5 Chapter Synaptic Transmission Types of Synapses o Electrical synapses Occur at specialized sites called gap junctions 3mm gaps spanned by clusters of special proteins called connexins o 6 connexins combine to form a channel called a connexon and two connexons combine to form a gap junction channel The channel allows ions to pass directly from the cytoplasm of one cell to the other Pore is relatively large (1-2nm diameter), big enough for all major cellular ions and many small organic molecules to pass through Most gap junctions allow ionic current to pass equally well in both direction Bidirectional Cells connected by gap junctions are said to be electrically coupled Transmission is fast and if synapse is large, failsafe Action potential in pre-synaptic neuron almost instantaneously makes an action potential in the postsynaptic neuron When ionic current flows across gap junction channel to postsynaptic neuron, the current causes a postsynaptic potential (PSP) in 2nd neuron When 2nd neuron generates action potential, a PSP is induced in the 1st neuron due to bidirectional movement o PSP generated by single electrical synapse is usually small (~1mv) and may not be large enough to trigger action potential in postsynaptic cell o Several PSPs occurring simultaneously may strongly excite a neuron o Chemical synapses Separated by synaptic cleft 20-50nm wide, 10times width of gap junctions Filled with matrix of fibrous extra-cellular protein o Matrix makes pre and postsynaptic membranes adhere to each other Presynaptic side of the synapse (presynaptic element) is usually an axon terminal o Typically contains dozens of small membrane-enclosed spheres, each about 50nm in diameter called synaptic vesicles Store neurotransmitters
o Larger vesicles about 100nm in diameter called secretory granules contain soluble protein that appears dark in the electron microscope so sometimes called dense-core vesicles Dense accumulations of protein next to and within membranes of synaptic cleft are called membrane differentiations Active zones are sites of neurotransmitter release Synaptic vesicles are clustered in the cytoplasm next to the active zone Postsynaptic density is a protein thickly accumulated in and just under the postsynaptic membrane that contains neurotransmitter receptors, which convert intercellular chemical into intracellular signal CNS Synapses If postsynaptic membrane is on dendrite, synapse is axodendritic If postsynaptic membrane is on cell body, synapse is aid to be axosomatic If postsynaptic membrane on another axon, the synapses are axoaxonic In certain specialized neurons, dendrites form synapses with each others and are called dendrodendritic Two general categories o Synapses which membrane differentiation on the postsynaptic side is thicker than that on the presynaptic side are called asymmetrical synapses, or Gray's type I synapses Usually excitatory o Those in which membrane differentiations are of similar thickness are called symmetrical synapses, or Gray's type II synapses Usually inhibitory Neuromuscular junction Chemical synapse that occur between axons of motor neurons of spinal cord and skeletal muscle Action potential in motor axon always causes an action potential in the muscle cell it innervates Most important specialization is its size- it is one of the largest synapses in the body Presynaptic terminal contains a large number of active zones o Precisely aligned with motor end plate fold and postsynaptic membrane of the folds is packed with NT receptors Ensures that many NT molecules are focally released onto a large surface of chemically sensitive membrane
Post-synaptic membrane aka motor end-plate contains series of shallow folds Principles of chemical synaptic transmission o Neurotransmitters Amino acids, Amines, Peptides are the three NT types Amino acids and amines are all small organic molecules containing at least one nitrogen atom and are stored in synaptic vesicles Peptide NTs are large molecules stored in and released from secretory granules o Often exist in the same axon terminals that contain amine or amino acid Nts Fast synaptic transmission is mediated by AAs glutamate, gammaaminobutyric acid (GABA), and glycine. The amine acetylcholine mediates fast synaptic transmission at all neuromuscular junctions NT synthesis and storage Different NTs are synthesized in different ways o Glutamate and glycine are among the 20 basic aa that are the building blocks of protein o GABA and amines are made only by the neurons that release them These neurons contain specific enzymes that synthesize the neurotransmitters from various metabolic precursors Once synthesized in the cytosol of the axon terminal, the amino acid and amine NTs are transported to the axon terminal, where they locally and rapidly direct transmitter synthesis o Transporters, special proteins embedded in the vesicle that transport the NTs through the vesicle membrane o Synthesizing and storing peptides in secretory granules is different NT release Triggered by arrival of an action potential in the axon terminal Depolarization of the terminal membrane causes voltage-gated calcium channels to open o Very similar to sodium channels o Large inward driving force on Ca(2+) o Internal calcium ion concentration at rest is very low Ca(2+) will flood cytoplasm of axon terminal as long as the calcium channels are open
Resulting elevation in [Ca(2+)]inside is the signal that causes NT to be released from synaptic vesicles o Exocytosis is process vesicles use to release NTs Membrane of synaptic vesicle fuses to the presynaptic membrane at the active zone allowing content of vesicle to spill out into the synaptic cleft Occurs within .2ms of Ca(2+) influx into the terminal In presence of high [Ca(2+)]in proteins alter their conformation so that the lipid bilayers of the vesicle and the presynaptic membranes fuse forming a pore that allows the NT to escape into the cleft o Vesicle membrane is later recovered by endocytosis and recycled vesicle is refilled with NT o Secretory granules also release peptide NTs by exocytosis in calcium-dependent fashion Release of peptides generally requires highfrequency trains of action potentials, so that the [Ca(2+)]I throughout the terminal can build to the level required to trigger release away from the active zones Release takes 50ms or more NT Receptors and Effectors Transmitter-gated ion channels o Membrane-spanning proteins consisting of four or five subunits that come together to form a pore between them
o Absence of NT, channel is closed, when NT binds to specific sites on extracellular region of channel, conformation change (slight twist of subunits) allows the pore to open in microseconds o Don't show same degree of ion selectivity as do voltage-gated channels Ex. Ach-gated ion channels at neuromuscular region are permeable to both Na+ and K+ If open channels are permeable to Na+, the net effect will be to depolarize the postsynaptic cell from the resting membrane potential Because it tends to bring membrane potential toward threshold, it is said to be excitatory A transient postsynaptic membrane depolarization caused by presynaptic release of NT is called an excitatory postsynaptic potential (EPSP) If transmitter-gated channels permeable to Cl-, net effect will be to hyperpolarize the postsynaptic cell from the resting membrane potential Bringing membrane potential away from threshold is said to inhibitory Transient hyperpolarization of postsynaptic membrane potential caused by presynaptic release of NT is called an inhibitory postsynaptic potential (IPSP) Synaptic activation of glycine-gated of GABA-gated ion channel cause an IPSP G-protein couple receptors o All three NT acting on G-protein coupled receptors can also have slower longer-lasting and much more diverse postsynaptic o actions Three steps NT molecules bind to receptor proteins embedded in the postsynaptic membrane Receptor proteins activate small proteins called G-protein that are free to move along the intracellular face of the postsynaptic membrane Activated G-proteins activate "effector" proteins o Effector proteins can be Gprotein-gated ion channels in the membrane or they can be enzymes that synthesize
molecules called second messengers that diffuse away in the cytosol 2nd messengers can activate additional enzyme in the cytosol that can regulate ion channel function and alter cellular metabolism o G-protein couple receptor trigger widespread metabolic effects so sometimes they are called metabotropic receptors o Same NT can have different postsynaptic actions depending on what receptors it binds to Ach slows rhythmic contraction of heart by slow hyperpolarization of cardian muscle cells but in skeletal muscle it induces contraction by causing rapid depolarization of the muscle fibers In heart, Ach receptor copled by Gprotein to a potassium channel Receptor in skeletal muscle is a transmitter-gated ion channel permeable to Na+ that depolarizes the muscle fibers Autoreceptors o Presynaptic receptors that are sensitive to the NT released by presynaptic terminals o Typically G-protein-couple receptors that stimulate second messenger formation o Consequence of activating these receptors vary, but a common effect is inhibition of NT release and sometimes NT synthesis o Allow presynaptic terminal to regulate itself Function as a safety valve to reduce release when the concentration of NT in the synaptic cleft gets toohigh NT Recovery and degradation Most NTs diffusion is aided by reuptake into presynaptic axon terminal Once inside cytosol of the terminal , the NTs may be enzymatically destroyed or they may be reloaded into synaptic vesicles o If enzyme such as AChE (acetylcholinesterase) is inhibited, as it is by various nerve gases, the Ach receptor will become desensitized and neuromuscular transmission will fail
Desensitization is a process in which transmitter-gated channel close despite the continued presence of Ach
Neuropharmacology Inhibitors inhibit normal function of specific proteins involved in synaptic transmission o Receptor antagonists bind to the receptors and block the normal action of the transmitter Receptor agonists mimic actions of the naturally occurring NT o Ex. Nicotine binds to and activates the Ach receptors in skeletal muscle Ach-gated ion channels in muscle are also called nicotinic Ach receptors to distinguish them from other types of Ach receptors Synaptic integration o Process by which multiple synaptic potentials combine within one postsynaptic neuron o Integration of EPSPs Quantal Analysis of EPSPs Vesicles each contain about the same number of transmitter molecules (several thousand) o Total amount of transmitter released is some multiple of this number At many synapses, exocytosis of vesicles occurs at some very low rate in absence of presynaptic stimulation Miniature postsynaptic potential is measured when exocytosis of vesicles occurs in absence of presynaptic stimulation. Quantal analysis is mothod of comparing the amplitudes of miniature and evoked postsynaptic potentials o Can be used to determine how many vesicles release NT during normal synaptic transmission o Reveals that a single action potential in presynaptic terminal triggers the exocytosis of about 200 synaptic vesicles causing an EPSP of 40mV or more o Contents of only a single vesicle are released in response to a presynaptic action potential, causing an ESP of only a few tenths of a millivolt EPSP summation o Represents the simplest form of synaptic integration in the CNS o Spatial summation is the adding together of EPSP generated simultaneously at many different synapses on a dendrite o Temporal summation is adding together of EPSPs generated at the same synapse if they occur in rapid successions, within about 1-15msec of one another
Contribution of Dendritic Properties to Synaptic Integration Dendritic Cable Properties o Depolarization of a dendrite falls off exponentially with increasing distance o Depolarization of membrane ata given distance (Vx) can be described by the equation Vx=V0/e^(x/lambda)w here V0 is depolarization at the origin and e=2.718, x is distance from synapse and l is conostant depends on properties of the dendrite. When x=lambda, then Vx=V0/e. The lambda distance where the depolarization is called the dendritic length constant Length constant is an index of how far depolarization can spread down a dendrite or axon o The longer the length constant, the more likely it is that EPSPs generated at distant synapses will depolarize the membrane at the axon hillock o Value of lambda is dependent on two things, the resistance to current flowing longitudinally down the dendrite, called the internal resistance (ri) and the resistance to current flowing across the membrane, called the membrane resistance (rm) o Lambda will increase as membrane resistance increases because more depolarizing current will flow down the inside of the dendrite Depends on number of open ion channels, which changes form moment to moment o Lambda will decrease as internal resistance increases because more current will flow across membrane Internal resistance depends only on the diameter of the dendrite and the electrical
properties of the cytoplasm Dendritic length is not constant at all Excitable dendrites o Dendrites rarely have enough ion channels to generate fully propagating action potentials as in axons Voltage-gated channels in dendrites can act as important amplifiers of small postsynaptic potentials generated far out on dendrites Inhibition Inhibitory synapses take the membrane potential away from action potential threshold IPSPs and shunting inhibition o Postsynaptic receptors of inhibitory synapses are also transmitter-gated ion channels They bind different NTs (not GABA or glycine) and they allow different ions to pass through their channels Most are only permeable to ClUsually brings membrane potential toward chloride equilibrium potential Ecl, about -65 mV o If membrane potential were less negative then -65mV when transmitter was released, activation of these channels would cause hyperpolarizing IPSP Synapses acts as an electrical shunt prevent current from flowing through the soma to the axon hillock (shunting inhibition) Actually physical basis of shunting inhibition is the inward movement of negatively charged chloride ions, which is formally equivalent to outward positive current flow Shunting inhibition acts to drastically deduce rm and consequently lambda, thus allowing positive current to flow out across membrane instead of internally down dendrite toward spike-initiation zone Geometry of Excitatory and Inhibitory synapses o Inhibitory synapses in the brain that use GABA or glycine as an NT always have a morphology characteristic to Gray's II
o Those that use glutamate have a Gray's type I morphology o Inhibitory synapses on many neurons are found clustered on soma and near axon hillock, where they are an especially powerful position to influence the activity of the postsynaptic neuron Modulation Receptors that don't directly evoke EPSPs and IPSPs but instead modifies the effectiveness of EPSPs generated by other synapses with transmitter-gated channels. Decreasing K+ conductance increase dendritic membrane resistant and therefore increase length constant o Biding of NE to beta receptors produce little change in membrane potential but activates adenylyl cyclase which catalyzes chemical reaction that converts ATP to cAMP which stimulates protein kinases which catalyze a chemical reaction called phosphorylation which can cause K+ channel to close there reducing membrane of K+ conductance