Kv1.2-Containing K⁺Channels Regulate Subthreshold Excitability of Striatal Medium Spiny Neurons

Abstract

. Kv1.2-containing K ϩ channels regulate subthreshold excitability of striatal medium spiny neurons. J Neurophysiol 91: [1337][1338][1339][1340][1341][1342][1343][1344][1345][1346][1347][1348][1349] 2004. First published September 17, 2003; 10.1152/jn.00414.2003. A slowly inactivating, lowthreshold K ϩ current has been implicated in the regulation of state transitions and repetitive activity in striatal medium spiny neurons. However, the molecular identity of the channels underlying this current and their biophysical properties remain to be clearly determined. Because previous work had suggested this current arose from Kv1 family channels, high-affinity toxins for this family were tested for their ability to block whole cell K ϩ currents activated by depolarization of acutely isolated neurons. ␣-Dendrotoxin, which blocks channels containing Kv1.1, Kv1.2, or Kv1.6 subunits, decreased currents evoked by depolarization. Three other Kv1 family toxins that lack a high affinity for Kv1.2 subunits, r-agitoxin-2, dendrotoxin-K, and r-margatoxin, failed to significantly reduce currents, implicating channels with Kv1.2 subunits. RT-PCR results confirmed the expression of Kv1.2 mRNA in identified medium spiny neurons. Currents attributable to Kv1.2 channels activated rapidly, inactivated slowly, and recovered from inactivation slowly. In the subthreshold range (ca. Ϫ60 mV), these currents accounted for as much as 50% of the depolarization-activated K ϩ current. Moreover, their rapid activation and relatively slow deactivation suggested that they contribute to spike afterpotentials regulating repetitive discharge. This inference was confirmed in current-clamp recordings from medium spiny neurons in the slice preparation where Kv1.2 blockade reduced first-spike latency and increased discharge frequency evoked from hyperpolarized membrane potentials resembling the "down-state" found in vivo. These studies establish a clear functional role for somato-dendritic Kv1.2 channels in the regulation of state transitions and repetitive discharge in striatal medium spiny neurons.

Developmentally coordinated extrinsic signals drive human pluripotent stem cell differentiation toward authentic DARPP-32+ medium-sized spiny neurons

“…Among the neurons able to sustain repetitive firing, 85% (11 out of 13) yielded a slow depolarization and a delay in generating the initial spike (Fig. 5F, inset), just as described for rat MSNs (Nisenbaum et al, 1996;Shen et al, 2004;Surmeier et al, 1989;Surmeier et al, 1991). This behavior suggests that, in those cells that show a delayed onset in generating the first spike, a fast inactivating K + current should also be elicited that has properties that resemble those of the I A current involved in firing frequency regulation and first spike latency (Ericsson et al, 2011;Jiang and North, 1991), a hallmark of MSNs.…”

Cholinergic Suppression of KCNQ Channel Currents Enhances Excitability of Striatal Medium Spiny Neurons

“…Recordings were made only from neurons having (1) a relatively hyperpolarized resting potential (Ϫ88.4 Ϯ 1.1 mV; n ϭ 27); (2) strong inward rectification; and (3) a slow voltage ramp to near rheobase current injection. They were classified as medium spiny neurons (Kerr and Plenz, 2002;Shen et al, 2004;Wilson, 2004).…”

“…All experiments were conducted in accord with the guidelines approved by the Northwestern University Animal Care and Use Committee. Standard techniques were used for the preparation of slices for recording (Shen et al, 2004). Briefly, Sprague Dawley rats of either sex, 16 -23 d of age, and M 1 muscarinic receptor knock-out mice (Hamilton et al, 1997) were anesthetized deeply with ketamine-xylazine and perfused transcardially with 5-10 ml of ice-cold artificial CSF (ACSF) comprising the following (in mM): 125 NaCl, 2.5 KCl, 1.25 NaH 2 PO 4 , 2.0 CaCl 2 , 1.0 MgCl 2 , 25 NaHCO 3 , and 14 glucose, bubbled continuously with carbogen (95% O 2 and 5% CO 2 ).…”

“…Kv4 channels activate in this voltage range, but they inactivate rapidly, making them poor regulators of sustained depolarizing inputs (Tkatch et al, 2000). Kv1.2 channels are also active in this range (Nisenbaum et al, 1994;Shen et al, 2004). However, these channels inactivate as well, albeit more slowly than Kv4 channels.…”

Distinct modulation of Kv1.2 channel gating by wild type, but not open form, of syntaxin-1A

“…Notably, an increase in the outward currents after the cleavage of endogenous SNAP-25 by botulinum neurotoxin A indicates that SNAP-25 inhibition of ESM K ϩ channels is physiological (15). K v 1.2 is an important delayed rectifier K ϩ channel in a number of nonsecretory cells, including vascular (1) and ESM cells (35) and cardiac myocytes (4) and is also present in certain neuronal tissues as well (34). K v 1.2 displays gating properties distinct from those of K v 2.1, including a hyperpolarized shift in V 1/2 (voltage for half-activation) and more rapid activation kinetics (33).…”