the substrate over which it is growing, while CAMs and cadherins promote the adhesion of neurites of different cells to each other in specific patterns. Some molecules and mechanisms that regulate neuronal development and differentiation may also regulate neurite outgrowth in adult nervous systems, either during recovery from injury or in response to novel stimuli from the environment.

Receptors and Transduction Mechanisms II: Indirectly Coupled Receptor/Ion Channel Systems

Extracellular signals must be recognized by the target cell and transduced into an appropriate biological response. Signal recognition is accomplished by the specific membrane receptors that are coupled to different kinds of transduction mechanisms, which in nerve cells often regulate the activity of ion channels. The purpose of diversity in the categories of receptor-channel coupling may be to provide a wide temporal range in the responses of neurons to neurotransmitters, hormones, and sensory stimuli. Diversity also exists within the category of second messenger–mediated receptor-channel coupling. At first glance, many second messenger systems appear to bear little relationship to one another. However, several share a common final mechanism of action on response systems, namely protein phosphorylation via one of several second messenger–dependent protein kinases. Modulation of neuronal excitability by protein phosphorylation often involves direct phosphorylation of the ion channel protein itself or of some closely associated regulatory component.