readerL9 - Synaptic Transmission Page 9-1 Two major types...

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Unformatted text preview: Synaptic Transmission Page 9-1 Two major types of synaptic transmissions: (1) Direct transmission can occur at either electrical synapses, or at chemical synapses with ionotropic receptors. (2) Indirect transmission occurs at chemical synapses with metabotropic receptors. Electrical synapses (1) Electrical synapses are much less common in the vertebrate brain than are chemical synapses. (2) Electrical synapses can easily be identified anatomically by the lack of synaptic vesicles seen by electron microscopy. (3)Unlike chemical synapses, which work through vesicular release of transmitter, electrical synapses function by directly connecting two cells. The sites of connection are called "gap junctions". (a)The connection of electrical synapse is mediated by connexons. Connexons are molecules with 6 subunits (called connexins) surrounding a pore. Connexons in the presynaptic membrane line up with connexons in the postsynaptic membrane, forming a pore that passes through both membranes. This directly electrically couples the two cells by allowing ions to flow across both membranes. Page 9-2 (4) No synaptic delay in electrical synapses. Because of this direct connection between cells, electrical transmission is very fast, having essentially no synaptic delay. Chemical transmission generally has a synaptic delay of a few milliseconds due primarily to the amount of time it takes for vesicles to fuse and release neurotransmitter. Experiments: The delay of a chemical synapse is seen in these recordings from a cell that receives both an electrical and a chemical synapse from the same presynaptic cell (chick ciliary ganglion cell). (A) Stimulation of the presynaptic cell leads to an action potential. (B) When the postsynaptic cell is hyperpolarized, the electrical synapse no longer drives the cell to action potential firing threshold, so a subthreshold depolarization is seen, followed by an action potential driven by the chemical synapse. (C) If the postsynaptic cell is further hyperpolarized, neither the electrical nor the chemical synapse drives the cell to threshold, so no action potential is fired, but two excitatory postsynaptic potentials are seen, a fast short electrical postsynaptic potential and a delayed, longer-lasting chemical postsynaptic potential. Page 9-3 (5) Electrical synapses are not only fast, they are also more reliable than chemical synapses: Chemical synapses may fail due to synaptic depression (a form of synaptic plasticity we will discuss in the next lecture) or due to the presence of neurotoxins. (a) Because they are fast an reliable, electrical synapses are often found in the neuronal pathways underlying escape reflexes. Chemical synapses - direct synaptic excitation (1) The neuromuscular junction is a best studied example for direct synaptic excitation. The postsynaptic potentials seen at the neuromuscular junction are caused by ACh released by the presynaptic terminal binding to nicotinic acetylcholine receptors in the muscle membrane. Using the voltage clamp technique, an IV plot can be made for the current flowing through the nAChR. With the muscle membrane potential clamped at -40 mV, nerve stimulation produced an inward current. At more negative holding potentials, the end plate current increased in amplitude. When the membrane was depolarized, the end plate current decreased in amplitude, and even reversed direction (outward). (2) The IV curve is linear, and crosses the x-axis at 0 mV. (a) The linearity of the plot indicates that they are not voltagegated channels. (b) The X-axis crossing at 0 mV tells us that the channel is not exclusive to sodium, potassium, calcium or chloride. (c) When a channel lets through more than one ion, the voltage at which there is no current flow is called the reversal potential (Erev, that is the potential at which the current reverses from inward to outward, or the potential at which there is no net current flow). Page 9-4 (3) Two approaches to determine which ions flow through the nAChR. (a) Radioactive isotopes uptake in the postsynaptic membrane. (b) Changing the concentration of ions in the bath to see if it will change the reversal potential. (4) It turns out that the channel is selective for cations, and allows sodium, calcium and potassium to flow through. The calcium conductance is very small and can be ignored. @Which direction will sodium flow through the channel? @ Which direction will potassium flow? (5) The conductance of the nAChR to sodium is slightly greater than its conductance to potassium. @ What would happen to the postsynaptic potential in the muscle cell if the permeability to sodium equaled the permeability to potassium? (6) The size of a PSP in chemical synapses depends on a number of factors: (a) It will depend on the reversal potential of the channel. The reversal potential for a given receptor at a given synapse is constant, because it depends on the selectivity of the channel and the driving forces on the ions, which will generally not change. (b) It will depend on the number of channels opened. The number of channels opened can be increased by increasing the amount of transmitter released, by increasing the number or duration of action potentials in the presynaptic cell. Page 9-5 (c) It depends on the resting conductance through leak channels, because this leak conductance counteracts the effect of the neurotransmitter receptor channel opening, tending to keep the cell close to resting membrane potential. The conductance through leak channels can be changed by closing some leak channels. @ What effect will this closing of leak channels have on the EPSP? Chemical synapses - direct synaptic inhibition Direct synaptic excitation: opening channels whose reversal potential is positive to threshold. Direct synaptic inhibition: opening channels whose reversal potential is negative to threshold. Direct synaptic inhibition generally opens receptor channels that are selective for either chloride or (less frequently) potassium. @ An example of an inhibitory transmitter receptor permeable to chloride is the GABAA receptor. The reversal potential for this receptor would be: @ If GABAA receptors are found on a cell that does not regulate its chloride concentration, will there be any current when these channels are open? @ Will the effect of GABAA receptor still be inhibitory? Page 9-6 Presynaptic inhibition Presynaptic inhibition is when a synapse onto a presynaptic terminal causes a decrease in the amount of transmitter released. In this case there is no direct effect of the inhibition on the postsynaptic cell. Example: An excitatory neuron (E) synapses onto a muscle, and an inhibitory neuron (I) synapses directly onto the muscle, but also synapses onto the excitatory neuron terminal. (A) Stimulating the excitatory neuron produces an EPSP. (B) Stimulating the inhibitory neuron produces an IPSP. The IPSP have close to zero amplitude is because reversal potential is very close to membrane potential. (C) If the excitatory neuron is stimulated and then the inhibitory neuron is stimulated, the EPSP looks normal. (D) If the order is reversed, with the inhibitory neuron firing first, the EPSP is nearly abolished. This is because the inhibitory synapse onto the terminal opens chloride channel, allowing negative ions to enter the terminal, reducing or eliminating the effects of the inward sodium current produced by the action potential. Therefore few or no voltage gated calcium channels open, so little or no transmitter is released, so there is little or no EPSP in the muscle. Presynaptic excitation Presynaptic excitation also exists. In this case, excitatory transmitter released onto the presynaptic terminal depolarizes the terminal increasing the amount of transmitter released for each action potential. Indirect synaptic transmission: chemical synapses with metabotropic receptors Page 9-7 The metabotropic receptors are not themselves ion channels as ionotropic receptors are. Instead, metabotropic receptors activate G proteins (proteins that bind guanine nucleotide) which activate second messenger pathways which eventually act to open or close ion channels. (1) G protein coupled metabotropic receptors have seven membrane crossing regions with an extracellular amino terminus and an intracellular carboxy terminus. (2) When neurotransmitter binds to a G-protein coupled metabotropic receptor, GDP is exchanged for GTP on the subunit of the G protein. This dissociates the subunit from the / complex, activating both halves and allowing them to interact with targets. (3) Activated G proteins can directly affect ion channels. An example is the muscarinic AChR in the heart. ACh binding to the receptor activates a G protein. The / subunit of this G protein binds to and activates potassium channels, slowing the heart rate. (4) G proteins can also work through second messenger cascades. An example is norepinephrine binding to -adrenergic receptors on the heart, increasing heart rate. In this case, the activated G protein subunits activate adenyl cyclase, converting ATP to cyclic AMP, which activates cAMPdependant protein kinases, which phosphorylate calcium channels, increasing the probability that they will open. (5) G proteins can activate other signaling pathways. G proteins can activate phospholipase C, hydrolyzing PIP2 into IP3 and diacylglycerol (DAG), which then activate protein kinase C which again phosphorylates calcium channels increasing their open probability. Page 9-8 G proteins can activate phospholipase A2 to release arachidonic acids from membrane phospholipids. Arachodonic acid can act directly on ion channels. It can act indirectly by activating protein kinase C, or act through the actions of its metabolites. (6) Learning and memory. The affects of metabotropic receptors are slower but longer lasting than the affects of ionotropic receptors. The second messenger cascades are slow, taking seconds to minutes to reach their peak affect. The affects of second messenger cascades can be extremely long lasting, because second messengers can activate transcription factors, which can alter gene expression, causing in some cases life-long changes in synapses. ...
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