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Wilfrid Laurier University
Irene Cheung

NROB60 Chapter 5 Introduction Imagine you stepped on a thumbtack and how it can be converted into a neural signal:  First, specialized ion channels of the sensory nerve endings allow positive charge to enter the axon  If this depolarization reaches threshold, then action potentials are generated o Because the axonal membrane is excitable and has voltage-gated sodium channels, action potentials can propagate without decrement up the long sensory nerves  For this information to be processed by the rest of the nervous system, it is necessary that these neural signals be passed on to the other neurons that lead to a coordinated reflex response (e.g. lifting foot). By the end of the 19 century, it was recognized that this transfer of information from one neuron to another occurs at specialized sites of contact.  In 1897, Charles Sherrington gave these sites their names: synapse.  The process of information transfer at a synapse is called synaptic transmission The physical nature of synaptic transmission was argued over and two prominent hypotheses arose:  One suggested it was electrical current flowing from one neuron to the next o The existence of such electrical synapses was finally proven in 1959 by Edwin Furshpan and David Potter.  The other hypothesis suggested it was a chemical transfer of information o This was also proven to be correct with solid support for the concept of chemical synapses by Otto Loewi in 1921. Types of Synapses  Electrical Synapses o Electrical synapses are relatively simple in structure and function, and the allow the direct transfer of ionic current from one cell to the next. o They occur at specialized sites called gap junctions  The membrane of two cells is separated by only about 3nm and this narrow gap is spanned by clusters of special proteins called connexins. Six of these combine to form a channel called a connexon and two connexons combine to form a gap junction channel  It allows ions to pass directly from the cytoplasm of one cell to the cytoplasm of the other.  The pore is relatively large (1-2 nm) and is big enough for all the major cellular ions and many small organic molecules to pass through  Most allow ionic current to pass equally well in both directions (unlike the majority of chemical synapses).  Cells connected by gap junctions are electrically coupled o Transmission at the electrical synapses is very fast and, if the synapse is large, fail-safe.  An action potential in the presynaptic neuron can produce almost instantaneously, and action potential in the postsynaptic neuron. o Also occur in the vertebrae brain and is common in every part of the mammalian CNS o When two neurons are electrically coupled, an action potential in the presynaptic neuron causes a small amount of ionic current to flow across the gap junction channels into the other neuron  Causes a postsynaptic potential (PSP) in the second neuron o Since most electrical synapses are bidirectional, when the second neuron generates an action potential, it will in turn induce a PSP in the first neuron o The PSP generated by a single electrical synapses in the mammalian brain is small and may not by large enough to trigger an action potential in the postsynaptic cell  One neuron usually makes electrical synapses with many other neurons so several PSPs occurring simultaneously may strongly excite a neuron (synaptic integration) o The precise roles of electrical synapses vary from one brain region to another. Chemical Synapses  Most synaptic transmission in the mature human nervous system is chemical  The presynaptic and postsynaptic membranes at chemical synapses are separated by a synaptic cleft that is 20 – 50 nm wide. o It is filled with a matrix of fibrous extracellular proteins. o One function is to make the pre- and post-synaptic membranes adhere to each other o The presynaptic side of the synapse is usually an axon terminal and typically contains dozens of small membrane-enclosed spheres called synaptic vesicles.  These vesicles store neurotransmitter, the chemical used to communicate with the postsynaptic neuron.  Many axon terminals also contain larger vesicles called secretory granules  They contain soluble protein that appears dark in the electron microscope and sometimes called dense-core vesicles. o Dense accumulations of protein adjacent to and within the membranes on either side of the synaptic cleft are collectively called membrane differentiations.  On the presynaptic side, proteins jutting into the cytoplasm of the terminal along the intracellular face of the membrane sometimes look like a field of tiny pyramids.  These are the actual sites of neurotransmitter release called active zones  Synaptic vesicles cluster adjacent to the active zones (Fig. 5.3) o The protein thickly accumulated in and just under the postsynaptic membrane is called the postsynaptic density.  It contains the neurotransmitter receptors, which convert the intercellular chemical signal into an intracellular signal in the postsynaptic cell o CNS Synapses  Different types of synapse may be distinguished by which part of the neuron is postsynaptic to the axon terminal  If the postsynaptic membrane is on a dendrite, the synapse is said to be axodendritic  If the postsynaptic membrane is on the cell body, the synapse is said to be axosomatic.  If the postsynaptic membrane is on another axon, these synapses are called axoaxonic  In certain specialized neurons, dendirtes actually form synapses with one another. These are called dendrodendritic synapses  CNS synapses may be further classified into two general categories based on the appearance of their presynaptic and postsynaptic membrane differentiations  Synapses in which the membrane differentiation on the postsynaptic side is thick than on the presynaptic side are called asymmetrical synapses or Gray’s type I synapses.  Those in which the membrane differentiations are of similar thickness are called symmetrical synapses or Gray’s type II synapses  These structural differences predict functional differences. o The Neuromuscular Junction  Chemical synapses also occur between the axons of motor neurons of the spinal cord and skeletal muscle.  This is called a neuromuscular junction  Has many of the structural feathers of chemical synapses in the CNS  It is fast and reliable o An action potential in the motor axon always causes an action potential in the muscle cell it innervates o Reliability is accounted for, in part, by structural specializations of the neuromuscular junction  Its most important specialization is its size o One of the largest synapses in the body  The presynaptic terminal also contains a large number of active zones  The post-synaptic membrane, motor end plate, contains a series of shallow folds  The presynaptic active zones are precisely aligned with these junctional folds, and the postsynaptic membrane of the folds Is packed with neurotransmitter receptors o It ensures that many neurotransmitter molecules are focally released onto a large surface of chemically sensitive membrane Principles of Chemical Synaptic Transmission  Neurotransmitters o Most neurotransmitters fall into one of three chemical categories:  Amino acids  Amines  Peptides o The amino acid and amine neurotransmitters are all small organic molecules containing at least one nitrogen atom, and they are stored in and released from synaptic vesicles. o Peptide neurotransmitters are large molecules stored in and released from secretory granules  Secretory granules and synaptic vesicles are frequently observed in the same axon terminals o Different neurons in the brain release different neurotransmitters  Fast synaptic transmission at most CNS synapses is mediated by the amino acids glutamate (Glu), gamma-aminobutyric acid (GABA) and glycine (Gly).  The amine acetylcholine (Ach) mediates fast synaptic transimission at all neuromuscular junctions. Slower forms of synaptic transmission in the CNS and in the periphery are mediated by transmitters from all three chemical categories.  Neurotransmitter Synthesis and Storage o Chemical synaptic transmission requires that neurotransmitters be synthesized and ready for release. o The synthesizing enzymes for both amino acid and amine neurotransmitters are transported to the axon terminal, where they locally and rapidly direct transmitter synthesis. o Once synthesized in the cytosol of the axon terminal, the amino acid and amin neurotransmitters must be taken up by the synaptic vesicles.  Concentrating these neurotransmitters is the job of transporters o Different mechanisms are used to synthesize and store peptides in secretory granules  This occurs in the rough ER  Generally, a long peptide synthesized in the rough ER is split in the Golgi apparatus, and of the smaller peptide fragments is the active neurotransmitter.  Secretory granules containing the peptide neurotransmitter bud off the Golgi apparatus and are carried to the axon terminal by axoplasmic transport  Neurotransmitter Release o Neurotransmitter release is triggered by the arrival of an action potential in the axon terminal o The depolarization of the terminal membrane causes voltage-gated calcium channels in the active zones to open.  These membrane channels are very similar to the sodium channels o There is a large inward driving force on Ca2+ o The resulting elevation in [Ca ]Iis the signal that causes neurotransmitter to be released from synaptic vesicles o The vesicle releases their contents by a process called exocytosis. o The membrane of the synaptic vesicle fuses to the presynaptic membrane at the active zone, allowing the contents of the vesicle to spill out into the synaptic cleft (See Fig. 5.11.). o Exocytosis is quick because Ca 2+enters at the active zone, precisely where synaptic vesicles are ready and waiting to release their contents 2+ o The precise mechanism by which [Ca ] stiIulates exocytosis is poor understood o The speed of neurotransmitter release suggests that the vesicles involved are those at ready “docked” at the active zones.  Docking is believed to involved interactions between proteins in the synaptic vesicle membrane and the active zone 2+  In the presence of high [Ca ]I these proteins alter their conformation so that the lipid bilayers of the vesicle and presynaptic membranes fuse, forming a pore that allows the neurotransmitter to escape into the cleft.  The mouth of this exocytotic fusion pore continues to expand until the membrane of the vesicle is fully incorporated into the presynaptic membrane  The vesicle membrane is later recovered by the process of endocytosis and the recycle vesicle is refilled with neurotransmitter o During periods of prolonged stimulation, vesicles are mobilized from a “reserve pool” that is bound to the cytoskeletons of the axon terminal  The release of these vesicles from the cytoskeleton, and their docking to the active zone, is also 2+ triggered by elevations of [Ca i. o Secretory Granules also release peptide neurotransmitters by exocytosis, in a calcium –dependent fashion, but not at the active zones  Because the sites of granule exocytosis occur at a distance from the sites of Ca 2+ entry, peptide neurotransmitters are usually not released in response to every action potential invading the terminal.  Release of peptides generally requires high-frequency trains of action potentials, so that the [Ca ] Ihroughout the terminal can build to the level required to trigger release away from the active zones  Neurotransmitter Receptors and Effectors o Transmitter-Gated Ion Channels  Receptors known as transmitter-gated ion channels are membrane-spanning proteins consisting of four or five subunits that come together to form a pore between them.  In the absence of neurotransmitter, the pore is usually closed.  When neurotransmitter binds to specific sites on the extracellular region of the channel, it induces a conformational change which opens the pore.  Transmitter-gated channels generally do not show the same degree of ion selectivity as do voltage-gated channels (e.g. Ach-gated ion channels are permeable to both Na ions and K ions).  As a rule, if the open channels are permeable to Na , the net effect will be to depolarize the postsynaptic cell from the resting membrane potential.  Since it tends to bring the membrane potential towards threshold for generating action potentials, this effect is said to be excitatory.  Transient postsynaptic membrane depolarization caused by the presynaptic release of neurotransmitter is called an excitatory postsynaptic potential (EPSP) (Fig. 5.14.).  Synaptic activation of Ach-gated and glutamate--ated ion channels causes EPSP’s.  If the transmitted gated channels are permeable to Cl , the net effect will be to hyperpolarize the postsynaptic cell from the resting membrane potential  Since it brings the membrane potential away from threshold for generating action potentials, this effect is said to be inhibitory.  A transient hyperpolarization of the postsynaptic membrane potential caused by the presynaptic release of neurotransmitter is called an inhibitory postsynaptic potential (IPSP) (Fig. 5.15).  Synaptic activation of glycine-gated or GABA-gated ion channels causes an IPSP. o G-Protein-Coupled Receptors  Fast chemical synaptic transmission is mediated by amino acid and amine neurotransmitters acting on transmitter-gated ion channels.  All three types of neurotransmitter, acting on G-protein-coupled receptors, can also have slower, longer-lasting and much more diverse postsynaptic actions.  This involves three steps:  Neurotransmitter molecules bind to receptor proteins embedded in the postsynaptic membrane  The receptor proteins activate small proteins, G-proteins, that are free to move along the intracellular face of the postsynaptic membrane  The activated G-proteins activate “effector” proteins.  Effector proteins can be G-protein-gated ion channels in the membrane (Fig 5.1.) or they can be enzymes that synthesize mole
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