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Chapter 5. Electrophysiology

Anthony A. Grace, Ph.D.; J. Amiel Rosenkranz, Ph.D.; Anthony R. West, Ph.D.
DOI: 10.1176/appi.books.9781585623860.408404

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Several approaches can be used to analyze the structure and function of the nervous system in health and disease. Many of these techniques—for example, the biochemical analysis of neurotransmitter and metabolite levels, anatomical studies of axonal projection sites or neurotransmitter enzymes, and molecular biological studies of messenger levels and turnover—examine the nervous system at the level of groups or populations of neurons. In contrast, by its very nature, electrophysiology is oriented toward the physiological analysis of individual neurons. In this chapter, we describe preparations and techniques that are in a general sense applicable to many systems, with specific examples from the dopaminergic system to draw on our field of expertise.

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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.

FIGURE 5–2. Detection of changes in firing rates and pattern of spike discharge by extracellular recording measurements.Extracellular recording techniques are an effective means of assessing the effects of afferent pathway stimulation or drug administration on neuron activity. On the other hand, the measurements that can be made are typically restricted to changes in firing rates or in the pattern of spike discharge. (A) This firing rate histogram illustrates the response of a substantia nigra–zona reticulata neuron to stimulation of the -aminobutyric acid (GABA)ergic striatonigral pathway. A common method for illustrating how a manipulation affects the firing rate of a neuron is by constructing a firing rate histogram. This is typically done by using some type of electronic discriminator and counter to count the number of spikes that a cell fires in a given time. In this example, the counter counts spikes over a 10-second interval and converts this number to a voltage, which is then plotted on a chart recorder. The counter then resets to zero and begins counting spikes over the next 10-second interval. Therefore, in this firing rate histogram, the height of each vertical line is proportional to the number of spikes that the cell fires during each 10-second interval, with the calibration bar on the left showing the equivalent firing frequency in spikes per second. During the period at which the striatonigral pathway is stimulated (horizontal bars above trace marked "STIM"), the cell is inhibited, as reflected by the decrease in the height of the vertical lines. When the stimulation is terminated, a rebound activation of cell firing is observed. (B) In this figure, a similar histogram is used to illustrate the effects of a drug on the firing of a neuron. (B1) This figure shows the well-known inhibition of dopamine neuron firing rate on administration of the dopamine agonist apomorphine (APO). Each of the filled arrows represents the intravenous administration of a dose of APO. After the cell is completely inhibited, the specificity of the response is tested by examining the ability of the dopamine antagonist haloperidol (HAL [open arrow]) to reverse this response. Typically, drug sensitivity is determined by administering the drug in a dose–response fashion. This is done by giving an initial drug dose that is subthreshold for altering the firing rate of the cell. The first dose is then repeated, with each subsequent dose given being twice that of the previous dose. This is continued until a plateau response is achieved (in this case, a complete inhibition of cell discharge). (B2) The drug is administered in a dose–response manner to facilitate the plotting of a cumulative dose–response curve, with drug doses plotted on a logarithmic scale (i.e., a log dose–response curve). To compare the potency of two drugs or the sensitivity of two cells to the same drug, a point on the curve is chosen during which the fastest rate of change of the response is obtained. The point usually chosen is that at which the drug dose administered causes 50% of the maximal change obtained (i.e., the ED50). As is shown in this example, the dopamine neurons recorded after a partial dopamine depletion (dashed line) are substantially more sensitive to inhibition by APO than the dopamine neurons recorded in control (solid line) rats. (C) In addition to determining the firing rate of a neuron, extracellular recording techniques may be used to assess the effects of drugs on the pattern of spike discharge. This is typically done by plotting an interspike interval histogram. In this paradigm, a computer is connected to a spike discriminator, and a train of about 500 spikes is analyzed. The computer is used to time the delay between subsequent spikes in the train (i.e., the time interval between spikes) and plots this in the form of a histogram, in which the x-axis represents time between subsequent spikes and the y-axis shows the number of interspike intervals that had a specific delay (bin = range of time; e.g., for 1-msec bins, all intervals between 200.0 and 200.99 msec). (C1) The cell is firing irregularly (as shown by the primarily normal distribution of intervals around 200 msec), with some spikes occurring after longer-than-average delays (i.e., bins greater than 400 msec, probably caused by spontaneous inhibitory postsynaptic potentials [IPSPs] delaying spike occurrence). (C2) In contrast, this cell is firing in bursts, which consist of a series of 3–10 spikes with comparatively short interspike intervals (i.e., approximately 70 msec) separated by long delays between bursts (i.e., events occurring at greater than 150-msec intervals). The computer determined that in this case, the cell was discharging 79% of its spikes in bursts, compared with 0% in (C1).Source. (A) 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. (B) Adapted from Pucak ML, Grace AA: "Partial Dopamine Depletions Result in an Enhanced Sensitivity of Residual Dopamine Neurons to Apomorphine." Synapse 9:144–155, 1991. Copyright 1991, Wiley. Used with permission. (C) Adapted from Grace AA, Bunney BS: "The Control of Firing Pattern in Nigral Dopamine Neurons: Single Spike Firing." Journal of Neuroscience 4:2866–2876, 1984a. Copyright 1984, Society for Neuroscience. Used with permission.

FIGURE 5–3. Relationship between action potentials recorded intracellularly and those recorded extracellularly from dopamine-containing neurons.(A) During intracellular recordings, an action potential is initiated from a negative resting membrane potential (e.g., ~55 mV), reaches a peak membrane potential (solid arrow), and is followed by a repolarization of the membrane and usually an afterhyperpolarization. An inflection in the rising phase of the spike (open arrow) is often observed. This reflects the delay between the initial segment spike that initiates the action potential (occurring prior to the open arrow) and the somatodendritic action potential that it triggers (occurring after the open arrow). (B) A computer was used to differentiate the membrane voltage deflection occurring in the action potential in (A) with respect to time, resulting in a pattern that shows the rate of change of membrane voltage. Note that the inflection is exaggerated (open arrow), and the peak of the action potential crosses zero (solid arrow), because at the peak of a spike, the rate of change reaches zero before reversing to a negative direction. (C) A trace showing a typical action potential in a dopamine neuron recorded extracellularly. The extracellular action potential resembles the differentiated intracellular action potential in (B). This is because the extracellular electrode is actually measuring the current crossing the membrane during the action potential and is therefore, by definition, equivalent to the absolute value of the first derivative of the voltage trace in (A). The amplitude of the extracellular spike is indicated in volts, because the parameter measured is actually the voltage drop produced across the electrode tip by the current flux and is therefore much smaller than the actual membrane voltage change that occurs in (A).Source. Adapted from Grace AA, Bunney BS: "Intracellular and Extracellular Electrophysiology of Nigral Dopaminergic Neurons, I: Identification and Characterization." Neuroscience 10:301–315, 1983. Copyright 1983, International Brain Research Organization. Used with permission.

FIGURE 5–4. Effects of intracellular manipulations of cGMP levels on basal activity of striatal medium spiny neurons.Intracellular application of selective pharmacological agents enables the investigator to examine the direct effects of these agents on the membrane activity of single neurons as well as to manipulate intracellular second-messenger systems. This figure demonstrates that manipulation of intracellular cyclic guanosine monophosphate (cGMP) levels potently and specifically modulates the membrane activity of striatal medium spiny neurons in a manner that cannot be achieved by extracellular application of drugs. Striatal neurons were recorded after intracellular application (~5 minutes) of either A) vehicle (control), a 0.5% solution of dimethylsulfoxide (DMSO); B) the drug 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ), which blocks cGMP synthesis by inhibiting the synthetic enzyme guanylyl cyclase; C) ODQ plus cGMP; or D) the drug zaprinast, which inhibits phosphodiesterase enzymes responsible for degrading cGMP. (A) Left: After vehicle injection, striatal neurons exhibited typical rapid spontaneous shifts in steady-state membrane potential and irregular spontaneous spike discharge. Right: Time interval plots of membrane potential activity recorded from control neurons demonstrated bimodal membrane potential distributions indicative of bistable membrane activity. (B) Left: Striatal neurons recorded after ODQ injection exhibited significantly lower-amplitude depolarizing events compared with vehicle-injected controls and rarely fired action potentials. Right: The depolarized portion of the membrane potential distribution of neurons recorded after ODQ injection was typically shifted leftward (i.e., hyperpolarized) compared with controls. (C) Left: Striatal neurons recorded after ODQ and cGMP coinjection rarely fired action potentials but exhibited high-amplitude depolarizing events with extraordinarily long durations. Right: The membrane potential distribution of neurons recorded after ODQ and cGMP coinjection was similar to that of controls, indicating that cGMP partially reversed some of the effects of ODQ. (D) Left: Striatal neurons recorded after intracellular injection of zaprinast exhibited high-amplitude depolarizing events with extraordinarily long durations. Additionally, all of the cells fired action potentials at relatively high rates (0.4–2.2 Hz). Right: The membrane potential distribution of these neurons was typically shifted rightward (i.e., depolarized) compared with controls. Because zaprinast blocks the degradation of endogenous cGMP, we can conclude that basal levels of cGMP depolarize the membrane potential of striatal neurons and facilitate spontaneous postsynaptic potentials. Arrows indicate the membrane potential at its maximal depolarized and hyperpolarized levels.Source. Adapted from West AR, Grace AA: "The Nitric Oxide–Guanylyl Cyclase Signaling Pathway Modulates Membrane Activity States and Electrophysiological Properties of Striatal Medium Spiny Neurons Recorded In Vivo." Journal of Neuroscience 24:1924–1935, 2004. Copyright 2004, Society for Neuroscience. Used with permission.

FIGURE 5–5. Intracellular staining of neuron recorded intracellularly.During intracellular recordings, the recording pipette is filled with an electrolyte to enable the transmission of membrane voltage deflections to the preamplifier. The electrode may also be filled with substances, such as a morphological stain, for injection into the impaled neuron. In this example, the electrode was filled with the highly fluorescent dye Lucifer yellow. Because this dye has a negative charge at neutral pH, it may be ejected from the electrode by applying a negative current across the electrode, with the result that the Lucifer yellow carries the negative current flow from the electrode and into the neuron. Because this dye diffuses rapidly in water, it quickly fills the entire neuron impaled. The tissue is then fixed in a formaldehyde compound, the lipids clarified by dehydration-defatting or by using dimethylsulfoxide (Grace and Llinás 1985), and the tissue examined under a fluorescence microscope. In this case, a brightly fluorescing pyramidal neuron in layer 3 of the neocortex of a guinea pig is recovered.

FIGURE 5–6. Patch clamp electrophysiology and calcium imaging.By combining patch clamping with injection of selective dyes, the dynamics of calcium can be imaged in real time within isolated neurons. (A) Using infrared differential interference contrast (IR-DIC) microscopy, the image of a patch pipette can be observed attached to a neuron during a whole-cell electrophysiology experiment. Note the relatively large size of the pipette tip (coming from the left side of the image). Calibration bar = 2 m. (B) After filling the neuron with a calcium-sensitive dye, bis-Fura 2, the live neuron can be imaged with a fluorescence microscope. The dye takes about 10 minutes to fill the neuron after rupturing the patch membrane. Calibration bar = 10 m. (C) A unique property of the dye bis-Fura 2 is that it changes its fluorescence properties as it binds calcium. This can be observed by the changes in the fluorescence signal in response to a single (top) or five (bottom) action potentials. The fluorescence traces correspond to two regions, one close to the cell body (red box and red trace) and one farther out in the apical dendrite (orange box, orange trace). In this way, one can observe changes in calcium dynamics and how they correspond to activity states within single neurons.

FIGURE 5–7. Determining the effects of systemic and direct drug administration on neuronal activity.There are several means of applying drugs to a neuron to examine their actions. During in vivo recording, drugs may be administered systemically (i.e., intravenously, intraperitoneally, subcutaneously, intraventricularly, intramuscularly) or directly to the neuron by microiontophoresis or pressure ejection. (A) Systemic administration of a drug is useful for determining how a drug affects neurons in the intact organism, regardless of whether the action is direct or indirect. In this case, intravenous administration of the -aminobutyric acid (GABA) agonist muscimol (solid arrows) causes a dose-dependent increase in the firing rate of this dopamine-containing neuron. (B) In contrast, direct administration of a drug to a neuron will provide information about the site of action of the drug, at least as it concerns the discharge of the neuron under study. In this case, GABA is administered directly to a dopamine neuron by microiontophoresis. In this technique, several drug-containing pipettes are attached to the recording electrode. The pH of the drug solutions is adjusted to ensure that the drug molecules are in a charged state (e.g., GABA is used at pH = 4.0 to give it a positive charge), and the drug is ejected from the pipette tip by applying very small currents to the drug-containing pipette. Because the total diameter of the microiontophoretic pipette tip is only about 5 m, the drugs ejected typically affect only the cell being recorded. In this case, GABA is applied to a dopamine neuron by microiontophoresis; the horizontal bars show the time during which the current is applied to the drug-containing pipette, and the amplitude of the current (indicated in nA) is listed above each bar. Note that, unlike the excitatory effects produced by a systemically administered GABA agonist in (A), direct application of GABA will inhibit dopamine neurons. This has been shown to be caused by inhibition of a much more GABA-sensitive inhibitory interneuron by the systemically administered drug and illustrates the need to compare systemic drug administration with direct drug administration to ascertain the site of action of the drug of interest.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.

FIGURE 5–8. Use of a microdialysis probe for delivering drugs locally during in vivo recordings to affect local circuits.(A) In this schematic diagram, the relationship between the microdialysis probe and the intracellular recording electrode is depicted. In this case, the neuron recorded is in the striatum. The active surface of the microdialysis probe is shown in gray; this is the area through which the compound is delivered. The probe is implanted very slowly so as not to disrupt the tissue (i.e., 3–6 m per second) and is perfused with artificial cerebrospinal fluid for 2–4 hours to allow equilibration and settling of the tissue prior to recording. The intracellular recording electrode is then advanced, and a neuron is impaled. After recording baseline activity for 10 minutes, the perfusate is changed to a drug-containing solution to examine the effects on the neuron. (B) The histology taken after the recording shows the track of the microdialysis probe; the termination site of the probe tip is indicated by a dashed arrow. To confirm that the neuron recorded was near the probe, the neuron is filled with a stain (in this case, biocytin) so as to allow visualization of the neuron. In this case, the neuron was confirmed to be a medium spiny striatal neuron (magnified in insert). ac = anterior commissure. (C) Recordings taken from the neuron labeled in B. The top trace shows the activity of the neuron while the microdialysis probe is being perfused with artificial cerebrospinal fluid. The neuron demonstrates a healthy resting membrane potential, and spontaneously occurring postsynaptic potentials are evident. The lower trace shows the same neuron 15 minutes after switching to a perfusate containing the dopamine D2 antagonist eticlopride. The neuron shows a strong depolarization of the resting potential (by 12 mV) as well as increased postsynaptic potential activity and spontaneous spike firing. Since the eticlopride is blocking the effects of dopamine that is being released spontaneously from dopamine terminals in this region, we can conclude that basal levels of dopamine D2 receptor stimulation cause a tonic hyperpolarization of the neuronal membrane and suppress spontaneous excitatory postsynaptic potentials.Source. Adapted from West AR, Grace AA "Opposite Influences of Endogenous Dopamine D1 and D2 Receptor Activation on Activity States and Electrophysiological Properties of Striatal Neurons: Studies Combining In Vivo Intracellular Recordings and Reverse Microdialysis." Journal of Neuroscience 22:294–304, 2002. Copyright 2002, Society for Neuroscience. Used with permission.

FIGURE 5–9. Variation (sometimes substantial) in patterns of activity of a neuron type, depending on the preparation in which it is recorded.(A) Extracellular recordings of a dopamine neuron in an intact anesthetized rat (i.e., in vivo) illustrate the typical irregular firing pattern of the cell, with single spikes occurring intermixed with bursts of action potentials. (B) In contrast, intracellular recordings of a dopamine neuron in an isolated brain slice preparation (i.e., in vitro) illustrate the pacemaker pattern that occurs exclusively in identified dopamine neurons in this preparation. For dopamine neurons, a pacemaker firing pattern is rarely observed in vivo, and burst firing has never been observed in the in vitro preparation. However, although the activity recorded in vitro is obviously an abstraction compared with the firing pattern of this neuron in vivo, a comparative study in each preparation does provide the opportunity to examine factors that may underlie the modulation of firing pattern in this neuronal type.Source. Adapted from Grace AA: "The Regulation of Dopamine Neuron Activity as Determined by In Vivo and In Vitro Intracellular Recordings," in The Neurophysiology of Dopamine Systems. Edited by Chiodo LA, Freeman AS. Detroit, MI, Lake Shore Publications, 1987, pp. 1–67 (Copyright 1987, Lake Shore Publications. Used with permission); and Grace AA, Bunney BS: "Intracellular and Extracellular Electrophysiology of Nigral Dopaminergic Neurons, I: Identification and Characterization." Neuroscience 10:301–315, 1983. Copyright 1983, International Brain Research Organization. Used with permission.

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The opening of which of the following ion channels is the mechanism through which -aminobutyric acid (GABA) decreases neuronal activity?
2.
Which of the following electrophysiological techniques is directed at assessing the response of individual ionic channels in the membrane of a neuron?
3.
A useful technique in psychopharmacological research is the in vivo preparation, wherein a drug that elicits a characteristic behavioral response can be administered to examine how that drug affects neurons that are likely to participate in the behavioral response. Although in vivo electrophysiological recordings provide the most direct link between neurophysiology and behavior, this technique has which of the following limitations?
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