NESC 2570 Module 2 - Lecture 2 - Transmission at Electrical and Chemical Synapses PDF

NESC / PSYO / PHYL 2570 Module 2 - Lecture 2 Transmission at electrical and chemical synapses Transmission ! Synaptical Dr. Stefan Krueger Dept of Physiology & Biophysics...

NESC / PSYO / PHYL 2570 Module 2 - Lecture 2 Transmission at electrical and chemical synapses Transmission ! Synaptical Dr. Stefan Krueger Dept of Physiology & Biophysics [email protected]  2. Transmission at electrical and chemical synapses 2.1. Synapses: Definition and classification 2.2. Electrical synapses: Structure and functional properties 2.3. Structure of chemical synapses 2.4. Sequence of events during transmission at chemical synapses Presynaptic- AP-> release NT 2.5. Postsynaptic currents and potentials Creates post-Synaptic potential neuron in post Synaptic 2.6. Excitatory and inhibitory synaptic currents and potentials 2.7. Dendritic integration of postsynaptic potentials  Synapses: Definition and classification Definition A synapse are specialized zone of contact at which one neuron communicates with another. Some Numbers ‣ Neurons in the human brain: 1012. - Can have neurons with few or many ‣ The average neuron receives 1000 synapses (large range). ‣ Number of synapses in the human brain: 10 15. Trillion Classes of synapses ‣ Electrical synapses: Junctions between neurons permitting direct, passive flow of electrical current ‣ Chemical synapses: Junctions between neurons that communicate via the secretion of neurotransmitters AP-> Chemical by NT - Post-Synaptic + turns back detects this Back to index 2 Selectrical ) 3 into electrical Signal  2.2. Electrical synapses 2.2.1. What structure do electrical synapses have? 2.2.2. What are the properties of transmission at electrical synapses? 2.2.3. Where do electrical synapses occur occur and what is their function? 2.2.4. Regulation of transmission at electrical synapses  Structure of electrical synapses Electrical synapses are gap junctions ‣ Gap junctions at sites of close (3 nm) cell apposition Gap polypeptides made Junction channels from - electrical ‣ Precisely aligned, paired hemichannels made of connexins Align hemichannels with of other cell connexin hemichannel gap junction gap junction x6 x2 x103 channel Back to index 2.2. 5  Properties of transmission at electrical synapses Transmitted signals Large pares ! Pores of gap junction channels > - act Slow as door changes wide (14-20 Å), non-selective => better than fast ‣ diffusion of all ions selectivity No filter ‣ Also other small compounds (e.g. second messengers) Properties of electrical transmission ‣ extremely fast (latency 2.3.1. What are common structural features of chemical synapses? 2.3.2. What features lead to structural and functional diversity of chemical synapses? 2.3.3. How does the location of synapses contribute to synaptic diversity? Back to main index  Common structural features of chemical synapses Common structural features 1. Presynaptic bouton of the presynaptic neuron 2. Synaptic vesicles containing neurotransmitter (NT) 3. Active zone: Specialized zone at the presynaptic membrane where exocytosis of NT occurs 4. Synaptic cleft: Extracellular space between pre- and postsynaptic neuron 5. Postsynaptic specialization containing NT receptors, signalling and scaffolding proteins - beneath of post-Synaptic plasma membrane cell 13 Back to index 2.3.  Structural diversity of chemical synapses Apparent symmetry of pre- and postsynaptic specialization (Gray) ‣ Asymmetrical synapses (type I; excitatory) ‣ Symmetrical synapses (type II; inhibitory) ↓ Post Synaptic much thicker 14  Diversity in the location of chemical synapses Synapses formed onto various postsynaptic structures: ‣ Axospinous synapses = synapses onto dendritic spines; often excitatory; structural plasticity and biochemical compartmentalization ‣ Axodendritic synapses = synapses onto dendritic shafts; excitatory or inhibitory ‣ Axosomatic synapses frequently inhibitory ‣ Axo-axonic synapses inhibitory ‣ Dendro-dendritic inhibitory ‣ Neuromuscular junctions excitatory (to contract) Back to main index 15  2.4. Sequence of events during transmission at chemical synapses 2.4.1. How does an action potential elicit the release of neurotransmitter in the presynaptic neuron? 2.4.2. How does NT receptor activation lead to postsynaptic potentials? 2.4.3. How is transmission at chemical synapses is terminated? Back to main index  How action potentials elicit the release of neurotransmitter Chemical Synapse : 1. Action potential arrives 2. Voltage-gated Ca2+ channels open In plasma membrane of pre-Synaptic-cytoplasmic cast Come rises dramatically. 3. Ca2+-triggered exocytosis of neurotransmitter by binding - 4. NT binds to receptors in membrane post-synaptic Back to index 2.4. 17  How NT receptor activation leads to postsynaptic potentials (1) Neurotransmitter binds to: A. Ionotropic neurotransmitter receptors = Ligand-gated ion channels conducting Na+/K+ or Na+/K+/Ca2+ or Cl- Anion or cation - Current fast in onset, decays quickly Leads to come Change in post-Synaptic potential - , -membrane potential change very fast B. Metabotropic receptors = G protein-coupled receptors that cause opening of ion channel (often K+) via G protein and or second messenger - Current slow in onset, long-lasting -Leads to development of post-synaptic potential > Slower than the conformation for Ionotropic change G-proteins inactivated But Post-synaptic more sustained ! B/ change18 in conductance keep going until  How NT receptor activation leads to postsynaptic potentials (2) 1. Action potential arrives 2. Voltage-gated Ca2+ channels open 3. Ca2+-triggered exocytosis of neurotransmitter 4. NT binds to ionotropic or metabotropic receptors, eliciting synaptic current 5. The postsynaptic current leads - to a postsynaptic potential - Post - Synaptic membrane potential Back to index 2.4. 19  How transmission at chemical synapses is terminated Need repolarization 1. Voltage-gated Na+ channels inactivate 2. Voltage-gated K+ channels open, presynaptic membrane repolarized 3. Voltage-gated calcium channels close after repolarization of the presynap- tic membrane. 4. Na+/K+-ATPase, PM Ca2+-ATPase re-establish presynaptic ion gradients. 5. Neurotransmitter is removed from synaptic cleft. prevent to degraded - NT activation continued by enzyme or 6. Some ionotropic receptors transported back into cell desensitize ligand in presence of 7. Postsynaptic potential dissipates causes decay ! Back to index 2.4. 20  2.5. Postsynaptic currents and potentials 2.5.1. What determines the time course of postsynaptic currents and potentials? 2.5.2. What determines direction and amplitude (=size) of postsynaptic currents and potentials? 2.5.3. How is the reversal potential of a synaptic current calculated and what can the reversal potential can tell us about ion flow across the membrane? Back to main index  Time course of postsynaptic currents and potentials (1) Studied with Patch Clamp ‣ Individual ligand-gated ion channels only open for few ms; closes as ligand unbinds or channel desensitizes In continued presence of ligand ion channel ‣ Synapse: Many ligand-gated ion When NT bind + unbind opens + closes channels open near simultaneously, close at different times => fast rise time, slower decay time of postsynaptic current ‣ Postsynaptic potential has sse and decay times (due to capacitive property of membranes) Jumps from when no current to lots of current 22 receptor opens  Time course of postsynaptic currents and potentials (2) ‣ Individual ligand-gated ion channels only open for few ms; closes as ligand unbinds or channel desensitizes ‣ Synapse: Many ligand-gated ion channels open near simultaneously, close at different times => fast rise time, slower decay time of postsynaptic current - membrane behaves as capacitor ‣ Postsynaptic potentials have slower rise and decay times (due to capacitive property of membranes) Back to index 2.5. 23  Direction postsynaptic currents and potentials come. gradient Jexent force ↑ electrical gradient ‣ Flux of ions across membrane determined by electrochemical gradient ‣ If membrane potential (Vm) is equal to reversal potential Erev, no net charge = O transfer across membrane, i.e. no synaptic current (I) and no potential change ‣ Um < Erev, Opening If VmEver = - > of cations (or efflux influx of channel will not lead to of anions): Inward any current (I < 0) current Um won't across membrane. change. ‣ If Vm > Erev, efflux of cations (or influx of anions): Outward current (I > 0) 24  Direction postsynaptic currents and potentials ‣ Flux of ions across membrane determined by electrochemical gradient ‣ If membrane potential (Vm) is equal to reversal potential Erev, no net charge transfer across membrane, i.e. no synaptic current (I) and no potential change Post-synaptic current depolarizes ‣ If Vm < Erev, influx of cations (or efflux of anions): Inward current of cations (I < 0) Electrical gradient exerts bigger ‣ If Vm > Erev, efflux of cations (or influx force ? into (vm) current (I > 0) cations membrane Outward of anions):potential of will Cytoplasm change in direction reversal potential (Ever) no further Um change ! 25  Direction postsynaptic currents and potentials ‣ Flux of ions across membrane determined by electrochemical gradient ‣ If membrane potential (Vm) is equal to reversal potential Erev, no net charge transfer across membrane, i.e. no synaptic current (I) and no potential change ‣ If Vm < Erev, influx of cations (or efflux of anions): Inward current of cations (I < 0) ‣ If Vm > Erev, efflux of cations (or influx of anions): Outward current of cations (I > 0) Conc - gradient will exertgreater force on ions than out ! Hyperpolarize ! electrical gradient. Cations go 26  > - Amplitude of driving Dependent on a conductance force. postsynaptic currents ‣ The greater the difference between membrane potential Vm and reversal potential Erev, the greater the synaptic current I: I = g * (Vm - Erev) ‣ Vm - Erev is called the driving force. ‣ Conductance g changes with the number of synaptic ion channels and their ability to facilitate diffusion of ions. -how easy membrane to cross ‣ Equation is called Ohm’s Law. Note: For some ion channels and synapses, g changes with membrane potential. Back to index 2.5. 27  Calculation of Erev if ion channel is selective for one ion species ‣ If ion channel is selective for a single ion species, its reversal potential is the equilibrium potential for this ion. The reversal potential can be calculated according to the Nernst equation: where [X]out and [X]in are the extracellular and intracellular concentrations of the ion, respectively, T is the temperature in Kelvin, z the charge of the ion, R the gas constant, and F the Faraday constant 28  Ionic currents through ion-selective channels Example: Postsynaptic currents and potentials of synapses containing chloride channels assuming [Cl-]out=110 mM and [Cl-]in = 15 mM ‣ The reversal potential is ‣ At Vm < -50 mV, Cl- flows out of the cell and membrane depolarizes ‣ At Vm > -50 mV, Cl- flows into the cell and membrane hyperpolarizes Inward current of (t) move in but Ap Ligand - ‣ Inhibitory postsynaptic currents and potentials (IPSCs and IPSPs) inhibit the generation of a postsynaptic action potential. ‣ Postsynaptic currents and potentials are inhibitory if Erev is more negative than the action potential threshold. Two cases: ‣ Erev < Vrest: Hyperpolarization ‣ Vrest < Erev < Vthreshold: Harder for excitatory input to move Vm to action potential threshold: Shunting inhibition 35 Example: GABAergic synapses  Inhibitory postsynaptic currents and potentials (2) ‣ Inhibitory postsynaptic currents and potentials (IPSCs and IPSPs) inhibit the generation of a postsynaptic action potential. ‣ Postsynaptic currents and potentials are inhibitory if Erev is more negative than the action potential threshold. Two cases: ‣ Erev < Vrest: HyperpolarizatAp ion cannot further depolarize than Ever ‣ Vrest < Erev < Vthreshold: Harder for excitatory input to move Vm to action potential threshold: Shunting inhibition * * Inhibitory Goldman - use Difference between more difficult equation to figure out new membrane potential - for excitatoryto Erev and action is smaller potential further Back to main index 36 depolarize  2.7. Dendritic integration of synaptic input 2.7.1. When does excitatory input elicit action potentials in the postsynaptic neuron? 2.7.2. How does the location of an excitatory synapse influence its ability to facilitate postsynaptic action potentials? 2.7.3. Is there a mechanism to amplify excitatory input at distal synapses? Back to main index  Spatial summation of EPSPs to elicit action potentials Needs depolarization ↓ ‣ EPSPs derived from activation of single synapses small: Cannot elicit action potentials by themselves ‣ Action potential threshold can be reached through spatial summation 4 of simultaneously activated depolarize EPSPs Summarize up ↓ AP excitatory synapses threshold ‣ Spatial summation usually occurs at the axon initial segment ‣ Inhibitory input (negatively) contributes to spatial summation ↳ IPSPs Back to index 2.6. 38  Synapse location matters: Effects of dendritic cable filtering ‣ Synapses on distal dendrites at disadvantage in eliciting action potentials in axon Proximal initial segment: Electrotonic decay of EPSP as it is propagated to action potential initiation site distal - Excitation from far away is at a great disadvantage EPSP needs to propogate from Synapse - to initial Segment EPSP Subject to electrotonic , - Leak channels cause EPSP decay to be smaller Back to index 2.6. 39.  Voltage-gated conductances in dendrites can amplify local EPSPs Distal (far away)Synapses get help from in dendrites voltage-gated channels (distal dendrites) ‣ In many neurons, coincident activation of clustered exci- tatory synapses can lead to opening of dendritic voltage- gated sodium or calcium channels ‣ Resulting dendritic spike amplifies EPSPs fam away Back to main index 40  Review questions for lecture 2 1. Describe the structure of electrical synapses and discuss their occurance and function. 2. Compare transmission at electrical and chemical synapses with respect to directionality, synaptic delay, sign and amplitude of postsynaptic potential changes. 3. Discuss common and discriminating (1,2,3) ultrastructural features of chemical synapses. 4. Describe the sequence of events of chemical synaptic transmission from the arrival of an action potential to the termination of transmission (continued on next slide) 41  Review questions for lecture 2 (continued from previous slide) 5. Describe the mechanisms governing the timecourse, direction (1,2,3), and amplitude of postsynaptic currents and postsynaptic potentials. 6. A synapse contains chloride-permeable ionotropic receptors. The resting membrane potential of the neuron is -70 mV and the action potential threshold has been determined to be -38 mV. The temperature is 310 K. Predict the effects of the receptor activation on membrane potential and excitability (1,2) if the chloride concentrations are a) [Cl-]in= 12 mM, [Cl-]out = 120 mM b) [Cl-]in= 32 mM, [Cl-]out = 120 mM. (continued on next slide) 42  Review questions for lecture 2 (continued from previous slide) 7. A researcher is characterizing synaptic connections conc conc in a squid. She hypothesizes that one of the ion inside outside synapses she is studying may utilize ionotropic NT (mM) (mM) receptors that are equally permeable to Na+ and K+ 400 20 K+. Extracellular and intracellular ion Na 40 420 concentrations shown in the table to the right. + What reversal potential should she find at this synapse if her hypothesis is correct? 8. Discuss, using the terms spatial summation, electrotonic decay, and dendritic spikes, how synapses E1, E2, and I in the figure on the right contribute to action potential generation in the postsynaptic neuron. 43