Control of Spontaneous Firing Patterns by the Selective Coupling of Calcium Currents to Calcium-Activated Potassium Currents in Striatal Cholinergic Interneurons

Abstract

The spontaneous firing patterns of striatal cholinergic interneurons are sculpted by potassium currents that give rise to prominent afterhyperpolarizations (AHPs). Large-conductance calcium-activated potassium (BK) channel currents contribute to action potential (AP) repolarization; small-conductance calcium-activated potassium channel currents generate an apamin-sensitive medium AHP (mAHP) after each AP; and bursts of APs generate long-lasting slow AHPs (sAHPs) attributable to apamin-insensitive currents. Because all these currents are calcium dependent, we conducted voltage-and current-clamp whole-cell recordings while pharmacologically manipulating calcium channels of the plasma membrane and intracellular stores to determine what sources of calcium activate the currents underlying AP repolarization and the AHPs. The Ca v 2.2 (N-type) blocker -conotoxin GVIA (1 M) was the only blocker that significantly reduced the mAHP, and it induced a transition to rhythmic bursting in one-third of the cells tested. Ca v 1 (L-type) blockers (10 M dihydropyridines) were the only ones that significantly reduced the sAHP. When applied to cells induced to burst with apamin, dihydropyridines reduced the sAHPs and abolished bursting. Depletion of intracellular stores with 10 mM caffeine also significantly reduced the sAHP current and reversibly regularized firing. Application of 1 M -conotoxin MVIIC (a Ca v 2.1/2.2 blocker) broadened APs but had a negligible effect on APs in cells in which BK channels were already blocked by submillimolar tetraethylammonium chloride, indicating that Ca v 2.1 (Q-type) channels provide the calcium to activate BK channels that repolarize the AP. Thus, calcium currents are selectively coupled to the calcium-dependent potassium currents underlying the AHPs, thereby creating mechanisms for control of the spontaneous firing patterns of these neurons.

Presynaptic Ca2+/Calmodulin-Dependent Protein Kinase II Modulates Neurotransmitter Release by Activating BK Channels atCaenorhabditis elegansNeuromuscular Junction

“…The differential effects of unc-43(gf) on ePSCs and mPSCs could be explained by different activities of SLO-1 at rest and during evoked responses. A number of studies have shown that the activity of BK channels is tightly controlled by colocalized voltage-gated Ca 2ϩ channels (Yazejian et al, 1997;Marrion and Tavalin, 1998;Davies et al, 1999;Yazejian et al, 2000;Edgerton and Reinhart, 2003;Sun et al, 2003;Goldberg and Wilson, 2005;Berkefeld et al, 2006). In the absence of Ca 2ϩ nanodomains created by Ca 2ϩ influx through Ca 2ϩ channels, BK channels are minimally activated despite significant membrane depolarization (Berkefeld et al, 2006).…”

Involvement ofIhin Dopamine Modulation of Tonic Firing in Striatal Cholinergic Interneurons

“…In our experiments, activation of D 2 receptor had no effect on sAHP amplitude. The most compelling explanation is that the calcium channels coupled to I sAHP are insensitive to D 2 receptor activation (Yan et al, 1997;Goldberg and Wilson, 2005). It is plausible that, although dopamine-induced potentiation of excitatory inputs triggers the occurrence of sAHP and, thus, the generation of pause in tonic firing in single-spiking neurons, inhibition of I h influences the time course of pause response.…”

“…Recordings of cholinergic interneurons in vivo (Wilson et al, 1990;Reynolds et al, 2004) and in vitro (Jiang and North, 1991;Bennett and Wilson, 1999;Goldberg and Wilson, 2005;Wilson, 2005) have revealed that these cells correspond to the tonically active neurons (TANs) in the striatum. The TANs exhibit pauses in tonic firing in response to salient stimuli during associative learning (Aosaki et al, 1994a,b;Apicella, 2002;Morris et al, 2004), which are dependent on dopaminergic inputs from the substantia nigra (Aosaki et al, 1994a;Watanabe and Kimura, 1998).…”

5-Azacytidine induces changes in electrophysiological properties of human mesenchymal stem cells

“…We determined that cell proliferation, measured as number of viable cells after a given period of time, is decreased by TEA at submillimolar concentration (a drug concentration that blocks MaxiK, Kv1.1, Kv3 and Kv7.2 channels [49,50]) and by micromolar concentration of clofilium (concentration effective to block HERG channels [51]). Significantly, we have previously shown that similar concentrations of TEA and clofilium inhibited I r and I s , respectively [18].…”