Spines are protrusions on the dendritic shafts of neurons and are the site of a large number of axonal contacts. The use of the silver impregnation techniques of Golgi or of the methylene blue used by Ehrlich in the late 19th century led to the discovery of spiny appendages on dendrites of a variety of neurons. The best known are those on pyramidal neurons and Purkinje cells, although spines occur on neuron types at all levels of the central nervous system. In 1896 Berkley observed that terminal boutons were closely apposed on spines (a fact that was later confirmed by Gray (1959) using electron microscopy) and suggested that spines may be involved in conducting impulses from neuron to neuron. In 1904, Santiago Ramón y Cajal suggested that spines could collect the electrical charge resulting from neuronal activity (Ramón y Cajal, 1955). He also noted that spines substantially increase the receptive surface of the dendritic arbor, which may represent an important factor in receiving the contacts made by the axonal terminals of other neurons. It has been calculated that the approximately 4000 spines of a pyramidal neuron account for more than 40% of its total surface area (Peters et al., 1991).

More recent analyses of spine electrical properties have demonstrated that spines are dynamic structures that can regulate many neurochemical events related to synaptic transmission and modulate synaptic efficacy (Coss et al., 1985) (see also Chapter 18). Spines are also known to undergo pathological alterations and have a reduced density in a number of experimental manipulations (such as deprivation of a sensory input) and in many developmental, neurological, and psychiatric conditions (such as dementing illnesses, chronic alcoholism, schizophrenia, and trisomy 21) (Scheibel and Scheibel, 1968). Morphologically, spines are characterized by a narrow portion emanating from the dendritic shaft, the neck, and an ovoid bulb or head. Spines have an average length of 2 ^m despite considerable variability in morphology. At the ultrastructural level (Fig. 1.3), spines are characterized by the presence of asymmetric synapses and a few vesicles and contain fine and quite indistinct filaments. These filaments most likely consist of actin and a- and p-tubulins. The microtubules and neurofilaments present in the dendritic shafts do not penetrate the spines. Mitochondria and free ribosomes are infrequent, although many spines contain polyribo-somes in their head and neck. Interestingly, most polyri-bosomes in dendrites are located at the bases of spines, where they are associated with endoplasmic reticulum, indicating that spines possess the machinery necessary for the local synthesis of proteins (Steward and Falk, 1986).

Another classic feature of the spine is the presence in the spine head of confluent tubular cisterns that represent an extension of the dendritic smooth endoplasmic reticulum. Those cisterns are referred to as the spine apparatus. The function of the spine apparatus is not fully understood but may be related to storage of calcium ions during synaptic transmission. For additional reviews on spines, see Zhang and Benson (2000) and Nimchinsky et al. (2002).

of neurofilaments than do dendrites, although this distinction can be difficult to make in small elements that contain fewer neurofilaments. In addition, the axon may be extremely ramified, as in certain local-circuit neurons; it may give out a large number of recurrent collaterals, as in neurons connecting different cortical regions; or it may be relatively straight in the case of projections to subcortical centers, as in cortical motor neurons that send their very long axons to the ventral horn of the spinal cord. At the interface of axon terminals with target cells are the synapses, which represent specialized zones of contact consisting of a presynaptic (axonal) element, a narrow synaptic cleft, and a postsynaptic element on a den-drite or perikaryon. We consider the fine structure of synapses later in this chapter. In the next section, we turn our attention to the principal morphological features of several neuronal types from the cerebral cortex, subcortical structures, and periphery as typical examples of the cellular diversity in the nervous system.

Pyramidal Cells Are the Main Excitatory Neurons in the Cerebral Cortex

All of the cortical output is mediated through pyramidal neurons, and the intrinsic activity of the neo-cortex can be viewed simply as a means of finely tuning their output. A pyramidal cell is a highly polarized neuron, with a major orientation axis per

FIGURE 1.3 Ultrastructure of a single dendritic spine (Sp). Note the narrow neck emanating from the main dendritic shaft (DS) and the spine head containing filamentous material, the cisterns of the spine apparatus, and the postsynaptic density of an asymmetric synapse (arrows). AT, axon terminal.

Dendritic Spine Ultrastructure

FIGURE 1.3 Ultrastructure of a single dendritic spine (Sp). Note the narrow neck emanating from the main dendritic shaft (DS) and the spine head containing filamentous material, the cisterns of the spine apparatus, and the postsynaptic density of an asymmetric synapse (arrows). AT, axon terminal.

pendicular (or orthogonal) to the pial surface of the cerebral cortex. In cross section, the cell body is roughly triangular (Fig. 1.2), although a large variety of morphological types exist with elongate, horizontal, or vertical fusiform or inverted perikaryal shapes. A pyramidal neuron typically has a large number of dendrites that emanate from the apex and form the base of the cell body. The span of the dendritic tree depends on the laminar localization of the cell body, but it may, as in giant pyramidal neurons, spread over several millimeters. The cell body and dendritic arborization may be restricted to a few layers or, in some cases, may span the entire cortical thickness (Jones, 1984).

In most cases, the axon of a large pyramidal cell extends from the base of the perikaryon and courses toward the subcortical white matter, giving off several collateral branches that are directed to cortical domains generally located within the vicinity of the cell of origin (as explained later in this section). Typically, a pyramidal cell has a large nucleus, a cyto-plasmic rim that contains, particularly in large pyra midal cells, a collection of granular material chiefly composed of lipofuscin. The deposition of lipofuscin increases with age and is considered a benign change. Although all pyramidal cells possess these general features, they can also be subdivided into numerous classes based on their morphology, laminar location, and connectivity (Fig. 1.4) (Jones, 1975). For instance, small pyramidal neurons in layers II and III of the neo-cortex have restricted dendritic trees and form vast arrays of axonal collaterals with neighboring cortical domains, whereas medium-to-large pyramidal cells in deep layer III and layer V have much more extensive dendritic trees and furnish long corticocortical connections. Layer V also contains very large pyramidal neurons arranged in clusters or as isolated, somewhat regularly spaced elements. These neurons project to subcortical centers such as the basal ganglia, brain-stem, and spinal cord. Finally, layer VI pyramidal cells exhibit a greater morphological variability than do pyramidal cells in other layers and are involved in certain corticocortical as well as corticothalamic projections (Feldman, 1984; Hof et al., 1995a,b).

Pyramidal Cell Array

Callosal Corticocortical


Thalamus Spinal cord Corticocortical Pons Claustrum Medulla (Callosal) Tectum

Thalamus Red nucleus Striatum (Cortical)

Callosal Corticocortical


Thalamus Spinal cord Corticocortical Pons Claustrum Medulla (Callosal) Tectum

Thalamus Red nucleus Striatum (Cortical)

FIGURE 1.4 Morphology and distribution of neocortical pyramidal neurons. Note the variability in cell size and dendritic arborization as well as the presence of axon collaterals, depending on the laminar localization (I-VI) of the neuron. Also, different types of pyramidal neurons with a precise laminar distribution project to different regions of the brain. Adapted with permission, from Jones (1984).

The excitatory inputs to pyramidal neurons can be divided into intrinsic afferents, such as recurrent collaterals from other pyramidal cells and excitatory interneurons, and extrinsic afferents of thalamic and cortical origin. The neurotransmitters in these excitatory inputs are thought to be glutamate and possibly aspartate. Although this division may appear relatively simplistic, the complexity and heterogeneity of excitatory transmission in the neocortex may not be derived from the presynaptic side, but rather from the postsynaptic side of the synapse. In other words, at the molecular level, a variety of glutamate receptor subunit combinations may confer different functional capacities on a given glutamatergic synapse (see Chapter 11).

Pyramidal cells not only furnish the major excitatory output of the neocortex, but also act as a major intrinsic excitatory input through axonal collaterals. The collaterals of the main axonal branch that exits from the cortex are referred to as recurrent collaterals because they ascend back to superficial layers; thus, the collateral branches of a pyramidal cell synapse in layers superficial to their origin, although a deep or local system of branches is also present (see Fig. 1.4). Although many of these branches ascend in a radial, vertical pattern of arborization, there are a separate set of projections that travel horizontally over long distances (in some instances as much as 7-8 mm). One of the major functions of the vertically oriented component of the recurrent collaterals may be to interconnect layers III and V, the two major output layers of the neocortex. In layer III pyramidal cells, 95% of the synaptic targets of the recurrent cells are other pyramidal cells. This is true of both the vertical and the distant horizontal recurrent projections. In addition, the majority of these synapses are on dendritic spines and, to some degree, on dendritic shafts. It is possible that there are regional and laminar specificities to these synaptic arrangements, although such fine patterns are not yet fully elucidated (Schmitt et al., 1981; Szentagothai and Arbib, 1974; Lund et al, 1995; Kisvarday et al., 1986a,b). These recurrent projections function to set up local excitatory patterns and coordinate multineuronal assemblies into an excitatory output.

Spiny Stellate Cells Are Excitatory Interneurons

The other major excitatory input to pyramidal cells of cortical origin is provided by the interneuron class referred to as spiny stellate cells, small multipolar neurons with local dendritic and axonal arborizations. These neurons resemble pyramidal cells in that they are the only other cortical neurons with large numbers of dendritic spines, but they differ from pyramidal neurons in that they lack an apical den-drite. Although the dendritic arbor of these neurons tends to be local, it can vary from a primarily radial orientation to one that is more horizontal. The relatively restricted dendritic arbor of these neurons is presumably a manifestation of the fact that they are high-resolution neurons that gather afferents to a very restricted region of cortex. The dendrites rarely leave the layer in which the cell body resides. The spiny stellate cell also resembles the pyramidal cell in that it provides asymmetric synapses that are presumed to be excitatory, and, like pyramidal cells, these neurons are thought to use either glutamate or aspartate as their neurotransmitter.

Spiny stellate cells exhibit extensive regional and laminar specificities in their distribution. Spiny stellate cells are found in highest concentration in layers IVC and IVA of the primary visual cortex, where they constitute the predominant neuronal type. They are also found in large numbers in layer IV of other

FIGURE 1.5 Drawing of Golgi-impregnated spiny stellate neurons in layer IV of the primary somatosensory cortex. The insets show the cortical localization of each neuron. Coarse branches represent the dendrites and fine branches represent the axonal plexus. Note that the axon is organized vertically. Adapted with permission, from Jones (1975).

primary sensory areas. However, several cortical regions have relatively few of these neurons, and even in areas in which these neurons are well represented, they are vastly outnumbered by aspiny interneurons (Peters and Jones, 1984; Lund et al., 1995).

The axons of spiny stellate neurons are primarily intrinsic in their targets and radial in orientation and appear to play an important role in forming links between layer IV, the major thalamorecipient layer, and layers III, V, and VI, the major projection layers (Fig. 1.5). In some respects, the axonal arbor of spiny stellate cells mirrors the vertical plexuses of recurrent collaterals; however, they are more restricted than recurrent collaterals. Given its axonal distribution, the spiny stellate neuron appears to function as a high-fidelity translator of thalamic inputs, maintaining strict topographic organization and setting up initial vertical links of information transfer within sensory areas. Presumably, both pyramidal cells and aspiny nonpyramidal cells receive these radially limited inputs of the spiny stellate neuron, suggesting that this interneuron plays a key role in setting up the excitatory component of a functional cortical domain (Peters and Jones, 1984).

Basket, Chandelier, and Double Bouquet Cells Are Inhibitory Interneurons

A large variety of inhibitory interneuron types are present in the cerebral cortex and in subcortical structures. These neurons contain the inhibitory neuro-transmitter 7-aminobutyric acid (GABA) and exert strong local inhibitory effects. Three major subtypes of cortical interneurons are discussed in this section as examples. In all three cases, the dendritic and axonal arborizations offer important clues to their role in the regulation of pyramidal cell function (Cobb et al., 1995; Sik et al., 1995). In addition, for several GABAergic interneurons, a subtype of a given morphological class can be further defined by a particular set of neurochemical characteristics (Somogyi et al., 1984). Although the following examples are taken from neurons prevalent in the neocortex and hippocampus of primates, inhibitory interneurons are present throughout the cerebral gray matter and exhibit a rich variety of morphologies, depending on the brain region as well as on the species studied (see Freund and Buzsaki, 1996).

Basket Cells

This class of GABAergic interneurons takes its name from the fact that its axonal endings form a basket of terminals surrounding a pyramidal cell soma (see Fig. 1.6) (Somogyi et al., 1983). Basket cells can be divided into large and small cells. This cell class provides most of the inhibitory GABAergic synapses to the somas and proximal dendrites of pyramidal cells, although the basket cells also synapse on the shaft of the apical dendrite. One basket cell may contact numerous pyramidal cells, and, in turn, several basket cells can contribute to the pericellular basket of one pyramidal cell. The basket cells have relatively large somas and multipolar morphology, with dendrites extending in all directions for several hundred micrometers such that the vertically oriented dendrites cross several layers. The axonal pattern is the defining characteristic of this cell. The axon rises vertically, quickly bifurcates, and travels long distances (1-2 mm), forming multiple pericellu-lar arrays as it spreads horizontally. The basket cells predominate in layers III and V in the neocortex and preferentially innervate the pyramidal cells within these layers, although they do not synapse exclusively on pyramidal cells. They are also numerous amid pyramidal neurons in the hippocampus. Thus, the basket cell is the primary source of horizontally

Fewer Spines The Hippocampus

FIGURE 1.6 Drawing of a Golgi-impregnated basket cell from layer IVA of the primary visual cortex. Note the widely ramified dendritic tree and the wide horizontal spread of the axon that makes contact with many local neuronal perikarya. Cortical layers are indicated by Roman numerals. Adapted with permission, from Somogyi et al. (1983).

FIGURE 1.6 Drawing of a Golgi-impregnated basket cell from layer IVA of the primary visual cortex. Note the widely ramified dendritic tree and the wide horizontal spread of the axon that makes contact with many local neuronal perikarya. Cortical layers are indicated by Roman numerals. Adapted with permission, from Somogyi et al. (1983).

directed inhibitory inputs to the soma, proximal dendrites, and apical shaft of a pyramidal neuron. Interestingly, these cells are also characterized by certain biochemical features in that the majority of them contain the calcium-binding protein parvalbu-min, and cholecystokinin appears to be the most likely neuropeptide in the large basket cells.

Chandelier Cells

The chandelier cell generally has a bitufted or multipolar dendritic tree, but the dendritic tree of this neuron is quite variable (Fig. 1.7) (Freund et al, 1983). The defining characteristic of this cell class is the very striking appearance of its axonal endings. In Golgi or immunohistochemical preparations, the axon terminals appear as vertically oriented "cartridges," each consisting of a series of axonal boutons, or swellings, linked together by thin connecting pieces. These axonal specializations look like old-style chandeliers, which explains why this cell type is so named. The most salient characteristic of the chandelier cell is the extraordinary specificity of its synaptic target. These

FIGURE 1.7 Drawing of an axoaxonic chandelier neuron from layer II of the primary visual cortex. The dendritic spread of this neuron is quite limited. Note the typical axon terminal specializations (arrow). Adapted, from Freund et al. (1983).

neurons synapse exclusively on the axon initial segment of pyramidal cells. This characteristic is responsible for their alternate name, axoaxonic cells (Somogyi et al., 1982). Most of the chandelier cells are located in layer III, and their primary target appears to be layer III pyramidal cells, although they also synapse to a lesser extent on pyramidal cells in the

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