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Basic Electrophysiology Valeria Fu November 3, 2014 Neurons • Cells in the nervous system • Vary in structure and properties • Their fundamental task is signaling • Neurons respond to stimuli, conduct impulses and send signals • Neurons encode information by a combination of electrical and chemical signals. Electrical Signaling in Neurons Electrical Signaling in Neurons Presynaptic neuron Postsynaptic neuron • Electrical signals in the presynaptic neuron cause the release of neurotransmitter; the neurotransmitter binds to receptors of the postsynaptic neuron and triggers electrical signal (synaptic potentials) Plasma Membrane • The entire neuron is enclosed by a plasma membrane • The plasma membrane: • a double layer (bilayer) of phospholipid molecules • provides a resistance to the flow of ions entering or leaving the cell (resistor) • Allows to store charge inside the cell (capacitor). • Separating electrical charges between extracellular and intracelluar spaces Membrane Potential • • • • • Uneven distribution of ions inside and outside of the membrane Sodium (Na+) and Chloride (Cl-) are more concentrated outside the cell. Potassium (K+) and organic anions (A-) are more concentrated inside the cell Inside cell membrane, it is negatively charged. The electrical potential difference across the membrane at any moment in time is known as the Membrane Potential (Vm) • Vm = Vin - Vout Resting Membrane Potential • • • • When the cell/axon is not conducting impulses; it is said to be at rest Resting potential ranges from about -60 mV to -70 mV Membrane is selectively permeable to K+ Permeable to Na+ is low • To maintain the steady resting membrane potential, the charge separation across the membrane must be constant: • Influx of positive charge ≈ efflux of positive charge • • • • • Resting state of the cell is achieved by: 1. Gibbs-Donnan Equilibrium 2. Equilibrium Potential & Nernst Equation 3. ATP-dependent 3 Na+-K+ Pump 4. Ion Channels 1. Gibbs-Donnan Equilibrium • Uneven distribution of charged ions on one side of a semipermeable membrane • Diffusion occurs when ions move from areas of high concentration to low concentration down a concentration gradient (Chemical driving force). • Concentration of 2 ions of opposite sign on each side (extracellular and intracellular) of the membrane are affected by the electrostatic repulsion (same sign repulses) and attraction (opposite sign attracts).(Electrical driving force) • At rest, K+ diffuses down to the concentration out of the cell (Chemical driving force)leaving surplus of anion (A-) inside the cell • Excess cation outside the cell pushes K+ back to the cell (Electrical driving force) • Until K+ concentration inside and outside the cell are in equilibrium (-75mV) • Resting membrane potential (Vr ) settles at K+ equilibrium potential (Ek) • Vr = Ek 2. Equilibrium Potential & Nernst Equation • membrane potential where the net flow through any open channels is zero • Depends on the concentration gradient of an ion • Equilibrium potential of an ion can be calculated from the Nernst equation derived by Walter Nernst (1888): • Ex = RT In [X+]o ZF [X+]i • Ex = membrane potential at which ion X is in equilibrium • R = gas constant • T = temperature • Z = charge on the ion • F = Faraday constant • [X+]o & [X+]I = concentration of ion inside and outside of the cell • For monovalent ions at room temperature, the Nernst equation reduces to: • Ex = 58 log10 [X+]o [X+]i Goldman-Hongkin Katz Equation • Changing extracellular concentration of each ion has a strong effect on resting membrane potential and could be calculated by: • Permeability ability ratios for membrane at rest : • PK:PNa:PCl = 1/0.04/0.45 3. ATP-dependent Na+-K+ pump • 3 Na+ transport outward for every 2 K+ inward • And contributes to the resting potential • Consequences: • 1. causes a net transfer of charge across the membrane. Pump is electrogenic: cause to cell to hyperpolarize • 2. passive movements of Na+ and K+ are unequal • 3. decreases the osmolarity of the intracellular fluid and balances the effect of impermeant anion in the cytosol 4. Ion Channels • Neuronal signaling is based on the movements of ions across cell membrane. • Hydrophilic pores through which ions flow from extracellular space to intracellular space or vice versa down their concentration gradients. • There are gated and non-gated ion channels in membrane. • Voltage-dependent gated ion channels: • 1. Probability of opening of channels is strongly influenced by voltage only • 2. Opening and closing of channels are influenced by changes in membrane potential close to normal resting potential. Ohm’s Law • Current flow (I) between extraceullar space and intracellular space depends on the voltage difference (V) and Resistance to current flow (R) • I= V R • Voltage difference (Vm – Ex) is called Driving Force • Conductance (G) is the inverse of resistance: • G = 1/R • Ix = (Vm – Ex) Gx • X = ion Equivalent Electrical Circuit • Membrane is a Capacitor and a Resistor connected in parallel. • Neuronal signaling is based on the movements of ions across cell membrane. • We can calculate the number of ions must move through membrane in order to give rise to the membrane potential: • V = Q/C • Q = charge • C = capacitance • V = electrical potential Neuronal Signal Transmission • Neurons use a single type of signal to transmit information over a long distance. Action Potentials • When the dendrite/axon/nerve is conducting an impulse. • Large, brief, invariant signals propagate along the axons without decrement. • “all-or-none” • Opening and closing of a sodium channel and a potassium channel in a precise timing give a transient changes in membrane potential which allows electrical signals travels along axons at speed up to 120 meter per second. • • • • • Four Stages: 1. Resting Potential 2. Depolarization (Rising phase) 3. Repolarization (Falling phase) 4. Undershoot (After-hyperpolarization) 1. Resting Potential • • • • When the axon is at rest (-70mV) Neither Na+ or K+ ion channel is open Steady Na+ influx is balanced by steady efflux of K+ ATP-dependent Na+-K+ pump is at work 2.Depolarization (Rising phase) • When the nerve fiber is stimulated, synaptic inputs (Post-synaptic neuron ) to a neuron cause the membrane to depolarize (membrane potentials are less negative) • A transient depolarizing potential (i.e. excitatory synaptic potential) causes opening of some voltage-gated Na+ channels. • Increase membrane Na+ permeability and allows influx of Na+ to further depolarize the membrane • Increase in depolarization allows influx of more positive charge flow inside the cell. • When depolarization of membrane exceeds threshold, Action Potentials result. Action Potentials • To transfer information from one part of the neuron to another • ‘All-or None’ law: • The strength of neuronal response is independent of stimulus strength; Once the stimulus is above threshold, it produces full size action potentials to minimize the possibility that the information is lost along the way down the axon. Action Potentials • Latency, the time delay from the onset of stimulus to the peak of action potentials, is the function of stimulus strength (strength-latency relationship) • The larger the depolarizing stimulus, the greater the frequency of action potential firing Frequency coding in axons 2. Depolarization (Rising Phase) • Sodium conductance exceeds Potassium conductance • Net inward current drives the membrane potentials toward Na+ equilibrium (+55mV) • Sodium permeability decreases when the action potential approaches the peak which results from inactivation of sodium channel -> no longer respond to depolarization • Potassium conductance responds more slowly and starts to increase when the action potential is near to its peak. 3. Repolarization (Falling phase) • Delay opening of Potassium channel • Inactivation of Sodium channel • Efflux of K+ increases carrying their positive charge with them • Thus lead to hyperpolarization (membrane potential is more negative) • Bring the membrane potential back to resting state (-60 mV to -70 mV) 4. After-hyperpolarization • Potassium conductance is higher than normal • Sodium conductance is lower than normal • Membrane potentials is driven closer to the equilibrium of K+ (-90mV) than it is at rest (60 – 70mV) Refractory Period • Immediately after an action potential • Refractory period: threshold is higher than normal to initiate another action potential. • Absolute refractory period: the threshold is infinite, impossible to evoke another action potential • Relative refractory period: requires a larger than normal stimulus to evoke an action potential. Review: Action Potential Action Potential Propagation • Passive spread (local potential): voltage change spreads from one point to another, but with attenuation with distance. • Vd = Voe -d/ • Even voltage changes at distance, local depolarization is large enough to spread to the adjacent region of the axon to generate a full size action potential Action Potential Propagation • Part of the inward Na+ current flows down to interior of axon to produce local potential in advance of an action potential • Local potential depolarizes the membrane • Activated voltage-gated Na+ channels • When reach threshold, inward current further depolarizes the membrane and acts as a source for local potential change. • The inward current flows downstream and moves the action potential along the axon. • Due to refractory period, inward current will not initial another action potential in towards the cell body. • Therefore, action potentials propagate in ONE direction. Saltatory Conduction • An axon is myelinated. • In the myelinated area, there is no inward current of Na+ when the Na+ channels open because there is no extracellular Na+ • The only place that the myelinated axon comes to contact with extracellular fluid is at the Node of Ranvier where the axon is unmyelinated. • Action potential jumps from node to node to propagate down the axon. This is called saltatory conduction. Synaptic Potentials • Action potential travels along the axon down to the presynaptic terminal • The depolarization of the presynaptic neuron triggers the release of neurotransmitter in the cleft. • When the neurotransmitter binds to the receptor of the post-synaptic neuron, it gives rise to the synaptic potentials. • In the central nervous system (CNS), glutamate is the major excitatory neurotransmitter which generate excitatory postsynaptic potentials (epsp). • While GABA or glycine is commonly the inhibitory neurotransmitter which open the channels of K+ and Cl-. In turn, it hyperpolarizes the cell and makes depolarization to threshold more difficult. This synaptic potential is called inhibitory postsynaptic potentials (ipsp). Passive Membrane Properties • They are constant during neuronal signaling • They affect the electrical signaling process: • 1. Time course of electrical signals • 2. Efficiency of signal conduction Time Course of Electrical Signals • Membrane acts as an electrical capacitor(Cm) and resistor (Rm) • The shape of change of a potential (voltage) is determined by the fact that membrane capacitance and resistance are in parallel. • Charged (discharged) of membrane capacitance does not occur instantaneously. • Time constant . • = Rm Cm • Voltage changes exponentially with time (t) • Vt = Vo e –t/ • Voltage falls to 1/ e of its initial value Vo in a time equal to one time constant (). • The longer the time constant, the longer duration of synaptic potential -> more chance for temporal summation (small potentials adding together) -> higher chance to drive membrane potential for an action potential Efficiency of Signal Conduction • 1. Axoplasmic resistance: • the greater length of the axoplasmic core, the greater the resistance (ion collisions along the dendrite) , the smaller the current. • Vm = Imrm • 2. Insulation of the membrane: • the better the insulation, the further the current spread along the dendrite/axon, the faster the velocity of action potential • Length constant () = rm/ra • Where rm = membrane resistance; ra = axial resistance • Myelination of axon affects velocity of action potential • 3. Axon Diameter: • The larger the axon diameter, the lower resistance of axoplasm to flow of current; more effective depolarization of membrane, the faster the velocity of action potential. Review Review Review Review Review Presynaptic neuron Postsynaptic neuron References • Principles of Neural Science (Kandel, Schwartz & Jessell) • Molecular Neurobiology (Zach Hall) • The Neuron (Levitan & Kaczmarek) • Ionic Channels of Excitable Membranes (Bertil Hille)