Chapter 1/Cytology and Organization of Cell Types 13 -loum 7p四 7. Dendrites labeled with antibodies to microtubule-associated protein (MAP)2. The technique of immunocytochemistry antibodies to localize specific proteins in neurons. These antibodies are detected by secondary antibodies tagged with an enzyme or gold particle. (A)The enzyme, such as peroxidase, catalyzes a reaction that results in an electron-dense precipitate. a seen in the light micrograph, in which antibodies to MAP 2 label the dendritic tree (arrowheads) of a Purkinje cell. B)Alternatively, the secondary antibody can be tagged with gold particles, seen as black dots in the electron micrograph, in which they localize MAP 2 to microtubules(arrowheads) and cross-bridges(arrows)between them. Pu, Purkinje cell; b, basket cell( Part A is reprinted from Bernhardt R, Matus A J Comp Neurol 1984; 226: 207, with permission of Wiley-Liss, a division of ohn Wiley Sons, Inc, New York 3.2. 4. CYTOSKELETAL-BASED TRANSPORT SYSTEM 8 mm/day, respectively. The fast component carries OF NEURONS membranous vesicles, and the slow compartment Neuronal processes span great distances to reach carries cytoskeletal proteins Fast transport involves movement of vesicles along be meters away from the cell body in large organ- tracks composed of microtubules. Microtubule motors isms Neuropeptides synthesized and packaged in the generate the force required to propel organelles along perikaryon must embark on long journeys to far the path. Two of these motors, kinesin and dynein,are removed nerve terminals. Although some synaptic ATPases that are activated on binding to the micro- components can be synthesized and recycled locally, of the microtubule and dynein toward the minus end returned there for degradation by lysosomes, for In axons, most microtubules have their positive end from these remote areas requires active mechanisms direction. In dendrites. about half of the microtubules because diffusion alone would take an inordinate are oriented with their plus ends toward the dendritic amount of time. Bidirectional traffic in axons deli- tip, and the other half have their minus ends toward the vers proteins and organelles to and from the nerve tip Ditferences in microtubule orientation in axons terminal by anterograde and retrograde transport, and dendrites may be one of the mechanisms under- respectively. Anterograde transport delivers neuro lying the selective transport of organelles into dendrites peptide-containing vesicles and cytoskeletal pro- or axons teins; retrograde transport returns endocytotic and other vesicles. Axonal transport has two compo 4. NEURONAL SYNAPSES nents: a fast component, traveling at rates of 200 to 400 mm/day, and a slow component, which consists Electrical signals can be conveyed directly from cell of a slow component a(SCa)and a slow component to cell at special sites called gap junctions( Fig 8) Ions b(SCb), moving at rates of 0. 2 to l mm/day and 2 to pass from one cell to another through relatively large
3.2.4. CYTOSKELETAL-BASED TRANSPORT SYSTEM OF NEURONS Neuronal processes span great distances to reach their presynaptic and postsynaptic targets, which can be meters away from the cell body in large organisms. Neuropeptides synthesized and packaged in the perikaryon must embark on long journeys to farremoved nerve terminals. Although some synaptic components can be synthesized and recycled locally, others must be imported from the cell body or returned there for degradation by lysosomes, for example. Molecular and organelle traffic to and from these remote areas requires active mechanisms, because diffusion alone would take an inordinate amount of time. Bidirectional traffic in axons delivers proteins and organelles to and from the nerve terminal by anterograde and retrograde transport, respectively. Anterograde transport delivers neuropeptide-containing vesicles and cytoskeletal proteins; retrograde transport returns endocytotic and other vesicles. Axonal transport has two components: a fast component, traveling at rates of 200 to 400 mm/day, and a slow component, which consists of a slow component a (SCa) and a slow component b (SCb), moving at rates of 0.2 to 1 mm/day and 2 to 8 mm/day, respectively. The fast component carries membranous vesicles, and the slow compartment carries cytoskeletal proteins. Fast transport involves movement of vesicles along tracks composed of microtubules. Microtubule motors generate the force required to propel organelles along the path. Two of these motors, kinesin and dynein, are ATPases that are activated on binding to the microtubule. Kinesin directs movement toward the plus end of the microtubule and dynein toward the minus end. In axons, most microtubules have their positive end toward the terminal and can guide movement in either direction. In dendrites, about half of the microtubules are oriented with their plus ends toward the dendritic tip, and the other half have their minus ends toward the tip. Differences in microtubule orientation in axons and dendrites may be one of the mechanisms underlying the selective transport of organelles into dendrites or axons. 4. NEURONAL SYNAPSES Electrical signals can be conveyed directly from cell to cell at special sites called gap junctions(Fig. 8). Ions pass from one cell to another through relatively large Fig. 7. Dendrites labeled with antibodies to microtubule-associated protein (MAP) 2. The technique of immunocytochemistry uses antibodies to localize specific proteins in neurons. These antibodies are detected by secondary antibodies tagged with an enzyme or gold particle. (A) The enzyme, such as peroxidase, catalyzes a reaction that results in an electron-dense precipitate, a seen in the light micrograph, in which antibodies to MAP 2 label the dendritic tree (arrowheads) of a Purkinje cell. (B) Alternatively, the secondary antibody can be tagged with gold particles, seen as black dots in the electron micrograph, in which they localize MAP 2 to microtubules (arrowheads) and cross-bridges (arrows) between them. Pu, Purkinje cell; b, basket cell. (Part A is reprinted from Bernhardt R, Matus A. J Comp Neurol 1984; 226:207, with permission of Wiley-Liss, a division of John Wiley & Sons, Inc., New York.) Chapter 1 / Cytology and Organization of Cell Types 13
14 Cohen and pfaff 3.5nm 0.1 umB Fig. 8. Structure of the gap junction.(A) In the electron micrograph, the membranes of two glial cell processes in close apposition form a gap junction(arrows). Notice the wider extrajunctional space(arrowheads) to the right of the gap junction ( B)The diagram shows a section of the half channels in each membrane that join to form a pore, which allows communication between the cytoplasm of the two cells. The space between the two membranes of the gap junction is only 3. 5 nm, much smaller than the extrajunctional space of 20 nm Fig 9. Basic features of synaptic junctions in the central nervous system. (A)The presynaptic terminal (PR)ends on a dendrite (D) characterized characterized by microtubules(), and (B)another that ends on a spine(s) characterized by an actin filament network(asterisk). In both cases, synaptic vesicles (sv) are seen in the presynaptic terminal, and a prominent postsynaptic density (arrowhead) is located behind the postsynaptic membrane In(A), the presynaptic terminal also contains dense-cored vesicles(circled), and in(B), the terminal contains a mitochondrion(mi). Some of the synaptic vesicles(white arrow)in(B)are located or docked near the presynaptic membrane. In the dendrite in(A), specializations called subsynaptic bodies(black arrows) are located on the cytoplasmic face of the postsynaptic densit
Fig. 8. Structure of the gap junction. (A) In the electron micrograph, the membranes of two glial cell processes in close apposition form a gap junction (arrows). Notice the wider extrajunctional space (arrowheads) to the right of the gap junction. (B) The diagram shows a section of the half channels in each membrane that join to form a pore, which allows communication between the cytoplasm of the two cells. The space between the two membranes of the gap junction is only 3.5 nm, much smaller than the extrajunctional space of 20 nm. Fig. 9. Basic features of synaptic junctions in the central nervous system. (A) The presynaptic terminal (PR) ends on a dendrite (D) characterized characterized by microtubules (m), and (B) another that ends on a spine (S) characterized by an actin filament network (asterisk). In both cases, synaptic vesicles (sv) are seen in the presynaptic terminal, and a prominent postsynaptic density (arrowhead) is located behind the postsynaptic membrane. In (A), the presynaptic terminal also contains dense-cored vesicles (circled), and in (B), the terminal contains a mitochondrion (mi). Some of the synaptic vesicles (white arrow) in (B) are located or docked near the presynaptic membrane. In the dendrite in (A), specializations called subsynaptic bodies (black arrows) are located on the cytop1asmic face of the postsynaptic density. 14 Cohen and Pfaff
Chapter 1/Cytology and Organization of Cell Types channels that connect the cytoplasm of the two cells shape, and number. These changes have important hile isolating the flow from the intracellular space. implications in synaptic transmission because they In neurons, these electrical synapses permit rapid and may modify the way in which incoming signals are direct electrical transmission and may also play a role received. Because morphologic alterations may preclude any major involvement in plastic events. lasting and signify the generation or maintenance Gap junctions are also found elsewhere in the nervous of long-term processes, such as memory system between supportive cells, called astrocytes, All synaptic junctions consist of presynaptic and where they participate in buffering the extracellular postsynaptic elements(Fig. 9). In synapses in the ionic milieu central nervous system, very fine filamentous mate- Chemical synapses are the main sites of interac- rial extends between the two processes in the cleft tions of nerve cells(Fig 9). All synaptic junctions region. The most conspicuous feature of the presy share common features that guarantee precise and haptic terminal are the small(40 nm in diameter) directed transmission of signals. Although the gen- clear synaptic vesicles containing acetylcholine or eral scheme remains relatively constant, variability in amino acid neurotransmitters. Mitochondria are some of the molecular components, such as neuro- also visible, as are dense-cored vesicles, some contain transmitter, ion channels, receptors, and second mes- ing neuropeptides imported from the perikaryon and sengers, and the dynamic properties of the supporting others containing catecholamines synthesized in the cytoskeleton enable each synapse to maintain its indi- terminal. The portion of presynaptic membrane viduality, record past experiences, and vary responses directly apposing the postsynaptic membrane is to new signals called the active zone. Sometimes this area is marked by a dense submembranous array. The presynaptic 4.1. Synaptic Structure Follows a Basic Plan nerve terminal contacts a postsynaptic element In the Chemical synapses conform to a basic architec- central nervous system, this may be a cell body, den- tural plan despite their location along the neuron drite(Fig. 9A), dendritic spine(Fig. 9B), another or within the nervous system itself, but during the axon, or axon terminal past two decades, it has become apparent that the The most striking postsynaptic feature is the dense morphology of synaptic connections in the adult submembrane filamentous array beneath the posts mammalian brain is not static. Synapses display naptic membrane called the PSD(Fig 9). Extending structural plasticity, undergoing alterations in size, from this area is a fine meshwork of actin filaments Fig 10 Neuromuscular junction seen by(A)light and(B)electron microscopy. In(A), an axon(a) gives rise to a motor end late(mep)on the muscle fiber(mf). The motor end plate exhibits many swellings(arrowheads ) These represent the presynaptic terminals, one of which is seen at higher magnification in(B). The presynaptic terminal(PR), filled with synaptic vesicles(sv) contacts the sarcolemma folds(asterisks)of the muscle cell (me). a basal lamina(arrowhead) is found in between the terminal and sarcolemma. A portion of glial cell, known as a Schwann cell (SC), surrounds the terminal (Part B courtesy of Virginia Kriho, University of Illinois at Chicago
channels that connect the cytoplasm of the two cells while isolating the flow from the intracellular space. In neurons, these electrical synapses permit rapid and direct electrical transmission and may also play a role in synchronizing neuronal activity. However, their invariant form and paucity of regulatory molecules preclude any major involvement in plastic events. Gap junctions are also found elsewhere in the nervous system between supportive cells, called astrocytes, where they participate in buffering the extracellular ionic milieu. Chemical synapses are the main sites of interactions of nerve cells (Fig. 9). All synaptic junctions share common features that guarantee precise and directed transmission of signals. Although the general scheme remains relatively constant, variability in some of the molecular components, such as neurotransmitter, ion channels, receptors, and second messengers, and the dynamic properties of the supporting cytoskeleton enable each synapse to maintain its individuality, record past experiences, and vary responses to new signals. 4.1. Synaptic Structure Follows a Basic Plan Chemical synapses conform to a basic architectural plan despite their location along the neuron or within the nervous system itself, but during the past two decades, it has become apparent that the morphology of synaptic connections in the adult mammalian brain is not static. Synapses display structural plasticity, undergoing alterations in size, shape, and number. These changes have important implications in synaptic transmission because they may modify the way in which incoming signals are received. Because morphologic alterations may reflect marked rearrangements of the molecular structure of synapses, these changes may be long lasting and signify the generation or maintenance of long-term processes, such as memory. All synaptic junctions consist of presynaptic and postsynaptic elements (Fig. 9). In synapses in the central nervous system, very fine filamentous material extends between the two processes in the cleft region. The most conspicuous feature of the presynaptic terminal are the small (40 nm in diameter), clear synaptic vesicles containing acetylcholine or amino acid neurotransmitters. Mitochondria are also visible, as are dense-cored vesicles, some containing neuropeptides imported from the perikaryon and others containing catecholamines synthesized in the terminal. The portion of presynaptic membrane directly apposing the postsynaptic membrane is called the active zone. Sometimes, this area is marked by a dense submembranous array. The presynaptic nerve terminal contacts a postsynaptic element. In the central nervous system, this may be a cell body, dendrite (Fig. 9A), dendritic spine (Fig. 9B), another axon, or axon terminal. The most striking postsynaptic feature is the dense, submembrane filamentous array beneath the postsynaptic membrane called the PSD (Fig. 9). Extending from this area is a fine meshwork of actin filaments Fig. 10. Neuromuscular junction seen by (A) light and (B) electron microscopy. In (A), an axon (a) gives rise to a motor end plate (mep) on the muscle fiber (mf). The motor end plate exhibits many swellings (arrowheads). These represent the presynaptic terminals, one of which is seen at higher magnification in (B). The presynaptic terminal (PR), filled with synaptic vesicles (sv), contacts the sarcolemma folds (asterisks) of the muscle cell (me). A basal lamina (arrowhead) is found in between the terminal and sarcolemma. A portion of glial cell, known as a Schwann cell (SC), surrounds the terminal. (Part B courtesy of Virginia Kriho, University of Illinois at Chicago.) Chapter 1 / Cytology and Organization of Cell Types 15
Cohen and pfaff and their binding proteins. In dendrites, this network proteins required to construct synaptic vesicles must is contiguous with microtubules; in dendritic spines, be imported from the cell body the filamentous web fills the head and neck region of Neurotransmitters are primarily released from this process. Some postsynaptic membranes lack a synaptic vesicles, although there is compelling evi- 'ell-developed PSD dence for additional nonvesicular release of acetyl- Synapses are also found between nerves and mus- choline from a cytoplasmic pool. Knowledge that cles(Fig. 10). With the light microscope, axons can be synaptic vesicles mediate neurotransmitter release seen to approach the muscle. At a specific site on the comes from the important discovery in 1952 by Paul muscle, called the end-plate region, the axons give rise Fatt and Bernard Katz that acetylcholine is released to several branches that display multiple swellings, from terminals at the neuromuscular junction in each of which represents a presynaptic terminal. quanta. A relatively constant number(about 10,000 Ultrastructural examination reveals that the nerve of neurotransmitter molecules is released simulta- terminal is closely apposed to the sarcolemma of neously. Since that time, neuroscientists have been skeletal muscle with a basal lamina lying in between actively engaged in experiments supporting this find the two components. The sarcolemma is thrown into distinctive folds. Acetylcholine receptors are located ng. Electron microscopic studies of nerve terminals on the portions of the membrane directly opposing vesicles were isolated, they were shown to contain the active zones. a dense microfilamentous network acetylcholine. It was then proposed that the number extends from the membrane on the cytoplasmic face of transmitter molecules in each quanta is equivalent of the postsynaptic membrane and holds the recep- to the number of acetylcholine molecules in each tors in place vesicle Synaptic vesicles occupy precise locales within the 4.2. The Presynaptic Nerve Terminal Is the Site terminal; they are clustered and then docked near the of transmitter release active zone(Fig. 9B). They appear to be held in place Information transfer between neurons occurs in a there by actin, which is connected to the vesicle by a matter of milliseconds. During this time, action neuron-specific protein, synapsin.However, vesicles potentials speed along the axonal membrane at that have already released transmitter must be rates between I and 100 m/s to the presynaptic replaced by those next in line, necessitating a transi- nerve terminal, where the frequency of their firing ent depolymerization of actin filaments so that the is translated into specific quantities of neurotrans- vesicles are free to approach the membrane. Phos- mitter release. The rapidity of signal conduction phorylation of synapsin releases vesicles from the over long distances demands that the nerve be cytoskeleton, permitting them to proceed to the dock ready to respond to a barrage of incoming action ing site at the presynaptic membrane. Specific pro potentials at all times. Although axonal transport teins within the vesicle membrane and presynaptic replenishes the terminal with some needed mole- membrane interact to hold the vesicle in place. Vesicle cules, organelles, and neuropeptide-containing vesi- fusion occurs so fast that it is thought to involve a cles, the rates of delivery are not fast enough to conformational change in a specific protein--perhaps prepare the terminal with the small molecules (i.e, a change in a preassembled calcium-dependent pore acetylcholine, amino acids, catecholamines)com- from a closed to an open state. The extra vesicle prising the bulk of chemical messengers that med- membrane, now a part of the presynaptic membrane, iate neurotransmission. Even fast anterograde is internalized by a clathrin-dependent mechanism transport can only convey membranous vesicles at and brought to an endosomal sac, where membrane a rate of 200 to 400 mm(l ft) each day. Conse- proteins are sorted and new vesicles pinch off the quently, the nerve terminal comes equipped with cisternae. It is thought that there are two release mechanisms for neurotransmitter synthesis, sto- pathways: one for clear vesicles and another for neu rage, and release and mechanisms for membrane rosecretory vesicles. The latter are not concentrated recycling. Presynaptic terminals, however, lack the near the active zone and require a lower calcium elaborate protein synthetic and packaging machin- concentration and a higher frequency of stimulation ery found in the perikaryon. Even free polyribo- for release at other sites along the terminal mem- somes are difficult to detect, although there is brane. Dense-cored vesicle release may represent a some evidence for presynaptic protein synthesis. basal secretion, in contrast with the phasic release of Most of the synthetic enzymes and some membrane clear vesicles
and their binding proteins. In dendrites, this network is contiguous with microtubules; in dendritic spines, the filamentous web fills the head and neck region of this process. Some postsynaptic membranes lack a well-developed PSD. Synapses are also found between nerves and muscles (Fig. 10). With the light microscope, axons can be seen to approach the muscle. At a specific site on the muscle, called the end-plate region, the axons give rise to several branches that display multiple swellings, each of which represents a presynaptic terminal. Ultrastructural examination reveals that the nerve terminal is closely apposed to the sarcolemma of skeletal muscle with a basal lamina lying in between the two components. The sarcolemma is thrown into distinctive folds. Acetylcholine receptors are located on the portions of the membrane directly opposing the active zones. A dense microfilamentous network extends from the membrane on the cytoplasmic face of the postsynaptic membrane and holds the receptors in place. 4.2. The Presynaptic Nerve Terminal Is the Site of Transmitter Release Information transfer between neurons occurs in a matter of milliseconds. During this time, action potentials speed along the axonal membrane at rates between 1 and 100 m/s to the presynaptic nerve terminal, where the frequency of their firing is translated into specific quantities of neurotransmitter release. The rapidity of signal conduction over long distances demands that the nerve be ready to respond to a barrage of incoming action potentials at all times. Although axonal transport replenishes the terminal with some needed molecules, organelles, and neuropeptide-containing vesicles, the rates of delivery are not fast enough to prepare the terminal with the small molecules (i.e., acetylcholine, amino acids, catecholamines) comprising the bulk of chemical messengers that mediate neurotransmission. Even fast anterograde transport can only convey membranous vesicles at a rate of 200 to 400 mm (1 ft) each day. Consequently, the nerve terminal comes equipped with mechanisms for neurotransmitter synthesis, storage, and release and mechanisms for membrane recycling. Presynaptic terminals, however, lack the elaborate protein synthetic and packaging machinery found in the perikaryon. Even free polyribosomes are difficult to detect, although there is some evidence for presynaptic protein synthesis. Most of the synthetic enzymes and some membrane proteins required to construct synaptic vesicles must be imported from the cell body. Neurotransmitters are primarily released from synaptic vesicles, although there is compelling evidence for additional nonvesicular release of acetylcholine from a cytoplasmic pool. Knowledge that synaptic vesicles mediate neurotransmitter release comes from the important discovery in 1952 by Paul Fatt and Bernard Katz that acetylcholine is released from terminals at the neuromuscular junction in quanta. A relatively constant number (about 10,000) of neurotransmitter molecules is released simultaneously. Since that time, neuroscientists have been actively engaged in experiments supporting this finding. Electron microscopic studies of nerve terminals revealed the presence of synaptic vesicles. When these vesicles were isolated, they were shown to contain acetylcholine. It was then proposed that the number of transmitter molecules in each quanta is equivalent to the number of acetylcholine molecules in each vesicle. Synaptic vesicles occupy precise locales within the terminal; they are clustered and then docked near the active zone (Fig. 9B). They appear to be held in place there by actin, which is connected to the vesicle by a neuron-specific protein, synapsin. However, vesicles that have already released transmitter must be replaced by those next in line, necessitating a transient depolymerization of actin filaments so that the vesicles are free to approach the membrane. Phosphorylation of synapsin releases vesicles from the cytoskeleton, permitting them to proceed to the docking site at the presynaptic membrane. Specific proteins within the vesicle membrane and presynaptic membrane interact to hold the vesicle in place. Vesicle fusion occurs so fast that it is thought to involve a conformational change in a specific protein—perhaps a change in a preassembled calcium-dependent pore from a closed to an open state. The extra vesicle membrane, now a part of the presynaptic membrane, is internalized by a clathrin-dependent mechanism and brought to an endosomal sac, where membrane proteins are sorted and new vesicles pinch off the cisternae. It is thought that there are two release pathways: one for clear vesicles and another for neurosecretory vesicles. The latter are not concentrated near the active zone and require a lower calcium concentration and a higher frequency of stimulation for release at other sites along the terminal membrane. Dense-cored vesicle release may represent a basal secretion, in contrast with the phasic release of clear vesicles. 16 Cohen and Pfaff
Chapter 1/Cytology and Organization of Cell Types 4.3. The Postsynaptic Element Is the Site of contains actin that, together with its binding proteins ignal Transduction also found here, may mediate dynamic changes in Neurotransmitters bind to specific sites called shape. The major protein in cerebral cortex PSDs, receptors on the postsynaptic membrane. This inter- for, example, is the 51-kDa, autophosphorylatable, transduce the chemical message into an intracellular comprises 30% to 50%of this structure Mutant mice signal that affects the behavior of the postsynaptic lacking one of the isoforms of this enzyme are also neuron Neuronal response incoming signals may deficient in their ability to produce long-term potentia include immediate alterations in membrane perme- tion(LTP). LTP is an electrophysiologic correlate of ability or more long-lasting modifications in synaptic memory, after a given input, a synapse gets stronger or neuronal architecture, which may modify the nat- and retains this new strength for a long period pathways in neurons attain an extraordinary level of which appears to regulate the expression and function complexity, Increasing the number of adaptive of some receptors in a synapse-specific manner responses by logarithmic proportions 4.3. 2. DENDRITIC SPINES 4.3.1. POSTSYNAPTIC DENSITY Approximately 100 years ago, Santiago Ramon Cajal o Beneath the postsynaptic membrane is a dense fila- wrote that cortical dendrites seem to"bristle with mentous array, the PSD(Fig 9). The intimacy of its teeth. He called these protuberances collateral spines, association with the overlying membrane suggests that and it is only recently that we have gained some insight it restricts receptors at that site, similar to the way into their precise function. Dendritic spines are protru- acetylcholine receptors are clustered at the sarcolem- sions of the dendritic surface that receive synapses, mal membrane of the neuromuscular junction by actin almost all of which are excitatory. They consist of and its binding proteins. However, several properties spine heads of various diameters that are connected of the PSD suggest a more dynamic role in nerve to the parent dendrite by necks, which also vary in transmission. Although the PSD usually is a saucer- length and thickness(Fig. 11). The spine shape is often shaped structure, there are variations of this basic categorized as thin, stubby, or mushroom shaped form, including differences in length, curvature, and Ribosomes have been found at the base of the spine the presence or absence of perforations. Moreover, neck, possibly functioning in local protein synthesis quantitative electron microscopic analyses reveal that Cortical neurons have thousands of dendritic spines these parameters change in specific brain areas with each located every few micrometers along the dendritic various physiologic and behavioral inputs. The PSD shaft B Fig. 11. Light micrographs of pyramidal cells and their processes in the hippocampus of an adult rat (A)Pyramidal cells and their processes are seen at low magnification with Golgi-Cox staining.(scale bar 100 mm).(B)High-magnification micrograph of the area delineated by the box in(A)shows the Golgi-impregnated cell body and dendrite of a neuron in the CAl structure of the hippocampus(scale bar 20 mm).(C) High-magnification micrograph of the area delineated by the box of a Golgi-impregnated dendrite in(B)shows dendritic spines, which appear as protuberances emanating from the dendrite. A spine with a long neck is indicated by the arrowhead scale bar= 10 mm). (Images courtesy of the laboratory of Dr. Subhash C. Pandey, Department of Psychiatry, University of Illinois at Chicago
4.3. The Postsynaptic Element Is the Site of Signal Transduction Neurotransmitters bind to specific sites called receptors on the postsynaptic membrane. This interaction is the initial step in a cascade of events that transduce the chemical message into an intracellular signal that affects the behavior of the postsynaptic neuron. Neuronal responses to incoming signals may include immediate alterations in membrane permeability or more long-lasting modifications in synaptic or neuronal architecture, which may modify the nature of the postsynaptic response. Signal transduction pathways in neurons attain an extraordinary level of complexity, increasing the number of adaptive responses by logarithmic proportions. 4.3.1. POSTSYNAPTIC DENSITY Beneath the postsynaptic membrane is a dense filamentous array, the PSD (Fig. 9). The intimacy of its association with the overlying membrane suggests that it restricts receptors at that site, similar to the way acetylcholine receptors are clustered at the sarcolemmal membrane of the neuromuscular junction by actin and its binding proteins. However, several properties of the PSD suggest a more dynamic role in nerve transmission. Although the PSD usually is a saucershaped structure, there are variations of this basic form, including differences in length, curvature, and the presence or absence of perforations. Moreover, quantitative electron microscopic analyses reveal that these parameters change in specific brain areas with various physiologic and behavioral inputs. The PSD contains actin that, together with its binding proteins also found here, may mediate dynamic changes in shape. The major protein in cerebral cortex PSDs, for example, is the 51-kDa, autophosphorylatable, Ca2+/calmodulin-dependent protein kinase II, which comprises 30% to 50% of this structure. Mutant mice lacking one of the isoforms of this enzyme are also deficient in their ability to produce long-term potentiation (LTP). LTP is an electrophysiologic correlate of memory; after a given input, a synapse gets stronger and retains this new strength for a long period. Another important protein at the PSD is PSD-95, which appears to regulate the expression and function of some receptors in a synapse-specific manner. 4.3.2. DENDRITIC SPINES Approximately 100 years ago, Santiago Ramon Cajal ´ wrote that cortical dendrites seem to ‘‘bristle with teeth.’’ He called these protuberances collateral spines, and it is only recently that we have gained some insight into their precise function. Dendritic spines are protrusions of the dendritic surface that receive synapses, almost all of which are excitatory. They consist of spine heads of various diameters that are connected to the parent dendrite by necks, which also vary in length and thickness (Fig. 11). The spine shape is often categorized as thin, stubby, or mushroom shaped. Ribosomes have been found at the base of the spine neck, possibly functioning in local protein synthesis. Cortical neurons have thousands of dendritic spines, each located every few micrometers along the dendritic shaft. Fig. 11. Light micrographs of pyramidal cells and their processes in the hippocampus of an adult rat. (A) Pyramidal cells and their processes are seen at low magnification with Golgi-Cox staining. (scale bar = 100 mm). (B) High-magnification micrograph of the area delineated by the box in (A) shows the Golgi-impregnated cell body and dendrite of a neuron in the CA1 structure of the hippocampus (scale bar = 20 mm). (C) High-magnification micrograph of the area delineated by the box of a Golgi-impregnated dendrite in (B) shows dendritic spines, which appear as protuberances emanating from the dendrite. A spine with a long neck is indicated by the arrowhead. (scale bar = 10 mm). (Images courtesy of the laboratory of Dr. Subhash C. Pandey, Department of Psychiatry, University of Illinois at Chicago.) Chapter 1 / Cytology and Organization of Cell Types 17