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FIGURE 5–1. Determining the ionic nature of a synaptic event.At least three techniques can be used to determine the ionic species that mediates a synaptic response: determining the reversal potential of the ion, reversing the membrane potential deflection produced by changing the concentration gradient of the ion across the membrane, and determining the reversal potential (or blocking the synaptic response) after applying a specific ion channel blocker. In this figure, three techniques are used to illustrate the involvement of a chloride ion conductance increase evoked in dopamine-containing neurons by stimulation of the striatonigral -aminobutyric acid (GABA)ergic projection. (A) The reversal potential of a response may be determined by examining the amplitude of the response as the membrane potential of the neuron is varied. In this example, we superimposed several responses of the neuron evoked at increasingly hyperpolarized membrane potentials (top traces), with the membrane potential altered by injecting current through the electrode and into the neuron (bottom traces = current injection). (A1) A synaptic response in the form of an inhibitory postsynaptic potential (IPSP) is evoked in a dopamine neuron by stimulating the GABAergic striatonigral pathway (arrow). When increasing amplitudes of hyperpolarizing current (lower traces) are injected into the neuron through the electrode, a progressive hyperpolarization of the membrane occurs (top traces). As the membrane is made more negative, the IPSP diminishes in amplitude, eventually being replaced by a depolarizing response. (A2) Plotting the amplitude of the evoked response (y-axis) against the membrane potential at which it was evoked (x-axis) illustrates how the synaptic response changes with membrane potential. The membrane voltage at which the synaptic response is equal to zero (i.e., ~69.2 mV in this case) is the reversal potential of the ion mediating the synaptic response (i.e., the potential at which the electrochemical forces working on the ion are zero). Therefore, there is no net flux of ions that cross the membrane. At more negative membrane potentials, the flow of the ion is reversed, causing the chloride ion (in this case) to exit the cell and result in a depolarization of the membrane. (B) The flow of an ion across a membrane may also be altered by changing the concentration gradient of the ion across the membrane. Normally, chloride ions flow from the outside of the neuron (where they are present at a higher concentration) to the inside of the neuron (where their concentration is lower), causing the membrane potential to become more negative. In this case, the concentration of chloride ions across the membrane of the dopamine neuron is reversed by using potassium chloride as the electrolyte in the intracellular recording electrode. (B1) Soon after the neuron is impaled with the potassium chloride–containing electrode, stimulation of the striatonigral pathway (arrow) evokes an IPSP (bottom trace). However, as the recording is maintained, chloride is diffusing from the electrode into the neuron, causing the electrochemical gradient to decrease progressively over time. As a result, each subsequent stimulation pulse evokes a smaller IPSP, eventually causing the IPSP to reverse to a depolarization (top trace). The depolarization is caused by an efflux of chloride ions out of the neuron and down its new electrochemical gradient. This has caused the reversal potential of the chloride-mediated response to change from a potential that was negative to the resting potential to one that is now positive to the resting potential. (B2) After injecting chloride ions into the neuron, spontaneously occurring IPSPs that were not readily observed in the control case are now readily seen as reversed IPSPs (i.e., depolarizations) occurring in this dopamine neuron recorded in vivo. (C) Another means for determining the ionic conductance involved in a response is by using a specific ion channel blocker. This can be done in two ways: by using the drug to block an evoked response or (as shown in this example) by examining the effects of administering the drug on the neuron to determine whether the cell is receiving synaptic events that alter the conductance of the membrane to this ion. To do this, the current–voltage relationship of the cell is first established. This is done by injecting hyperpolarizing current pulses into the neuron (x-axis) and recording the membrane potential that is present during the current injection (y-axis). These values are then plotted on the graph (filled circles), with the resting membrane potential being the membrane potential at which no current is being injected into the neuron (y-intercept). The slope of the resultant regression line (solid line) is equal to the input resistance of the neuron (Rinput = 36 megohms). After administration of the chloride ion channel blocker picrotoxin (open boxes), a new current–voltage relationship is established in a similar manner. Picrotoxin caused a depolarization of the membrane (y-intercept of dashed line is more positive) and an increase in the neuron input resistance (the slope of the dashed line is larger). The intersection of the membrane current–voltage plots obtained before and after picrotoxin administration is then calculated. By definition, this point of intersection (i.e., ~75 mV) is the reversal potential of the response to picrotoxin, because a neuron at this membrane potential would show no net change in membrane potential on drug administration.Source. Adapted from Grace AA, Bunney BS: "Opposing Effects of Striatonigral Feedback Pathways on Midbrain Dopamine Cell Activity." Brain Research 333:271–284, 1985. Copyright 1985, Elsevier. Used with permission.

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