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Apamin-Sensitive Small Conductance Calcium-Activated Potassium

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Apamin-Sensitive Small Conductance Calcium-Activated Potassium The Journal of Neuroscience, August 20, 2003 • 23(20):7525–7542 • 7525 Cellular/Molecular Apamin-Sensitive Small Conductance Calcium-Activated Potassium Channels, through their Selective Coupling to Voltage-Gated Calcium Channels, Are Critical Determinants of the Precision, Pace, and Pattern of Action Potential Generation in Rat Subthalamic Nucleus Neurons In Vitro Nicholas E. Hallworth,1 Charles J. Wilson,2 and Mark D. Bevan3 1University of Tennessee, Anatomy and Neurobiology, Memphis, Tennessee 38163, 2Division of Life Science, University of Texas, San Antonio, Texas 78294, and 3Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611-3008 Distinct activity patterns in subthalamic nucleus (STN) neurons are observed during normal voluntary movement and abnormal move- ment in Parkinson’s disease (PD). To determine how such patterns of activity are regulated by small conductance (SK) calcium-activated potassium channels (KCa ) and voltage-gated calcium (Cav ) channels, STN neurons were recorded in the perforated patch configuration in slices, [which were prepared from postnatal day 16 (P16)–P30 rats and held at 37°C] and then treated with the SK KCa channel ␻ antagonist apamin or the SK KCa agonist 1-ethyl-2-benzimidazolinone or the Cav channel antagonists -conotoxin GVIA (Cav2.2- selective) or nifedipine (Cav1.2–1.3-selective). In other experiments, fura-2 was introduced as an indicator of intracellular calcium dynamics. A component of the current underlying single-spike afterhyperpolarization was sensitive to apamin, phase-locked to calcium entry via Cav2.2 channels, and necessary for precise, autonomous, single-spike oscillation. SK KCa /Cav2.2 channel coupling did not underlie spike-frequency adaptation but limited activity in response to current injection by encoding the accumulation of intracellular calcium, maintainedthecharacteristicsigmoidalfrequency–intensityrelationshipandgeneratedapost-trainafterhyperpolarization.Inaddition, Ͻ SK KCa channels terminated rebound burst activity more effectively in neurons with short-duration bursts ( 100 msec) than neurons Ͼ with long-duration bursts ( 100 msec), presumably through their activation by Cav3 channels. Cav1.2–1.3 channels were not strongly coupled to SK KCa channels and therefore supported secondary range and long-duration rebound burst firing. In summary, SK KCa channels play a fundamental role in autonomous, driven, and rebound activity and oppose the transition from autonomous, rhythmic, single-spike activity to burst firing in STN neurons. Key words: basal ganglia; oscillation; afterhyperpolarization; rebound burst; apamin; EBIO Introduction sumara et al., 1992; Fujimoto and Kita, 1993; Wichmann et al., The glutamatergic subthalamic nucleus (STN) is a key compo- 1994; Mouroux et al., 1995). In Parkinson’s disease (PD), abnor- nent of the basal ganglia, a collection of subcortical brain nuclei mal, rhythmic, bursting activity of the STN plays a key role in the involved in motor, sensory, associative, and limbic functions (for expression of symptoms (Bergman et al., 1994; Levy et al., 2000, review, see Wise et al., 1996). Under resting conditions, the tonic 2002). Indeed, therapies like high-frequency electrical stimula- activity of the STN drives, in part, the tonic activity of its target tion of the STN have been successful in ameliorating the symp- nuclei. During movement, sporadic high-frequency activity of toms of PD (for review, see Benabid et al., 2001). the STN plays a pivotal role in the response of the basal ganglia to In recent years, several groups have defined intrinsic mem- cortical and thalamic activation (Kitai and Deniau, 1981; Mat- brane properties of STN neurons in vitro that are likely to con- tribute to their pattern of activity and integration of synaptic input in vivo (Nakanishi et al., 1987; Beurrier et al., 1999, 2000; Received Jan. 16, 2003; revised June 24, 2003; accepted June 30, 2003. Bevan and Wilson, 1999; Song et al., 2000; Wigmore and Lacey, This work was supported by National Institute of Neurological Disorders and Stroke Grants NS41280 (M.D.B.), NS20702(M.D.B.),NS047085(M.D.B.andC.J.W.),andNS26473(C.J.W.).NicholasHallworthisinreceiptofaCenter 2000; Otsuka et al., 2001; Bevan et al., 2002; Zhu et al., 2002; for Neuroscience Predoctoral Fellowship at the University of Tennessee. We thank Drs. William Armstrong, Jay Baufreton et al., 2003; Do and Bean, 2003). These properties Callaway, and Robert Foehring for helpful discussions throughout this study. include: (1) autonomous, rhythmic single-spike activity, (2) the Correspondence should be addressed to Dr. Mark D. Bevan, Department of Physiology-M211, Feinberg School of Med- icine, Northwestern University, 303 East Chicago Avenue, Chicago, IL 60611-3008. E-mail: [email protected]. ability to fire at high frequencies (100–500 Hz), (3) a primary Copyright © 2003 Society for Neuroscience 0270-6474/03/237525-18$15.00/0 range of activity (Ͻ40 Hz) that is approximately half as sensitive • 7526 • J. Neurosci., August 20, 2003 • 23(20):7525–7542 Hallworth et al. Coupling of SK KCa and Cav Channels in the Subthalamus to input as a secondary range of activity (Ͼ40 Hz), and (4) het- operated using Pulse 8.5 software (Heka). Signals were low-pass filtered erogeneous rebound burst activity. Further analyses of the ion at a frequency (1.7–33.3 kHz) that was one-third the frequency of digiti- channels underlying these properties will be critical for our un- zation (5–100 kHz). Junction potentials were not corrected in the perfo- derstanding of the function and dysfunction of the STN and for rated configuration because, in contrast to the whole-cell configuration, the development and refinement of treatments for PD that are the composition of ions in the recorded neuron cannot be assumed to be the same as electrode solution (Marty and Neher, 1983; Neher, 1992; based on the modulation of STN activity. Bevan et al., 2000, 2002). Deliberate or accidental establishment of the In recent whole-cell patch clamp recording studies of STN whole-cell configuration was recognized as a sudden drop in series resis- neurons, calcium entry via voltage-gated calcium (Cav) channels tance, an increase in the amplitude of recorded action potentials, and an predominantly activated small conductance (SK) calcium- ϳ6 mV offset in membrane potential. The latter was measured as an activated potassium channels (KCa) channels, which played a piv- increase in the threshold for the generation of action potentials that otal, largely suppressive role in shaping activity or activated non- accompanied break-in. The value of the offset was similar to the empir- specific cation channels, which augmented activity (Bevan and ically calculated junction potential between the electrode solution and Wilson, 1999; Beurrier et al., 1999, 2000; Otsuka et al., 2001). the external media of 8.7 mV (Neher, 1992; Barry, 1994; Bevan et al., 2000, 2002). The voltages reported in this paper are therefore likely to be Because the whole-cell configuration of the patch-clamp tech- Ͻ nique can introduce alien calcium buffers and anions that disrupt 3 mV more depolarized than the actual voltages. While fast capacitive transients of the pipette were nulled on-line, intracellular calcium dynamics (Neher and Augustine, 1992; there was no compensation of series resistance or whole-cell capacitance, Zhang et al., 1995; Helmchen and Tank, 1999; Velumian and thus voltage errors attributable to series resistance were subtracted off- Carlen, 1999) and block intrinsic ion channels (Zhang et al., line as described previously (Bevan et al., 2000). 1994; Velumian et al., 1997), we applied the perforated patch- Drugs. Drugs were diluted in ACSF and bath-applied. Fast synaptic trans- clamp technique, with gramicidin as the pore-forming substance mission was blocked by the continuous application of 50 ␮MD-(Ϫ)-2- (Myers and Haydon, 1972; Abe et al., 1994; Kyrozis and Reich- amino-5-phosphonopentanoic acid (APV), 20 ␮M 6,7-dinitroquinoxaline- ling, 1995) to study in a more definitive manner the role of 2,3-dione (DNQX), and 20 ␮M SR 95531 hydrobromide (GABAzine) so that the action of SK and Ca channel drugs on intrinsic properties could be apamin-sensitive SK KCa channels and their coupling to Cav v channels in STN neurons. In other cases, we deliberately intro- studied in isolation from effects on synaptic transmission. Synaptic trans- duced the calcium indicator fura-2 to track the dynamic changes mission receptor blockers, 1-ethyl-2-benzimidazolinone (EBIO) and nifed- ipine were obtained from Tocris (Ellisville, MO). Apamin (1 pM-100 nM) and in intracellular calcium (Grynkiewicz et al., 1985; Lev-Ram et al., ␻-conotoxin GVIA (1 ␮M) were obtained from Sigma (St. Louis, MO). 1992) that are presumably related to the activation of SK KCa Data analysis. Data were analyzed using Pulsefit (Heka) and Origin 5.0 channels. (Microcal, Northampton, MA). Descriptive statistics refer to the mean Ϯ SEM. Frequency distributions of the experimental data were compared Materials and Methods with normal distributions of similar means and SDs, which were con- Electrophysiology structed using random numbers generated by Statview 5.0 (SAS, Cary, Slice preparation. Electrophysiological studies were performed on brain NC), using the Kolmogorov–Smirnov (K–S) test. Although datasets were slices prepared from 43 16- to 30-d-old Sprague Dawley rats. Animals typically not significantly different from a normal distribution, our sam- were deeply
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