SK channels control the firing pattern of midbrain dopaminergic neurons in vivo

Abstract

A vast body of experimental in vitro work and modelling studies suggests that the firing pattern and/or rate of a majority of midbrain dopaminergic neurons may be controlled in part by Ca2+-activated K+ channels of the SK type. However, due to the lack of suitable tools, in vivo evidence is lacking. We have taken advantage of the development of the water-soluble, medium potency SK blocker N-methyl-laudanosine (CH3-L) to test this hypothesis in anaesthetized rats. In the lateral ventral tegmental area, CH3-L iontophoresis onto dopaminergic neurons significantly increased the coefficient of variation of their interspike intervals and the percentage of spikes generated in bursts as compared to the control condition. The effect of CH3-L persisted in the presence of a specific GABA(A) antagonist, suggesting a direct effect. It was robust and reversible, and was also observed in the substantia nigra. Control experiments demonstrated that the effect of CH3-L could be entirely ascribed to its blockade of SK channels. On the other hand, the firing pattern of noradrenergic neurons was much less affected by CH3-L. We provide here the first demonstration of a major role of SK channels in the control of the switch between tonic and burst firing of dopaminergic neurons in physiological conditions. This study also suggests a new strategy to develop modulators of the dopaminergic (DA) system, which could be of interest in the treatment of Parkinson's disease, and perhaps other diseases in which DA pathways are dysfunctional.

Physiologie, pharmacologie et modélisation de canaux potassiques

“…La structure de ces dérivés bis-isoquinolinium ( Figure 5) s'adapte bien au pharmacophore identifié en 2005 qui avait révélé, entre autres, une distance optimale de 5,6 Å entre deux charges positives azotées [44]. Plus récemment, un composé d'une autre classe également accroître l'excitabilité des neurones dopaminergiques de la substance noire, ce qui pourrait être utile dans le traitement de certaines maladies liées à un dysfonctionnement de ces systèmes [1,24]. Des études plus récentes ont également présenté les canaux SK comme cibles potentielles dans d'autres pathologies sévères telles que le cancer du sein [4], la fibrillation auriculaire [25] ou encore les désordres cognitifs liés à la schizophrénie [26].…”

“…Cette étude a révélé que le DTG bloquait directement les courants potassiques de type SK2 et SK3 avec une puissance faible, les valeurs d'IC 50 étant proches de 200 μM [46]. Finalement, la NML a été également utilisée comme outil pharmacologique dans le but d'évaluer les effets du blocage des canaux SK sur l'activité électrique des neurones monoaminergiques [23,24].…”

Pallidal control of substantia nigra dopaminergic neuron firing pattern and its relation to extracellular neostriatal dopamine levels

“…It must be noted that bicuculline methiodide (and other quarternary salts, but not picrotoxin or bicuculline free base) are potent antagonists of the calcium-activated potassium channels (Johnson and Seutin, 1997;Seutin and Johnson, 1999) that underlie the long lasting spike after-hyperpolarization in dopaminergic and other neurons. Blocking this conductance also leads to increases in burst firing (Waroux et al, 2005;Ji and Shepard, 2006). Thus, the picrotoxin results are crucial for demonstrating the burst promoting effects of GABA A blockade on dopaminergic neuron firing pattern (Fig.…”

“…The production of the different firing patterns, especially burst firing, in dopaminergic neurons is currently the subject of considerable study, and there is likely to be more than a single mechanism responsible (e.g., Zhang et al, 1994;Overton and Clark, 1997;Kitai et al, 1999;Waroux et al, 2005;Ji and Shepard, 2006). As the different patterns are essentially absent in vitro Grace and Onn, 1989; but see Mereu et al, 1997) afferent input is considered to be a crucial modulator of firing pattern.…”

Modulation of the activity of dopaminergic neurons by SK channels: a potential target for the treatment of Parkinson’s disease?

“…Interestingly, SK channels exert contradictory effects in the regulation of dopamine release and in the alteration of dopamine phenotype [28] . Firstly, SK modulation results in alterations of dopamine release [29] . Blockade of SK channels in vivo induces a shift of substantia nigra cells from tonic to burst firing, which dramatically increases the amount of dopamine release from synaptic terminals of substantia nigra neurons.…”